ID AT132_HUMAN Reviewed; 1180 AA. AC Q9NQ11; O75700; Q5JXY1; Q5JXY2; Q6S9Z9; DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 2. DT 28-JAN-2026, entry version 210. DE RecName: Full=Polyamine-transporting ATPase 13A2 {ECO:0000305|PubMed:31996848}; DE EC=7.6.2.- {ECO:0000269|PubMed:31996848}; GN Name=ATP13A2 {ECO:0000312|HGNC:HGNC:30213}; GN Synonyms=PARK9 {ECO:0000303|PubMed:21542062}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RA Rhodes S., Huckle E.; RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RA Liu J.-P., Li H.; RT "Homo sapiens putative ATPase (N-ATPase) mRNA."; RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). RC TISSUE=Brain, and Fetus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 705-1180 (ISOFORM A). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 855-1180 (ISOFORM B). RA Casciano I., Volpi E.V., De Ambrosis A., Marchi J.M., Romani M.; RT "YAC analysis and genes identification at a site of viral integration in RT the 1p36.1-36.2 chromosomal site."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [9] RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=22186024; DOI=10.1093/hmg/ddr606; RA Ramonet D., Podhajska A., Stafa K., Sonnay S., Trancikova A., Tsika E., RA Pletnikova O., Troncoso J.C., Glauser L., Moore D.J.; RT "PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and RT regulates cation homeostasis and neuronal integrity."; RL Hum. Mol. Genet. 21:1725-1743(2012). RN [10] RP INVOLVEMENT IN KRS. RX PubMed=16964263; DOI=10.1038/ng1884; RA Ramirez A., Heimbach A., Gruendemann J., Stiller B., Hampshire D., RA Cid L.P., Goebel I., Mubaidin A.F., Wriekat A.-L., Roeper J., Al-Din A., RA Hillmer A.M., Karsak M., Liss B., Woods C.G., Behrens M.I., Kubisch C.; RT "Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, RT encoding a lysosomal type 5 P-type ATPase."; RL Nat. Genet. 38:1184-1191(2006). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-151, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24603074; DOI=10.1093/hmg/ddu099; RA Kong S.M., Chan B.K., Park J.S., Hill K.J., Aitken J.B., Cottle L., RA Farghaian H., Cole A.R., Lay P.A., Sue C.M., Cooper A.A.; RT "Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis RT and promotes alpha-Synuclein externalization via exosomes."; RL Hum. Mol. Genet. 23:2816-2833(2014). RN [13] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25392495; DOI=10.1523/jneurosci.1629-14.2014; RA Tsunemi T., Hamada K., Krainc D.; RT "ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein."; RL J. Neurosci. 34:15281-15287(2014). RN [14] RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, TOPOLOGY, RP AUTOPHOSPHORYLATION, ACTIVE SITE, GLYCOSYLATION AT ASN-1033, AND RP MUTAGENESIS OF GLY-59; 66-ARG--LYS-68; 74-ARG--ARG-78; 160-LYS--ARG-164 AND RP ASN-1033. RX PubMed=26134396; DOI=10.1073/pnas.1508220112; RA Holemans T., Soerensen D.M., van Veen S., Martin S., Hermans D., RA Kemmer G.C., Van den Haute C., Baekelandt V., Guenther Pomorski T., RA Agostinis P., Wuytack F., Palmgren M., Eggermont J., Vangheluwe P.; RT "A lipid switch unlocks Parkinson's disease-associated ATP13A2."; RL Proc. Natl. Acad. Sci. U.S.A. 112:9040-9045(2015). RN [15] RP FUNCTION. RX PubMed=31132336; DOI=10.1016/j.bbamem.2019.05.015; RA Marcos A.L., Corradi G.R., Mazzitelli L.R., Casali C.I., RA Fernandez Tome M.D.C., Adamo H.P., de Tezanos Pinto F.; RT "The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid RT homeostasis."; RL Biochim. Biophys. Acta 1861:182993-182993(2019). RN [16] RP FUNCTION, INTERACTION WITH HDAC6, AND CHARACTERIZATION OF VARIANTS KRS RP LEU-182 AND ARG-504. RX PubMed=30538141; DOI=10.1083/jcb.201804165; RA Wang R., Tan J., Chen T., Han H., Tian R., Tan Y., Wu Y., Cui J., Chen F., RA Li J., Lv L., Guan X., Shang S., Lu J., Zhang Z.; RT "ATP13A2 facilitates HDAC6 recruitment to lysosome to promote RT autophagosome-lysosome fusion."; RL J. Cell Biol. 218:267-284(2019). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL RP PROPERTIES, CHARACTERIZATION OF VARIANTS KRS MET-12; ARG-533; THR-746 AND RP ARG-877, CHARACTERIZATION OF VARIANT SPG8 ILE-517, AND MUTAGENESIS OF RP GLU-348; ALA-472; ASP-513; ASP-967 AND LYS-1067. RX PubMed=31996848; DOI=10.1038/s41586-020-1968-7; RA van Veen S., Martin S., Van den Haute C., Benoy V., Lyons J., Vanhoutte R., RA Kahler J.P., Decuypere J.P., Gelders G., Lambie E., Zielich J., RA Swinnen J.V., Annaert W., Agostinis P., Ghesquiere B., Verhelst S., RA Baekelandt V., Eggermont J., Vangheluwe P.; RT "ATP13A2 deficiency disrupts lysosomal polyamine export."; RL Nature 578:419-424(2020). RN [18] RP VARIANTS KRS MET-12; ARG-504 AND ARG-533. RX PubMed=17485642; DOI=10.1212/01.wnl.0000260963.08711.08; RA Di Fonzo A., Chien H.F., Socal M., Giraudo S., Tassorelli C., Iliceto G., RA Fabbrini G., Marconi R., Fincati E., Abbruzzese G., Marini P., RA Squitieri F., Horstink M.W., Montagna P., Libera A.D., Stocchi F., RA Goldwurm S., Ferreira J.J., Meco G., Martignoni E., Lopiano L., RA Jardim L.B., Oostra B.A., Barbosa E.R., Bonifati V.; RT "ATP13A2 missense mutations in juvenile parkinsonism and young onset RT Parkinson disease."; RL Neurology 68:1557-1562(2007). RN [19] RP VARIANT KRS LEU-182. RX PubMed=18413573; DOI=10.1212/01.wnl.0000310427.72236.68; RA Ning Y.P., Kanai K., Tomiyama H., Li Y., Funayama M., Yoshino H., Sato S., RA Asahina M., Kuwabara S., Takeda A., Hattori T., Mizuno Y., Hattori N.; RT "PARK9-linked parkinsonism in eastern Asia: mutation detection in ATP13A2 RT and clinical phenotype."; RL Neurology 70:1491-1493(2008). RN [20] RP VARIANT THR-746. RX PubMed=19015489; DOI=10.1212/01.wnl.0000335167.72412.68; RA Lin C.H., Tan E.K., Chen M.L., Tan L.C., Lim H.Q., Chen G.S., Wu R.M.; RT "Novel ATP13A2 variant associated with Parkinson disease in Taiwan and RT Singapore."; RL Neurology 71:1727-1732(2008). RN [21] RP VARIANTS SER-49; GLN-294; LEU-389; GLY-578; TRP-762; ILE-776 AND PHE-946. RX PubMed=19085912; DOI=10.1002/humu.20877; RA Vilarino-Guell C., Soto A.I., Lincoln S.J., Ben Yahmed S., Kefi M., RA Heckman M.G., Hulihan M.M., Chai H., Diehl N.N., Amouri R., Rajput A., RA Mash D.C., Dickson D.W., Middleton L.T., Gibson R.A., Hentati F., RA Farrer M.J.; RT "ATP13A2 variability in Parkinson disease."; RL Hum. Mutat. 30:406-410(2009). RN [22] RP INVOLVEMENT IN KRS. RX PubMed=20683840; DOI=10.1002/mds.22996; RA Behrens M.I., Bruggemann N., Chana P., Venegas P., Kagi M., Parrao T., RA Orellana P., Garrido C., Rojas C.V., Hauke J., Hahnen E., Gonzalez R., RA Seleme N., Fernandez V., Schmidt A., Binkofski F., Kompf D., Kubisch C., RA Hagenah J., Klein C., Ramirez A.; RT "Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with RT ATP13A2 mutations."; RL Mov. Disord. 25:1929-1937(2010). RN [23] RP VARIANT KRS ARG-1059, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT RP KRS ARG-1059. RX PubMed=21542062; DOI=10.1002/humu.21527; RA Park J.S., Mehta P., Cooper A.A., Veivers D., Heimbach A., Stiller B., RA Kubisch C., Fung V.S., Krainc D., Mackay-Sim A., Sue C.M.; RT "Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) RT causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism."; RL Hum. Mutat. 32:956-964(2011). RN [24] RP VARIANT KRS ARG-877. RX PubMed=20853184; DOI=10.1007/s10048-010-0259-0; RA Santoro L., Breedveld G.J., Manganelli F., Iodice R., Pisciotta C., RA Nolano M., Punzo F., Quarantelli M., Pappata S., Di Fonzo A., Oostra B.A., RA Bonifati V.; RT "Novel ATP13A2 (PARK9) homozygous mutation in a family with marked RT phenotype variability."; RL Neurogenetics 12:33-39(2011). RN [25] RP VARIANT KRS ARG-854. RX PubMed=22388936; DOI=10.1093/hmg/dds089; RA Bras J., Verloes A., Schneider S.A., Mole S.E., Guerreiro R.J.; RT "Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid- RT lipofuscinosis."; RL Hum. Mol. Genet. 21:2646-2650(2012). RN [26] RP VARIANT KRS VAL-522, AND FUNCTION. RX PubMed=22296644; DOI=10.1016/j.neurobiolaging.2011.12.035; RA Gruenewald A., Arns B., Seibler P., Rakovic A., Muenchau A., Ramirez A., RA Sue C.M., Klein C.; RT "ATP13A2 mutations impair mitochondrial function in fibroblasts from RT patients with Kufor-Rakeb syndrome."; RL Neurobiol. Aging 33:1843.E1-1843.E7(2012). RN [27] RP FUNCTION, CHARACTERIZATION OF VARIANTS KRS MET-12; LEU-182; ARG-504; RP ARG-533; THR-746 AND ARG-877, AND SUBCELLULAR LOCATION. RX PubMed=22768177; DOI=10.1371/journal.pone.0039942; RA Podhajska A., Musso A., Trancikova A., Stafa K., Moser R., Sonnay S., RA Glauser L., Moore D.J.; RT "Common pathogenic effects of missense mutations in the P-type ATPase RT ATP13A2 (PARK9) associated with early-onset parkinsonism."; RL PLoS ONE 7:E39942-E39942(2012). RN [28] RP FUNCTION, AND INTERACTION WITH MYCBP2. RX PubMed=27278822; DOI=10.1038/ncomms11803; RA Bento C.F., Ashkenazi A., Jimenez-Sanchez M., Rubinsztein D.C.; RT "The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate RT autophagy via a common pathway."; RL Nat. Commun. 7:11803-11803(2016). RN [29] RP INVOLVEMENT IN SPG78. RX PubMed=27217339; DOI=10.1093/brain/aww111; RA Kara E., Tucci A., Manzoni C., Lynch D.S., Elpidorou M., Bettencourt C., RA Chelban V., Manole A., Hamed S.A., Haridy N.A., Federoff M., Preza E., RA Hughes D., Pittman A., Jaunmuktane Z., Brandner S., Xiromerisiou G., RA Wiethoff S., Schottlaender L., Proukakis C., Morris H., Warner T., RA Bhatia K.P., Korlipara L.V., Singleton A.B., Hardy J., Wood N.W., RA Lewis P.A., Houlden H.; RT "Genetic and phenotypic characterization of complex hereditary spastic RT paraplegia."; RL Brain 139:1904-1918(2016). RN [30] RP INVOLVEMENT IN SPG78, VARIANT SPG78 ILE-517, CHARACTERIZATION OF VARIANTS RP KRS LEU-182 AND ARG-533, CHARACTERIZATION OF VARIANT SPG78 ILE-517, RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF ASP-513. RX PubMed=28137957; DOI=10.1093/brain/aww307; RA Estrada-Cuzcano A., Martin S., Chamova T., Synofzik M., Timmann D., RA Holemans T., Andreeva A., Reichbauer J., De Rycke R., Chang D.I., RA van Veen S., Samuel J., Schoels L., Poeppel T., Mollerup Soerensen D., RA Asselbergh B., Klein C., Zuchner S., Jordanova A., Vangheluwe P., RA Tournev I., Schuele R.; RT "Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated RT hereditary spastic paraplegia (SPG78)."; RL Brain 140:287-305(2017). RN [31] RP VARIANTS KRS PHE-441 AND THR-1069. RX PubMed=29903538; DOI=10.1016/j.braindev.2018.05.017; RA Suleiman J., Hamwi N., El-Hattab A.W.; RT "ATP13A2 novel mutations causing a rare form of juvenile-onset Parkinson RT disease."; RL Brain Dev. 40:824-826(2018). RN [32] RP VARIANT SPG78 PRO-927, AND CHARACTERIZATION OF VARIANT SPG78 PRO-927. RX PubMed=38252374; DOI=10.1007/s10072-024-07334-w; RA Zhang F., Liu P., Li J., Cen Z., Luo W.; RT "A novel ATP13A2 variant causing complicated hereditary spastic RT paraplegia."; RL Neurol. Sci. 45:1749-1753(2024). CC -!- FUNCTION: ATPase which acts as a lysosomal polyamine exporter with high CC affinity for spermine (PubMed:31996848). Also stimulates cellular CC uptake of polyamines and protects against polyamine toxicity CC (PubMed:31996848). Plays a role in intracellular cation homeostasis and CC the maintenance of neuronal integrity (PubMed:22186024). Contributes to CC cellular zinc homeostasis (PubMed:24603074). Confers cellular CC protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress CC (PubMed:26134396). Required for proper lysosomal and mitochondrial CC maintenance (PubMed:22296644, PubMed:28137957). Regulates the CC autophagy-lysosome pathway through the control of SYT11 expression at CC both transcriptional and post-translational levels (PubMed:27278822). CC Facilitates recruitment of deacetylase HDAC6 to lysosomes to CC deacetylate CTTN, leading to actin polymerization, promotion of CC autophagosome-lysosome fusion and completion of autophagy CC (PubMed:30538141). Promotes secretion of exosomes as well as secretion CC of SCNA via exosomes (PubMed:24603074, PubMed:25392495). Plays a role CC in lipid homeostasis (PubMed:31132336). {ECO:0000269|PubMed:22186024, CC ECO:0000269|PubMed:22296644, ECO:0000269|PubMed:24603074, CC ECO:0000269|PubMed:25392495, ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:28137957, CC ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:31132336, CC ECO:0000269|PubMed:31996848}. CC -!- CATALYTIC ACTIVITY: CC Reaction=spermidine(out) + ATP + H2O = spermidine(in) + ADP + phosphate CC + H(+); Xref=Rhea:RHEA:29999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57834, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:31996848}; CC -!- CATALYTIC ACTIVITY: CC Reaction=spermine(out) + ATP + H2O = spermine(in) + ADP + phosphate + CC H(+); Xref=Rhea:RHEA:63368, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:45725, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:31996848}; CC -!- ACTIVITY REGULATION: Accumulates in an inactive autophosphorylated CC state (PubMed:26134396). The presence of spermine results in a dose- CC dependent reduction in autophosphorylation (PubMed:31996848). CC {ECO:0000269|PubMed:26134396, ECO:0000269|PubMed:31996848}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=76 uM for spermine {ECO:0000269|PubMed:31996848}; CC Vmax=159 nmol/min/mg enzyme {ECO:0000269|PubMed:31996848}; CC -!- SUBUNIT: Interacts with MYCBP2; the interaction inhibits the CC ubiquitination of TSC2 by MYCBP2 (PubMed:27278822). Interacts with CC HDAC6; the interaction results in recruitment of HDAC6 to lysosomes to CC promote CTTN deacetylation (PubMed:30538141). CC {ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30538141}. CC -!- INTERACTION: CC Q9NQ11; Q2M2I8: AAK1; NbExp=2; IntAct=EBI-6308763, EBI-1383433; CC Q9NQ11; O60238: BNIP3L; NbExp=2; IntAct=EBI-6308763, EBI-849893; CC Q9NQ11; O14976: GAK; NbExp=2; IntAct=EBI-6308763, EBI-714707; CC Q9NQ11; Q9UBN7: HDAC6; NbExp=2; IntAct=EBI-6308763, EBI-301697; CC Q9NQ11; P11142: HSPA8; NbExp=2; IntAct=EBI-6308763, EBI-351896; CC Q9NQ11; Q9BT88: SYT11; NbExp=2; IntAct=EBI-6308763, EBI-751770; CC Q9NQ11; O95070: YIF1A; NbExp=2; IntAct=EBI-6308763, EBI-2799703; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:21542062, CC ECO:0000269|PubMed:22186024, ECO:0000269|PubMed:22768177, CC ECO:0000269|PubMed:24603074, ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:28137957}; Multi-pass membrane protein CC {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:24603074, CC ECO:0000269|PubMed:25392495, ECO:0000269|PubMed:26134396}; Multi-pass CC membrane protein {ECO:0000255}. Endosome, multivesicular body membrane CC {ECO:0000269|PubMed:24603074, ECO:0000269|PubMed:25392495}; Multi-pass CC membrane protein {ECO:0000255}. Cytoplasmic vesicle, autophagosome CC membrane {ECO:0000269|PubMed:24603074}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=A; CC IsoId=Q9NQ11-1; Sequence=Displayed; CC Name=B; CC IsoId=Q9NQ11-2; Sequence=VSP_007310, VSP_007311, VSP_007312; CC Name=3; CC IsoId=Q9NQ11-3; Sequence=VSP_007310; CC -!- TISSUE SPECIFICITY: Expressed in brain; protein levels are markedly CC increased in brain from subjects with Parkinson disease and subjects CC with dementia with Lewy bodies. Detected in pyramidal neurons located CC throughout the cingulate cortex (at protein level). In the substantia CC nigra, it is found in neuromelanin-positive dopaminergic neurons (at CC protein level). {ECO:0000269|PubMed:22186024}. CC -!- DOMAIN: The N-terminal region is required for targeting to late CC endosomes/lysosomes. It does not traverse the membrane but contains a CC membrane-embedded intramembrane domain and interacts with the lipids CC phosphatidic acid (PA) and phosphatidylinositol 3,5-bisphosphate CC (PI(3,5)P2) (PubMed:26134396). PA and PI(3,5)P2 are required for the CC protective effect against mitochondrial stress (PubMed:26134396). CC {ECO:0000269|PubMed:26134396}. CC -!- PTM: Autophosphorylated (PubMed:26134396, PubMed:28137957). Accumulates CC in an inactive autophosphorylated state and autophosphorylation is CC stimulated by phosphatidic acid and phosphatidylinositol 3,5- CC bisphosphate but not by Mn(2+) or Zn(2+) (PubMed:26134396). The CC presence of spermine results in a dose-dependent reduction in CC autophosphorylation (PubMed:31996848). {ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:31996848, ECO:0000305|PubMed:28137957}. CC -!- DISEASE: Kufor-Rakeb syndrome (KRS) [MIM:606693]: A rare form of CC autosomal recessive juvenile or early-onset, levodopa-responsive CC parkinsonism. In addition to typical parkinsonian signs, clinical CC manifestations of Kufor-Rakeb syndrome include behavioral problems, CC facial tremor, pyramidal tract dysfunction, supranuclear gaze palsy, CC and dementia. {ECO:0000269|PubMed:16964263, CC ECO:0000269|PubMed:17485642, ECO:0000269|PubMed:18413573, CC ECO:0000269|PubMed:20683840, ECO:0000269|PubMed:20853184, CC ECO:0000269|PubMed:21542062, ECO:0000269|PubMed:22296644, CC ECO:0000269|PubMed:22388936, ECO:0000269|PubMed:22768177, CC ECO:0000269|PubMed:28137957, ECO:0000269|PubMed:29903538, CC ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:31996848}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. KRS has also been referred to as neuronal ceroid lipofuscinosis CC 12 (CLN12), due to neuronal and glial lipofuscin deposits detected in CC the cortex, basal nuclei and cerebellum of some patients. CC {ECO:0000269|PubMed:22388936}. CC -!- DISEASE: Spastic paraplegia 78, autosomal recessive (SPG78) CC [MIM:617225]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. CC {ECO:0000269|PubMed:27217339, ECO:0000269|PubMed:28137957, CC ECO:0000269|PubMed:38252374}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type) (TC 3.A.3) CC family. Type V subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA08912.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL354615; CAB89728.1; -; mRNA. DR EMBL; AY461712; AAR23423.1; -; mRNA. DR EMBL; AK290210; BAF82899.1; -; mRNA. DR EMBL; AL049569; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471134; EAW94825.1; -; Genomic_DNA. DR EMBL; CH471134; EAW94827.1; -; Genomic_DNA. DR EMBL; BC030267; AAH30267.1; -; mRNA. DR EMBL; AL833966; CAD38813.2; -; mRNA. DR EMBL; AJ009947; CAA08912.1; ALT_FRAME; mRNA. DR CCDS; CCDS175.1; -. [Q9NQ11-1] DR CCDS; CCDS44072.1; -. [Q9NQ11-2] DR CCDS; CCDS44073.1; -. [Q9NQ11-3] DR RefSeq; NP_001135445.1; NM_001141973.3. [Q9NQ11-3] DR RefSeq; NP_001135446.1; NM_001141974.3. [Q9NQ11-2] DR RefSeq; NP_071372.1; NM_022089.4. [Q9NQ11-1] DR PDB; 7FJM; EM; 3.30 A; A=1-1180. DR PDB; 7FJP; EM; 3.00 A; B=1-1180. DR PDB; 7FJQ; EM; 3.60 A; A=1-1180. DR PDB; 7M5V; EM; 2.90 A; A=1-1180. DR PDB; 7M5X; EM; 2.70 A; A=1-1180. DR PDB; 7M5Y; EM; 3.00 A; A=1-1180. DR PDB; 7N70; EM; 2.80 A; A=1-1180. DR PDB; 7N72; EM; 2.50 A; A=1-1180. DR PDB; 7N73; EM; 2.90 A; A=1-1180. DR PDB; 7N74; EM; 2.80 A; A=1-1180. DR PDB; 7N75; EM; 2.90 A; A=1-1180. DR PDB; 7N76; EM; 2.90 A; A=1-1180. DR PDB; 7N77; EM; 3.20 A; A=1-1180. DR PDB; 7N78; EM; 3.00 A; A=1-1180. DR PDB; 7VPI; EM; 3.50 A; A=1-1180. DR PDB; 7VPJ; EM; 3.50 A; A=1-1180. DR PDB; 7VPK; EM; 3.50 A; A=1-1180. DR PDB; 7VPL; EM; 3.50 A; A=1-1180. DR PDB; 8IEK; EM; 3.20 A; P=1-1180. DR PDB; 8IEL; EM; 5.65 A; P=36-1169. DR PDB; 8IEM; EM; 3.35 A; P=36-1169. DR PDB; 8IEN; EM; 3.25 A; P=1-1180. DR PDB; 8IEO; EM; 3.78 A; P=1-1180. DR PDB; 8IER; EM; 4.87 A; P=1-1180. DR PDB; 8IES; EM; 3.73 A; P=36-1180. DR PDBsum; 7FJM; -. DR PDBsum; 7FJP; -. DR PDBsum; 7FJQ; -. DR PDBsum; 7M5V; -. DR PDBsum; 7M5X; -. DR PDBsum; 7M5Y; -. DR PDBsum; 7N70; -. DR PDBsum; 7N72; -. DR PDBsum; 7N73; -. DR PDBsum; 7N74; -. DR PDBsum; 7N75; -. DR PDBsum; 7N76; -. DR PDBsum; 7N77; -. DR PDBsum; 7N78; -. DR PDBsum; 7VPI; -. DR PDBsum; 7VPJ; -. DR PDBsum; 7VPK; -. DR PDBsum; 7VPL; -. DR PDBsum; 8IEK; -. DR PDBsum; 8IEL; -. DR PDBsum; 8IEM; -. DR PDBsum; 8IEN; -. DR PDBsum; 8IEO; -. DR PDBsum; 8IER; -. DR PDBsum; 8IES; -. DR AlphaFoldDB; Q9NQ11; -. DR EMDB; EMD-23683; -. DR EMDB; EMD-23684; -. DR EMDB; EMD-23685; -. DR EMDB; EMD-24212; -. DR EMDB; EMD-24213; -. DR EMDB; EMD-24214; -. DR EMDB; EMD-24215; -. DR EMDB; EMD-24216; -. DR EMDB; EMD-24217; -. DR EMDB; EMD-24218; -. DR EMDB; EMD-24219; -. DR EMDB; EMD-24221; -. DR EMDB; EMD-24222; -. DR EMDB; EMD-24223; -. DR EMDB; EMD-31623; -. DR EMDB; EMD-31626; -. DR EMDB; EMD-31627; -. DR EMDB; EMD-32066; -. DR EMDB; EMD-32067; -. DR EMDB; EMD-32068; -. DR EMDB; EMD-32069; -. DR EMDB; EMD-35384; -. DR EMDB; EMD-35385; -. DR EMDB; EMD-35386; -. DR EMDB; EMD-35387; -. DR EMDB; EMD-35388; -. DR EMDB; EMD-35391; -. DR EMDB; EMD-35392; -. DR SMR; Q9NQ11; -. DR BioGRID; 116973; 116. DR FunCoup; Q9NQ11; 1150. DR IntAct; Q9NQ11; 115. DR MINT; Q9NQ11; -. DR STRING; 9606.ENSP00000327214; -. DR TCDB; 3.A.3.10.7; the p-type atpase (p-atpase) superfamily. DR GlyCosmos; Q9NQ11; 2 sites, No reported glycans. DR GlyGen; Q9NQ11; 4 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q9NQ11; -. DR PhosphoSitePlus; Q9NQ11; -. DR SwissPalm; Q9NQ11; -. DR BioMuta; ATP13A2; -. DR DMDM; 14285364; -. DR jPOST; Q9NQ11; -. DR MassIVE; Q9NQ11; -. DR PaxDb; 9606-ENSP00000327214; -. DR PeptideAtlas; Q9NQ11; -. DR ProteomicsDB; 63479; -. DR ProteomicsDB; 82052; -. [Q9NQ11-1] DR ProteomicsDB; 82053; -. [Q9NQ11-2] DR ProteomicsDB; 82054; -. [Q9NQ11-3] DR Pumba; Q9NQ11; -. DR Antibodypedia; 29290; 196 antibodies from 24 providers. DR DNASU; 23400; -. DR Ensembl; ENST00000326735.13; ENSP00000327214.8; ENSG00000159363.19. [Q9NQ11-1] DR Ensembl; ENST00000341676.9; ENSP00000341115.5; ENSG00000159363.19. [Q9NQ11-2] DR Ensembl; ENST00000452699.5; ENSP00000413307.1; ENSG00000159363.19. [Q9NQ11-3] DR GeneID; 23400; -. DR KEGG; hsa:23400; -. DR MANE-Select; ENST00000326735.13; ENSP00000327214.8; NM_022089.4; NP_071372.1. DR UCSC; uc001baa.3; human. [Q9NQ11-1] DR AGR; HGNC:30213; -. DR ClinPGx; PA134897221; -. DR CTD; 23400; -. DR DisGeNET; 23400; -. DR GeneCards; ATP13A2; -. DR GeneReviews; ATP13A2; -. DR HGNC; HGNC:30213; ATP13A2. DR HPA; ENSG00000159363; Tissue enhanced (brain). DR MalaCards; ATP13A2; -. DR MIM; 606693; phenotype. DR MIM; 610513; gene. DR MIM; 617225; phenotype. DR OpenTargets; ENSG00000159363; -. DR Orphanet; 513436; Autosomal recessive spastic paraplegia type 78. DR Orphanet; 314632; CLN12 disease. DR Orphanet; 306674; Kufor-Rakeb syndrome. DR VEuPathDB; HostDB:ENSG00000159363; -. DR eggNOG; KOG0208; Eukaryota. DR GeneTree; ENSGT00940000159714; -. DR HOGENOM; CLU_001828_0_0_1; -. DR InParanoid; Q9NQ11; -. DR OMA; SGWKDPL; -. DR OrthoDB; 48943at2759; -. DR PAN-GO; Q9NQ11; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q9NQ11; -. DR PathwayCommons; Q9NQ11; -. DR Reactome; R-HSA-936837; Ion transport by P-type ATPases. DR SignaLink; Q9NQ11; -. DR Agora; ENSG00000159363; -. DR BioGRID-ORCS; 23400; 14 hits in 1156 CRISPR screens. DR ChiTaRS; ATP13A2; human. DR GeneWiki; ATP13A2; -. DR GenomeRNAi; 23400; -. DR Pharos; Q9NQ11; Tbio. DR PRO; PR:Q9NQ11; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9NQ11; protein. DR Bgee; ENSG00000159363; Expressed in right frontal lobe and 166 other cell types or tissues. DR ExpressionAtlas; Q9NQ11; baseline and differential. DR GO; GO:0005776; C:autophagosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005770; C:late endosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0005771; C:multivesicular body; IDA:ParkinsonsUK-UCL. DR GO; GO:0032585; C:multivesicular body membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0030133; C:transport vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0031982; C:vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0015417; F:ABC-type polyamine transporter activity; IEA:RHEA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; NAS:ParkinsonsUK-UCL. DR GO; GO:0019829; F:ATPase-coupled monoatomic cation transmembrane transporter activity; IBA:GO_Central. DR GO; GO:1903135; F:cupric ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0030145; F:manganese ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0015662; F:P-type ion transporter activity; IEA:InterPro. DR GO; GO:0070300; F:phosphatidic acid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0015203; F:polyamine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:1905037; P:autophagosome organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0061909; P:autophagosome-lysosome fusion; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0071287; P:cellular response to manganese ion; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0071294; P:cellular response to zinc ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0097734; P:extracellular exosome biogenesis; IMP:ParkinsonsUK-UCL. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IDA:ParkinsonsUK-UCL. DR GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0030003; P:intracellular monoatomic cation homeostasis; TAS:ParkinsonsUK-UCL. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0055088; P:lipid homeostasis; IMP:UniProtKB. DR GO; GO:0007041; P:lysosomal transport; IMP:UniProtKB. DR GO; GO:0034220; P:monoatomic ion transmembrane transport; TAS:Reactome. DR GO; GO:1905166; P:negative regulation of lysosomal protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902047; P:polyamine transmembrane transport; IDA:ParkinsonsUK-UCL. DR GO; GO:1903543; P:positive regulation of exosomal secretion; IDA:ParkinsonsUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0050714; P:positive regulation of protein secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0061462; P:protein localization to lysosome; IMP:UniProtKB. DR GO; GO:0016243; P:regulation of autophagosome size; IDA:ParkinsonsUK-UCL. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:1904714; P:regulation of chaperone-mediated autophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0033157; P:regulation of intracellular protein transport; NAS:ParkinsonsUK-UCL. DR GO; GO:1905165; P:regulation of lysosomal protein catabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0016241; P:regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:ParkinsonsUK-UCL. DR GO; GO:1900180; P:regulation of protein localization to nucleus; IMP:UniProtKB. DR GO; GO:1903710; P:spermine transmembrane transport; IMP:UniProtKB. DR CDD; cd07542; P-type_ATPase_cation; 1. DR FunFam; 1.20.1110.10:FF:000023; Cation-transporting ATPase; 1. DR FunFam; 2.70.150.10:FF:000060; Cation-transporting ATPase; 1. DR FunFam; 3.40.1110.10:FF:000026; Cation-transporting ATPase; 1. DR FunFam; 3.40.50.1000:FF:000068; Cation-transporting ATPase; 1. DR Gene3D; 3.40.1110.10; Calcium-transporting ATPase, cytoplasmic domain N; 1. DR Gene3D; 2.70.150.10; Calcium-transporting ATPase, cytoplasmic transduction domain A; 1. DR Gene3D; 1.20.1110.10; Calcium-transporting ATPase, transmembrane domain; 1. DR Gene3D; 3.40.50.1000; HAD superfamily/HAD-like; 1. DR InterPro; IPR023299; ATPase_P-typ_cyto_dom_N. DR InterPro; IPR018303; ATPase_P-typ_P_site. DR InterPro; IPR023298; ATPase_P-typ_TM_dom_sf. DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A_sf. DR InterPro; IPR059000; ATPase_P-type_domA. DR InterPro; IPR036412; HAD-like_sf. DR InterPro; IPR023214; HAD_sf. DR InterPro; IPR006544; P-type_TPase_V. DR InterPro; IPR047819; P5A-ATPase_N. DR InterPro; IPR047821; P5B-type_ATPase. DR InterPro; IPR001757; P_typ_ATPase. DR InterPro; IPR044492; P_typ_ATPase_HD_dom. DR NCBIfam; TIGR01494; ATPase_P-type; 2. DR NCBIfam; TIGR01657; P-ATPase-V; 1. DR PANTHER; PTHR45630; CATION-TRANSPORTING ATPASE-RELATED; 1. DR PANTHER; PTHR45630:SF2; POLYAMINE-TRANSPORTING ATPASE 13A2; 1. DR Pfam; PF13246; Cation_ATPase; 1. DR Pfam; PF00122; E1-E2_ATPase; 1. DR Pfam; PF12409; P5-ATPase; 1. DR PRINTS; PR00119; CATATPASE. DR SFLD; SFLDG00002; C1.7:_P-type_atpase_like; 1. DR SFLD; SFLDS00003; Haloacid_Dehalogenase; 1. DR SFLD; SFLDF00027; p-type_atpase; 1. DR SUPFAM; SSF81653; Calcium ATPase, transduction domain A; 1. DR SUPFAM; SSF81665; Calcium ATPase, transmembrane domain M; 1. DR SUPFAM; SSF56784; HAD-like; 1. DR SUPFAM; SSF81660; Metal cation-transporting ATPase, ATP-binding domain N; 1. DR PROSITE; PS00154; ATPASE_E1_E2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasmic vesicle; KW Disease variant; Endosome; Glycoprotein; Hereditary spastic paraplegia; KW Lipid-binding; Lysosome; Magnesium; Membrane; Metal-binding; KW Neurodegeneration; Neuronal ceroid lipofuscinosis; Nucleotide-binding; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Translocase; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..1180 FT /note="Polyamine-transporting ATPase 13A2" FT /id="PRO_0000046423" FT TOPO_DOM 1..44 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT INTRAMEM 45..65 FT /evidence="ECO:0000255" FT TOPO_DOM 66..235 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 236..253 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 254..256 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 257..276 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 277..427 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 428..448 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 449..463 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 464..484 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 485..930 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 931..951 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 952..957 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 958..978 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 979..994 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 995..1015 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1016..1048 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1049..1069 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1070..1080 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1081..1101 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1102..1117 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1118..1138 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1139..1180 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT ACT_SITE 513 FT /note="4-aspartylphosphate intermediate" FT /evidence="ECO:0000269|PubMed:26134396" FT BINDING 878 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT BINDING 882 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT MOD_RES 151 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CARBOHYD 1033 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:26134396" FT CARBOHYD 1110 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 155..159 FT /note="Missing (in isoform B and isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2, FT ECO:0000303|Ref.8" FT /id="VSP_007310" FT VAR_SEQ 805..843 FT /note="Missing (in isoform B)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.8" FT /id="VSP_007311" FT VAR_SEQ 1079..1180 FT /note="VPFLVALALLSSVLVGLVLVPGLLQGPLALRNITDTGFKLLLLGLVTLNFVG FT AFMLESVLDQCLPACLRRLRPKRASKKRFKQLERELAEQPWPPLPAGPLR -> ERARP FT VPPRLPAPPPAQAGLQEALQAAGTRAGRAALAAAARRPPEVVQAHGHPRHWNSLPLSHQ FT LDPSPATPPPPPPTSLRLATVYTPPPRPPPPWGSVDYCPLPWTIPRRGGSPQLPSVLLS FT V (in isoform B)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.8" FT /id="VSP_007312" FT VARIANT 12 FT /note="T -> M (in KRS; uncertain significance; no effect on FT stability; no effect on location; decreased ATPase FT activity; dbSNP:rs151117874)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_058451" FT VARIANT 49 FT /note="G -> S (in dbSNP:rs56379718)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058452" FT VARIANT 182 FT /note="F -> L (in KRS; decreased protein stability; loss of FT autophosphorylation; increased degradation by proteasome; FT novel location to endoplasmic reticulum; loss of lysosomal FT membrane location; impaired autophagosome-lysosome fusion; FT impaired degradation of protein aggregates)" FT /evidence="ECO:0000269|PubMed:18413573, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:30538141" FT /id="VAR_066019" FT VARIANT 294 FT /note="R -> Q (in dbSNP:rs56367069)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058453" FT VARIANT 389 FT /note="P -> L (in dbSNP:rs56275621)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058454" FT VARIANT 441 FT /note="I -> F (in KRS; uncertain significance; associated FT in cis with Thr-1069 in one individual; dbSNP:rs772446950)" FT /evidence="ECO:0000269|PubMed:29903538" FT /id="VAR_083537" FT VARIANT 504 FT /note="G -> R (in KRS; decreased protein stability; FT increased degradation by proteasome; novel location to FT endoplasmic reticulum; loss of lysosomal membrane location; FT impaired autophagosome-lysosome fusion; impaired FT degradation of protein aggregates; dbSNP:rs121918227)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:30538141" FT /id="VAR_058455" FT VARIANT 517 FT /note="T -> I (in SPG78; no effect on protein stability; FT loss of autophosphorylation; loss of lysosomal location; FT loss of ATPase activity; dbSNP:rs1057519291)" FT /evidence="ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:31996848" FT /id="VAR_078055" FT VARIANT 522 FT /note="G -> V (in KRS; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22296644" FT /id="VAR_078056" FT VARIANT 533 FT /note="G -> R (in KRS; uncertain significance; decreased FT ATPase activity; no effect on autophosphorylation; no FT effect on stability; no effect on location)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:31996848" FT /id="VAR_058456" FT VARIANT 578 FT /note="V -> G (in dbSNP:rs56186751)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058457" FT VARIANT 746 FT /note="A -> T (in KRS; decreased ATPase activity; no effect FT on stability; no effect on location; dbSNP:rs147277743)" FT /evidence="ECO:0000269|PubMed:19015489, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_058458" FT VARIANT 762 FT /note="R -> W (in dbSNP:rs55635527)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058459" FT VARIANT 776 FT /note="V -> I (in dbSNP:rs56170027)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058460" FT VARIANT 854 FT /note="M -> R (in KRS; some patients manifest FT neuropathologic findings suggestive of neuronal ceroid FT lipofuscinosis; dbSNP:rs587777053)" FT /evidence="ECO:0000269|PubMed:22388936" FT /id="VAR_070194" FT VARIANT 877 FT /note="G -> R (in KRS; found in two affected brothers also FT carrying C-481 in FBXO7; decreased protein stability; FT increased degradation by proteasome; novel location to FT endoplasmic reticulum; loss of ATPase activity; loss of FT autophosphorylation; dbSNP:rs144701072)" FT /evidence="ECO:0000269|PubMed:20853184, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_066020" FT VARIANT 927 FT /note="L -> P (in SPG78; uncertain significance; contrary FT to the wild type, it does not localize to LAMP1-positive FT cytoplasmic vesicles)" FT /evidence="ECO:0000269|PubMed:38252374" FT /id="VAR_089312" FT VARIANT 946 FT /note="I -> F (in dbSNP:rs55708915)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058461" FT VARIANT 1059 FT /note="L -> R (in KRS; the mutant protein is retained in FT the endoplasmic reticulum; dbSNP:rs137853967)" FT /evidence="ECO:0000269|PubMed:21542062" FT /id="VAR_066021" FT VARIANT 1069 FT /note="A -> T (in KRS; uncertain significance; associated FT in cis with Phe-441 in one individual; dbSNP:rs774238872)" FT /evidence="ECO:0000269|PubMed:29903538" FT /id="VAR_083538" FT MUTAGEN 59 FT /note="G->A: No effect on lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 66..68 FT /note="RWK->AWA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 74..78 FT /note="RLRLR->ALALA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 160..164 FT /note="KRVLR->AAVLA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 348 FT /note="E->A: Autophosphorylated but displays limited FT spermine-induced ATPase activity and lacks spermine-induced FT dephosphorylation." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 472 FT /note="A->V: Reduced spermine-induced ATPase activity and FT lack of spermine-induced dephosphorylation." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 513 FT /note="D->N: Loss of ATPase function, autophosphorylation FT and protection against mitochondrial stress." FT /evidence="ECO:0000269|PubMed:26134396, FT ECO:0000269|PubMed:28137957, ECO:0000269|PubMed:31996848" FT MUTAGEN 967 FT /note="D->N: Reduced spermine-induced ATPase activity." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 1033 FT /note="N->A: Abolishes glycosylation." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 1067 FT /note="K->A: Reduced spermine-induced ATPase activity." FT /evidence="ECO:0000269|PubMed:31996848" FT CONFLICT 322 FT /note="Q -> R (in Ref. 6; AAH30267)" FT /evidence="ECO:0000305" FT CONFLICT 855..858 FT /note="APEQ -> IPRA (in Ref. 8; CAA08912)" FT /evidence="ECO:0000305" FT CONFLICT 861 FT /note="E -> V (in Ref. 8; CAA08912)" FT /evidence="ECO:0000305" FT STRAND 36..41 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 60..67 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 69..76 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 77..79 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 82..84 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 86..91 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 102..106 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 109..111 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 117..119 FT /evidence="ECO:0007829|PDB:7FJP" FT HELIX 120..123 FT /evidence="ECO:0007829|PDB:7FJP" FT HELIX 130..132 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 147..149 FT /evidence="ECO:0007829|PDB:7FJM" FT STRAND 159..161 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 164..168 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 171..176 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 177..180 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 181..184 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 185..187 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 188..191 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 194..199 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 200..202 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 206..216 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 228..235 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 239..253 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:7FJM" FT HELIX 257..289 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 294..299 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 300..302 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 303..308 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 309..311 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 317..320 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 329..341 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 343..346 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 350..355 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 361..363 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 366..369 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 370..372 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 379..384 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 386..397 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 399..401 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 403..412 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 422..449 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 473..491 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 493..497 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 498..505 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 508..512 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 516..518 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 524..529 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 532..534 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 540..542 FT /evidence="ECO:0007829|PDB:7M5X" FT HELIX 543..545 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 550..557 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 562..564 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 567..570 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 572..581 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 584..586 FT /evidence="ECO:0007829|PDB:7M5X" FT STRAND 593..596 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 602..604 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 610..612 FT /evidence="ECO:0007829|PDB:7M5V" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:7M5V" FT STRAND 622..628 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 632..634 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 636..642 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 650..655 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 657..660 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 661..663 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 666..668 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 673..681 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 682..684 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 686..694 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 701..704 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 709..713 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 714..725 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 732..741 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 745..749 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 754..763 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:7N70" FT STRAND 771..779 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 783..785 FT /evidence="ECO:0007829|PDB:7M5X" FT STRAND 788..794 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 821..826 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 827..836 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 838..840 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 841..847 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 848..853 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 856..868 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 873..877 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 880..882 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 883..888 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 889..894 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 897..900 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 901..903 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 905..912 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 915..953 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 960..967 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 969..978 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 995..998 FT /evidence="ECO:0007829|PDB:7N74" FT HELIX 999..1024 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 1025..1028 FT /evidence="ECO:0007829|PDB:7M5V" FT STRAND 1034..1036 FT /evidence="ECO:0007829|PDB:7N73" FT TURN 1038..1041 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1045..1065 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 1069..1071 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1075..1077 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1079..1097 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 1100..1102 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 1103..1107 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1114..1149 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1158..1168 FT /evidence="ECO:0007829|PDB:7N72" SQ SEQUENCE 1180 AA; 128794 MW; 98D13745D3B615BE CRC64; MSADSSPLVG STPTGYGTLT IGTSIDPLSS SVSSVRLSGY CGSPWRVIGY HVVVWMMAGI PLLLFRWKPL WGVRLRLRPC NLAHAETLVI EIRDKEDSSW QLFTVQVQTE AIGEGSLEPS PQSQAEDGRS QAAVGAVPEG AWKDTAQLHK SEEAVSVGQK RVLRYYLFQG QRYIWIETQQ AFYQVSLLDH GRSCDDVHRS RHGLSLQDQM VRKAIYGPNV ISIPVKSYPQ LLVDEALNPY YGFQAFSIAL WLADHYYWYA LCIFLISSIS ICLSLYKTRK QSQTLRDMVK LSMRVCVCRP GGEEEWVDSS ELVPGDCLVL PQEGGLMPCD AALVAGECMV NESSLTGESI PVLKTALPEG LGPYCAETHR RHTLFCGTLI LQARAYVGPH VLAVVTRTGF CTAKGGLVSS ILHPRPINFK FYKHSMKFVA ALSVLALLGT IYSIFILYRN RVPLNEIVIR ALDLVTVVVP PALPAAMTVC TLYAQSRLRR QGIFCIHPLR INLGGKLQLV CFDKTGTLTE DGLDVMGVVP LKGQAFLPLV PEPRRLPVGP LLRALATCHA LSRLQDTPVG DPMDLKMVES TGWVLEEEPA ADSAFGTQVL AVMRPPLWEP QLQAMEEPPV PVSVLHRFPF SSALQRMSVV VAWPGATQPE AYVKGSPELV AGLCNPETVP TDFAQMLQSY TAAGYRVVAL ASKPLPTVPS LEAAQQLTRD TVEGDLSLLG LLVMRNLLKP QTTPVIQALR RTRIRAVMVT GDNLQTAVTV ARGCGMVAPQ EHLIIVHATH PERGQPASLE FLPMESPTAV NGVKDPDQAA SYTVEPDPRS RHLALSGPTF GIIVKHFPKL LPKVLVQGTV FARMAPEQKT ELVCELQKLQ YCVGMCGDGA NDCGALKAAD VGISLSQAEA SVVSPFTSSM ASIECVPMVI REGRCSLDTS FSVFKYMALY SLTQFISVLI LYTINTNLGD LQFLAIDLVI TTTVAVLMSR TGPALVLGRV RPPGALLSVP VLSSLLLQMV LVTGVQLGGY FLTLAQPWFV PLNRTVAAPD NLPNYENTVV FSLSSFQYLI LAAAVSKGAP FRRPLYTNVP FLVALALLSS VLVGLVLVPG LLQGPLALRN ITDTGFKLLL LGLVTLNFVG AFMLESVLDQ CLPACLRRLR PKRASKKRFK QLERELAEQP WPPLPAGPLR // ID ATX2_HUMAN Reviewed; 1313 AA. AC Q99700; A6NLD4; Q24JQ7; Q6ZQZ7; Q99493; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 204. DE RecName: Full=Ataxin-2; DE AltName: Full=Spinocerebellar ataxia type 2 protein; DE AltName: Full=Trinucleotide repeat-containing gene 13 protein; GN Name=ATXN2; Synonyms=ATX2, SCA2, TNRC13; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896555; DOI=10.1038/ng1196-269; RA Pulst S.-M., Nechiporuk A., Nechiporuk T., Gispert S., Chen X.-N., RA Lopes-Cendes I., Pearlman S., Starkman S., Orozco-Diaz G., Lunkes A., RA DeJong P., Rouleau G.A., Auburger G., Korenberg J.R., Figueroa C., RA Sahba S.; RT "Moderate expansion of a normally biallelic trinucleotide repeat in RT spinocerebellar ataxia type 2."; RL Nat. Genet. 14:269-276(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP AND TISSUE SPECIFICITY. RX PubMed=8896556; DOI=10.1038/ng1196-277; RA Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., RA Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T., Koide R., Saito M., RA Sato A., Tanaka T., Hanyu S., Takiyama Y., Nishizawa M., Shimizu N., RA Nomura Y., Segawa M., Iwabuchi K., Eguchi I., Tanaka H., Takahashi H., RA Tsuji S.; RT "Identification of the spinocerebellar ataxia type 2 gene using a direct RT identification of repeat expansion and cloning technique, DIRECT."; RL Nat. Genet. 14:277-284(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-1313 (ISOFORM 2), POLYMORPHISM, RP INVOLVEMENT IN SCA2, TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896557; DOI=10.1038/ng1196-285; RA Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Garnier J.-M., RA Weber C., Mandel J.-L., Cancel G., Abbas N., Duerr A., Didierjean O., RA Stevanin G., Agid Y., Brice A.; RT "Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high RT sensitivity to expanded CAG/glutamine repeats."; RL Nat. Genet. 14:285-291(1996). RN [7] RP ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY. RX PubMed=9480749; DOI=10.1006/geno.1997.5131; RA Sahba S., Nechiporuk A., Figueroa K.P., Nechiporuk T., Pulst S.-M.; RT "Genomic structure of the human gene for spinocerebellar ataxia type 2 RT (SCA2) on chromosome 12q24.1."; RL Genomics 47:359-364(1998). RN [8] RP INTERACTION WITH RBFOX1. RX PubMed=10814712; DOI=10.1093/hmg/9.9.1303; RA Shibata H., Huynh D.P., Pulst S.-M.; RT "A novel protein with RNA-binding motifs interacts with ataxin-2."; RL Hum. Mol. Genet. 9:1303-1313(2000). RN [9] RP INTERACTION WITH POLYRIBOSOMES. RX PubMed=16835262; DOI=10.1093/hmg/ddl173; RA Satterfield T.F., Pallanck L.J.; RT "Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with RT polyribosomes."; RL Hum. Mol. Genet. 15:2523-2532(2006). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [11] RP FUNCTION, AND INTERACTION WITH EGFR; SH3GL2 AND SH3GL3. RX PubMed=18602463; DOI=10.1016/j.cellsig.2008.05.018; RA Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J., RA Auburger G.; RT "Ataxin-2 associates with the endocytosis complex and affects EGF receptor RT trafficking."; RL Cell. Signal. 20:1725-1739(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-554; SER-684; RP THR-741; SER-857; SER-861; SER-888 AND SER-889, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-684, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP INTERACTION WITH TARDBP, INVOLVEMENT IN ALS13, AND POLY-GLN REPEAT RP EXPANSION. RX PubMed=20740007; DOI=10.1038/nature09320; RA Elden A.C., Kim H.J., Hart M.P., Chen-Plotkin A.S., Johnson B.S., Fang X., RA Armakola M., Geser F., Greene R., Lu M.M., Padmanabhan A., Clay-Falcone D., RA McCluskey L., Elman L., Juhr D., Gruber P.J., Rub U., Auburger G., RA Trojanowski J.Q., Lee V.M., Van Deerlin V.M., Bonini N.M., Gitler A.D.; RT "Ataxin-2 intermediate-length polyglutamine expansions are associated with RT increased risk for ALS."; RL Nature 466:1069-1075(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-393; SER-684 AND SER-784, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784; SER-861 AND SER-865, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [20] RP INTERACTION WITH ATXN2L. RX PubMed=23209657; DOI=10.1371/journal.pone.0050134; RA Kaehler C., Isensee J., Nonhoff U., Terrey M., Hucho T., Lehrach H., RA Krobitsch S.; RT "Ataxin-2-like is a regulator of stress granules and processing bodies."; RL PLoS ONE 7:E50134-E50134(2012). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-478; SER-508; RP SER-624; SER-642; SER-684; SER-772; SER-784 AND SER-889, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-624 AND SER-728, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-640, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [24] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-893, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). CC -!- FUNCTION: Involved in EGFR trafficking, acting as negative regulator of CC endocytic EGFR internalization at the plasma membrane. CC {ECO:0000269|PubMed:18602463}. CC -!- SUBUNIT: Monomer (By similarity). Can also form homodimers (By CC similarity). Interacts with TARDBP; the interaction is RNA-dependent CC (PubMed:20740007). Interacts with RBFOX1 (PubMed:10814712). Interacts CC with polyribosomes (PubMed:16835262). Interacts with SH3GL2 and SH3GL3 CC (PubMed:18602463). Interacts with SH3KBP1 and CBL (By similarity). CC Interacts with EGFR (PubMed:18602463). Interacts with ATXN2L CC (PubMed:23209657). {ECO:0000250|UniProtKB:O70305, CC ECO:0000269|PubMed:10814712, ECO:0000269|PubMed:16835262, CC ECO:0000269|PubMed:18602463, ECO:0000269|PubMed:20740007, CC ECO:0000269|PubMed:23209657}. CC -!- INTERACTION: CC Q99700; P54253: ATXN1; NbExp=4; IntAct=EBI-697691, EBI-930964; CC Q99700; P26196: DDX6; NbExp=14; IntAct=EBI-697691, EBI-351257; CC Q99700; Q13283: G3BP1; NbExp=4; IntAct=EBI-697691, EBI-1047359; CC Q99700; P11940: PABPC1; NbExp=8; IntAct=EBI-697691, EBI-81531; CC Q99700; Q99962: SH3GL2; NbExp=9; IntAct=EBI-697691, EBI-77938; CC Q99700; Q99963: SH3GL3; NbExp=11; IntAct=EBI-697691, EBI-473910; CC Q99700; Q13148: TARDBP; NbExp=3; IntAct=EBI-697691, EBI-372899; CC Q99700-5; P54253: ATXN1; NbExp=6; IntAct=EBI-25891409, EBI-930964; CC Q99700-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25891409, EBI-10988864; CC Q99700-5; Q9BTH3: BIN1; NbExp=3; IntAct=EBI-25891409, EBI-25891390; CC Q99700-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25891409, EBI-2837444; CC Q99700-5; P20963: CD247; NbExp=3; IntAct=EBI-25891409, EBI-1165705; CC Q99700-5; P11940: PABPC1; NbExp=3; IntAct=EBI-25891409, EBI-81531; CC Q99700-5; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-25891409, EBI-12123390; CC Q99700-5; Q8IVP1: SH3GL3; NbExp=3; IntAct=EBI-25891409, EBI-6503765; CC Q99700-5; Q9UJZ1: STOML2; NbExp=3; IntAct=EBI-25891409, EBI-1044428; CC Q99700-5; P55854: SUMO3; NbExp=3; IntAct=EBI-25891409, EBI-474067; CC Q99700-5; P40337-2: VHL; NbExp=3; IntAct=EBI-25891409, EBI-12157263; CC Q99700-5; Q96E88; NbExp=3; IntAct=EBI-25891409, EBI-10976904; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=Q99700-1; Sequence=Displayed; CC Name=2; CC IsoId=Q99700-2; Sequence=VSP_011575, VSP_011577; CC Name=3; CC IsoId=Q99700-3; Sequence=VSP_011574, VSP_011576, VSP_011578, CC VSP_011579, VSP_011580, VSP_011581; CC Name=4; CC IsoId=Q99700-4; Sequence=VSP_011582; CC Name=5; CC IsoId=Q99700-5; Sequence=VSP_057285, VSP_057286, VSP_057287; CC -!- TISSUE SPECIFICITY: Expressed in the brain, heart, liver, skeletal CC muscle, pancreas and placenta. Isoform 1 is predominant in the brain CC and spinal cord. Isoform 4 is more abundant in the cerebellum. In the CC brain, broadly expressed in the amygdala, caudate nucleus, corpus CC callosum, hippocampus, hypothalamus, substantia nigra, subthalamic CC nucleus and thalamus. {ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557, CC ECO:0000269|PubMed:9480749}. CC -!- POLYMORPHISM: The poly-Gln region of ATXN2 is polymorphic: 17 to 29 CC repeats are found in the normal population. Higher numbers of repeats CC result in different disease phenotypes depending on the length of the CC expansion. {ECO:0000269|PubMed:20740007, ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557}. CC -!- DISEASE: Spinocerebellar ataxia 2 (SCA2) [MIM:183090]: Spinocerebellar CC ataxia is a clinically and genetically heterogeneous group of CC cerebellar disorders. Patients show progressive incoordination of gait CC and often poor coordination of hands, speech and eye movements, due to CC cerebellum degeneration with variable involvement of the brainstem and CC spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias CC type I (ADCA I) which are characterized by cerebellar ataxia in CC combination with additional clinical features like optic atrophy, CC ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy CC and dementia. SCA2 is characterized by hyporeflexia, myoclonus and CC action tremor and dopamine-responsive parkinsonism. In some patients, CC SCA2 presents as pure familial parkinsonism without cerebellar signs. CC {ECO:0000269|PubMed:8896555, ECO:0000269|PubMed:8896556, CC ECO:0000269|PubMed:8896557}. Note=The disease is caused by variants CC affecting the gene represented in this entry. SCA2 is caused by CC expansion of a CAG repeat resulting in about 36 to 52 repeats in some CC patients. Longer expansions result in earlier the expansion, onset of CC the disease. CC -!- DISEASE: Amyotrophic lateral sclerosis 13 (ALS13) [MIM:183090]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:20740007}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC An increased risk for developing amyotrophic lateral sclerosis seems to CC be conferred by CAG repeat intermediate expansions greater than 23 but CC below the threshold for developing spinocerebellar ataxia. CC -!- SIMILARITY: Belongs to the ataxin-2 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U70323; AAB19200.1; -; mRNA. DR EMBL; AK128613; BAC87528.1; -; mRNA. DR EMBL; AC002395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137055; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF455720; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC114546; AAI14547.1; -; mRNA. DR EMBL; Y08262; CAA69589.1; -; mRNA. DR CCDS; CCDS81738.1; -. [Q99700-5] DR RefSeq; NP_001297052.1; NM_001310123.1. [Q99700-5] DR RefSeq; NP_002964.4; NM_002973.4. DR PDB; 3KTR; X-ray; 1.70 A; B=912-928. DR PDBsum; 3KTR; -. DR AlphaFoldDB; Q99700; -. DR SMR; Q99700; -. DR BioGRID; 112218; 327. DR DIP; DIP-33372N; -. DR ELM; Q99700; -. DR FunCoup; Q99700; 1901. DR IntAct; Q99700; 166. DR MINT; Q99700; -. DR STRING; 9606.ENSP00000446576; -. DR BindingDB; Q99700; -. DR ChEMBL; CHEMBL1795085; -. DR GlyCosmos; Q99700; 7 sites, 1 glycan. DR GlyGen; Q99700; 26 sites, 1 O-linked glycan (23 sites). DR iPTMnet; Q99700; -. DR MetOSite; Q99700; -. DR PhosphoSitePlus; Q99700; -. DR SwissPalm; Q99700; -. DR BioMuta; ATXN2; -. DR DMDM; 215273941; -. DR jPOST; Q99700; -. DR MassIVE; Q99700; -. DR PaxDb; 9606-ENSP00000366843; -. DR PeptideAtlas; Q99700; -. DR ProteomicsDB; 61268; -. DR ProteomicsDB; 78409; -. [Q99700-1] DR ProteomicsDB; 78410; -. [Q99700-2] DR ProteomicsDB; 78412; -. [Q99700-4] DR Pumba; Q99700; -. DR Antibodypedia; 18563; 277 antibodies from 36 providers. DR DNASU; 6311; -. DR Ensembl; ENST00000535949.5; ENSP00000439338.1; ENSG00000204842.19. [Q99700-5] DR Ensembl; ENST00000550104.5; ENSP00000446576.2; ENSG00000204842.19. [Q99700-1] DR Ensembl; ENST00000616825.4; ENSP00000481448.1; ENSG00000204842.19. [Q99700-5] DR GeneID; 6311; -. DR KEGG; hsa:6311; -. DR UCSC; uc001tsj.3; human. [Q99700-1] DR AGR; HGNC:10555; -. DR ClinPGx; PA34968; -. DR CTD; 6311; -. DR DisGeNET; 6311; -. DR GeneCards; ATXN2; -. DR GeneReviews; ATXN2; -. DR HGNC; HGNC:10555; ATXN2. DR HPA; ENSG00000204842; Low tissue specificity. DR MalaCards; ATXN2; -. DR MIM; 183090; phenotype. DR MIM; 601517; gene. DR OpenTargets; ENSG00000204842; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 98756; Spinocerebellar ataxia type 2. DR VEuPathDB; HostDB:ENSG00000204842; -. DR eggNOG; KOG2375; Eukaryota. DR GeneTree; ENSGT00940000156812; -. DR InParanoid; Q99700; -. DR OMA; RMQMSAS; -. DR OrthoDB; 2275718at2759; -. DR PAN-GO; Q99700; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q99700; -. DR PathwayCommons; Q99700; -. DR SignaLink; Q99700; -. DR SIGNOR; Q99700; -. DR Agora; ENSG00000204842; -. DR BioGRID-ORCS; 6311; 15 hits in 1159 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR ChiTaRS; ATXN2; human. DR GeneWiki; ATXN2; -. DR GenomeRNAi; 6311; -. DR Pharos; Q99700; Tbio. DR PRO; PR:Q99700; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q99700; protein. DR Bgee; ENSG00000204842; Expressed in buccal mucosa cell and 197 other cell types or tissues. DR ExpressionAtlas; Q99700; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002091; P:negative regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0033962; P:P-body assembly; IMP:UniProtKB. DR GO; GO:0006417; P:regulation of translation; NAS:UniProtKB. DR GO; GO:0016070; P:RNA metabolic process; NAS:UniProtKB. DR GO; GO:0050658; P:RNA transport; NAS:UniProtKB. DR GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB. DR CDD; cd00600; Sm_like; 1. DR IDEAL; IID00580; -. DR InterPro; IPR045117; ATXN2-like. DR InterPro; IPR010920; LSM_dom_sf. DR InterPro; IPR009604; LsmAD_domain. DR InterPro; IPR009818; PAM2_motif. DR InterPro; IPR047575; Sm. DR InterPro; IPR025852; SM_dom_ATX. DR PANTHER; PTHR12854; ATAXIN 2-RELATED; 1. DR PANTHER; PTHR12854:SF11; ATAXIN-2; 1. DR Pfam; PF06741; LsmAD; 1. DR Pfam; PF07145; PAM2; 1. DR Pfam; PF14438; SM-ATX; 1. DR SMART; SM01272; LsmAD; 1. DR SUPFAM; SSF81995; beta-sandwich domain of Sec23/24; 1. DR SUPFAM; SSF50182; Sm-like ribonucleoproteins; 1. DR PROSITE; PS52002; SM; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cytoplasm; Isopeptide bond; Methylation; Neurodegeneration; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Spinocerebellar ataxia; Triplet repeat expansion; Ubl conjugation. FT CHAIN 1..1313 FT /note="Ataxin-2" FT /id="PRO_0000064756" FT DOMAIN 267..344 FT /note="Sm" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01346" FT REGION 1..255 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 459..954 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1137..1219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..12 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 48..65 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 104..114 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 141..154 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 166..187 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 204..234 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 235..244 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 459..471 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 478..492 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 508..544 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 552..562 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 563..581 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 582..598 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 627..637 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 666..681 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 768..777 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 788..804 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 807..820 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 821..844 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 847..871 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 880..891 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 893..910 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 925..936 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1155..1192 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1206..1219 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 248 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 393 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 466 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 640 FT /note="Asymmetric dimethylarginine; alternate" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 640 FT /note="Omega-N-methylarginine; alternate" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 642 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 684 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 728 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 741 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 772 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 784 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 856 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 857 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 861 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692" FT MOD_RES 865 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692" FT MOD_RES 867 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 888 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 889 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 893 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..981 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011574" FT VAR_SEQ 1..265 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057285" FT VAR_SEQ 277..300 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057286" FT VAR_SEQ 980..995 FT /note="PLYPIPMTPMPVNQAK -> YQICPNSGKTSIIRVP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011575" FT VAR_SEQ 982..998 FT /note="YPIPMTPMPVNQAKTYR -> MYYAVEILFNRQSAFFS (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011576" FT VAR_SEQ 996..1313 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011577" FT VAR_SEQ 1106..1124 FT /note="ACPKLPYNKETSPSFYFAI -> V (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057287" FT VAR_SEQ 1106..1123 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011578" FT VAR_SEQ 1124 FT /note="I -> V (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011579" FT VAR_SEQ 1244..1313 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_011582" FT VAR_SEQ 1249..1257 FT /note="AHVQSGMVP -> VIPALANFL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011580" FT VAR_SEQ 1258..1313 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011581" FT VARIANT 107 FT /note="L -> V (in dbSNP:rs695871)" FT /evidence="ECO:0000269|PubMed:8896555, FT ECO:0000269|PubMed:8896557" FT /id="VAR_047629" FT VARIANT 248 FT /note="S -> N (in dbSNP:rs7969300)" FT /id="VAR_047630" FT CONFLICT 188 FT /note="Missing (in Ref. 1; AAB19200 and 6; CAA69589)" FT /evidence="ECO:0000305" SQ SEQUENCE 1313 AA; 140283 MW; 40A2883FF9D5D118 CRC64; MRSAAAAPRS PAVATESRRF AAARWPGWRS LQRPARRSGR GGGGAAPGPY PSAAPPPPGP GPPPSRQSSP PSASDCFGSN GNGGGAFRPG SRRLLGLGGP PRPFVVLLLP LASPGAPPAA PTRASPLGAR ASPPRSGVSL ARPAPGCPRP ACEPVYGPLT MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAV PNMPQQRQDQ HHQSAMMHPA SAAGPPIAAT PPAYSTQYVA YSPQQFPNQP LVQHVPHYQS QHPHVYSPVI QGNARMMAPP THAQPGLVSS SATQYGAHEQ THAMYACPKL PYNKETSPSF YFAISTGSLA QQYAHPNATL HPHTPHPQPS ATPTGQQQSQ HGGSHPAPSP VQHHQHQAAQ ALHLASPQQQ SAIYHAGLAP TPPSMTPASN TQSPQNSFPA AQQTVFTIHP SHVQPAYTNP PHMAHVPQAH VQSGMVPSHP TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM THPSVQAHHQ QQL // ID CMPK2_HUMAN Reviewed; 449 AA. AC Q5EBM0; A2RUB0; A5D8T2; B7ZM18; Q6ZRU2; Q96AL8; DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 147. DE RecName: Full=UMP-CMP kinase 2, mitochondrial; DE EC=2.7.4.14; DE AltName: Full=Nucleoside-diphosphate kinase; DE EC=2.7.4.6; DE Flags: Precursor; GN Name=CMPK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17999954; DOI=10.1074/jbc.m707997200; RA Xu Y., Johansson M., Karlsson A.; RT "Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized RT in mitochondria."; RL J. Biol. Chem. 283:1563-1571(2008). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 9-449 (ISOFORM 1). RC TISSUE=Lymph, and Prostate; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [5] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=23416111; DOI=10.1016/j.biocel.2013.02.004; RA Amiri M., Conserva F., Panayiotou C., Karlsson A., Solaroli N.; RT "The human adenylate kinase 9 is a nucleoside mono- and diphosphate RT kinase."; RL Int. J. Biochem. Cell Biol. 45:925-931(2013). RN [6] RP FUNCTION, AND INDUCTION BY INTERFERON-ALPHA. RX PubMed=30083606; DOI=10.1126/sciadv.aat0843; RA El-Diwany R., Soliman M., Sugawara S., Breitwieser F., Skaist A., RA Coggiano C., Sangal N., Chattergoon M., Bailey J.R., Siliciano R.F., RA Blankson J.N., Ray S.C., Wheelan S.J., Thomas D.L., Balagopal A.; RT "CMPK2 and BCL-G are associated with type 1 interferon-induced HIV RT restriction in humans."; RL Sci. Adv. 4:eaat0843-eaat0843(2018). RN [7] RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=34142025; DOI=10.1016/j.isci.2021.102498; RA Lai J.H., Wu D.W., Wu C.H., Hung L.F., Huang C.Y., Ka S.M., Chen A., RA Chang Z.F., Ho L.J.; RT "Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities RT through IFN-dependent and IFN-independent pathways."; RL IScience 24:102498-102498(2021). RN [8] RP INVOLVEMENT IN IBGC10, VARIANT IBGC10 CYS-414, CHARACTERIZATION OF VARIANT RP IBGC10 CYS-414, AND SUBCELLULAR LOCATION. RX PubMed=36443312; DOI=10.1038/s41421-022-00475-2; RA Zhao M., Su H.Z., Zeng Y.H., Sun Y., Guo X.X., Li Y.L., Wang C., Zhao Z.Y., RA Huang X.J., Lin K.J., Ye Z.L., Lin B.W., Hong S., Zheng J., Liu Y.B., RA Yao X.P., Yang D., Lu Y.Q., Chen H.Z., Zuo E., Yang G., Wang H.T., RA Huang C.W., Lin X.H., Cen Z., Lai L.L., Zhang Y.K., Li X., Lai T., Lin J., RA Zuo D.D., Lin M.T., Liou C.W., Kong Q.X., Yan C.Z., Xiong Z.Q., Wang N., RA Luo W., Zhao C.P., Cheng X., Chen W.J.; RT "Loss of function of CMPK2 causes mitochondria deficiency and brain RT calcification."; RL Cell Discov. 8:128-128(2022). RN [9] RP FUNCTION. RX PubMed=36930652; DOI=10.1371/journal.pbio.3002039; RA Zhu M., Lv J., Wang W., Guo R., Zhong C., Antia A., Zeng Q., Li J., Liu Q., RA Zhou J., Zhu X., Fan B., Ding S., Li B.; RT "CMPK2 is a host restriction factor that inhibits infection of multiple RT coronaviruses in a cell-intrinsic manner."; RL PLoS Biol. 21:e3002039-e3002039(2023). RN [10] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=37075076; DOI=10.1371/journal.ppat.1011286; RA Pawlak J.B., Hsu J.C., Xia H., Han P., Suh H.W., Grove T.L., Morrison J., RA Shi P.Y., Cresswell P., Laurent-Rolle M.; RT "CMPK2 restricts Zika virus replication by inhibiting viral translation."; RL PLoS Pathog. 19:e1011286-e1011286(2023). CC -!- FUNCTION: Mitochondrial nucleotide monophosphate kinase needed for CC salvage dNTP synthesis that mediates immunomodulatory and antiviral CC activities through IFN-dependent and IFN-independent pathways CC (PubMed:17999954, PubMed:30083606, PubMed:36930652, PubMed:37075076). CC Restricts the replication of multiple viruses including flaviviruses or CC coronaviruses (PubMed:30083606, PubMed:36930652, PubMed:37075076). CC Together with viperin/RSAD2 and ddhCTP, suppresses the replication of CC several coronaviruses through inhibition of the viral RNA-dependent RNA CC polymerase activities (PubMed:36930652). Concerning flaviviruses, CC restricts RNA translation when localized to the mitochondria CC independently of its kinase activity (PubMed:37075076). Is able to CC phosphorylate dUMP, dCMP, CMP, UMP and monophosphates of the pyrimidine CC nucleoside analogs ddC, dFdC, araC, BVDU and FdUrd with ATP as CC phosphate donor. Efficacy is highest for dUMP followed by dCMP while CC CMP and UMP are poor substrates. Controls therefore mitochondrial DNA CC synthesis by supplying required deoxyribonucleotides (By similarity). CC CMPK2-dependent mitochondrial DNA synthesis is necessary for the CC production of oxidized mitochondrial DNA fragments after exposure to CC NLRP3 activators (By similarity). In turn, cytosolic oxidized mtDNA CC associates with the NLRP3 inflammasome complex and is required for its CC activation (By similarity). {ECO:0000250|UniProtKB:Q3U5Q7, CC ECO:0000269|PubMed:17999954, ECO:0000269|PubMed:23416111, CC ECO:0000269|PubMed:30083606, ECO:0000269|PubMed:34142025, CC ECO:0000269|PubMed:36930652, ECO:0000269|PubMed:37075076}. CC -!- CATALYTIC ACTIVITY: CC Reaction=CMP + ATP = CDP + ADP; Xref=Rhea:RHEA:11600, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:58069, ChEBI:CHEBI:60377, CC ChEBI:CHEBI:456216; EC=2.7.4.14; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dCMP + ATP = dCDP + ADP; Xref=Rhea:RHEA:25094, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57566, ChEBI:CHEBI:58593, CC ChEBI:CHEBI:456216; EC=2.7.4.14; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-diphosphate + ATP = a 2'- CC deoxyribonucleoside 5'-triphosphate + ADP; Xref=Rhea:RHEA:44640, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61560, ChEBI:CHEBI:73316, CC ChEBI:CHEBI:456216; EC=2.7.4.6; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ribonucleoside 5'-diphosphate + ATP = a ribonucleoside 5'- CC triphosphate + ADP; Xref=Rhea:RHEA:18113, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:61557, ChEBI:CHEBI:456216; EC=2.7.4.6; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=3.09 mM for CMP; CC KM=6.3 mM for UMP; CC KM=1.31 mM for dCMP; CC KM=0.1 mM for dUMP; CC Vmax=1.64 umol/min/mg enzyme towards CMP; CC Vmax=0.19 umol/min/mg enzyme towards UMP; CC Vmax=1.77 umol/min/mg enzyme towards dCMP; CC Vmax=0.48 umol/min/mg enzyme towards dUMP; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:17999954, CC ECO:0000269|PubMed:34142025, ECO:0000269|PubMed:36443312, CC ECO:0000269|PubMed:37075076}. Note=Mitochondrial localization is CC required for its antiviral function. {ECO:0000269|PubMed:37075076}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q5EBM0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q5EBM0-2; Sequence=VSP_033238, VSP_033239; CC Name=3; CC IsoId=Q5EBM0-3; Sequence=VSP_033240; CC Name=4; CC IsoId=Q5EBM0-4; Sequence=VSP_033241; CC -!- TISSUE SPECIFICITY: High levels are observed in myeloid, lymphoid and CC mesenchymal tissues. {ECO:0000269|PubMed:34142025}. CC -!- INDUCTION: By interferon-alpha (PubMed:30083606). IRF1 is crucial for CC the transcriptional activation of CMPK2 (PubMed:36930652). CC {ECO:0000269|PubMed:30083606, ECO:0000269|PubMed:36930652}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 10, autosomal CC recessive (IBGC10) [MIM:621018]: A form of basal ganglia calcification, CC a genetically heterogeneous condition characterized by symmetric CC calcification in the basal ganglia and other brain regions. Affected CC individuals can either be asymptomatic or show a wide spectrum of CC neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, CC ataxia, dementia, psychosis, seizures, and chronic headache. Serum CC levels of calcium, phosphate, alkaline phosphatase and parathyroid CC hormone are normal. The neuropathological hallmark of the disease is CC vascular and pericapillary calcification, mainly of calcium phosphate, CC in the affected brain areas. IBGC10 is a progressive form characterized CC by motor dysfunction, speech impairment, and impaired cognition. CC {ECO:0000269|PubMed:36443312}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the thymidylate kinase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK127983; BAC87217.1; -; mRNA. DR EMBL; BC016969; AAH16969.1; -; mRNA. DR EMBL; BC141802; AAI41803.1; -; mRNA. DR EMBL; BC132821; AAI32822.1; -; mRNA. DR EMBL; BC089425; AAH89425.1; -; mRNA. DR EMBL; BC144202; AAI44203.1; -; mRNA. DR CCDS; CCDS42648.1; -. [Q5EBM0-1] DR CCDS; CCDS58695.1; -. [Q5EBM0-3] DR CCDS; CCDS58696.1; -. [Q5EBM0-4] DR RefSeq; NP_001243406.1; NM_001256477.1. [Q5EBM0-4] DR RefSeq; NP_001243407.1; NM_001256478.1. [Q5EBM0-3] DR RefSeq; NP_997198.2; NM_207315.4. [Q5EBM0-1] DR AlphaFoldDB; Q5EBM0; -. DR SMR; Q5EBM0; -. DR BioGRID; 126200; 1. DR FunCoup; Q5EBM0; 1752. DR STRING; 9606.ENSP00000256722; -. DR iPTMnet; Q5EBM0; -. DR PhosphoSitePlus; Q5EBM0; -. DR BioMuta; CMPK2; -. DR DMDM; 296439392; -. DR jPOST; Q5EBM0; -. DR MassIVE; Q5EBM0; -. DR PaxDb; 9606-ENSP00000256722; -. DR PeptideAtlas; Q5EBM0; -. DR ProteomicsDB; 62766; -. [Q5EBM0-1] DR ProteomicsDB; 62767; -. [Q5EBM0-2] DR ProteomicsDB; 62768; -. [Q5EBM0-3] DR ProteomicsDB; 62769; -. [Q5EBM0-4] DR Pumba; Q5EBM0; -. DR Antibodypedia; 26409; 91 antibodies from 21 providers. DR DNASU; 129607; -. DR Ensembl; ENST00000256722.10; ENSP00000256722.5; ENSG00000134326.12. [Q5EBM0-1] DR Ensembl; ENST00000404168.1; ENSP00000384915.1; ENSG00000134326.12. [Q5EBM0-4] DR Ensembl; ENST00000458098.5; ENSP00000396385.1; ENSG00000134326.12. [Q5EBM0-3] DR GeneID; 129607; -. DR KEGG; hsa:129607; -. DR MANE-Select; ENST00000256722.10; ENSP00000256722.5; NM_207315.4; NP_997198.2. DR UCSC; uc002qyo.5; human. [Q5EBM0-1] DR AGR; HGNC:27015; -. DR ClinPGx; PA162382556; -. DR CTD; 129607; -. DR DisGeNET; 129607; -. DR GeneCards; CMPK2; -. DR HGNC; HGNC:27015; CMPK2. DR HPA; ENSG00000134326; Tissue enhanced (salivary). DR MalaCards; CMPK2; -. DR MIM; 611787; gene. DR MIM; 621018; phenotype. DR OpenTargets; ENSG00000134326; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000134326; -. DR eggNOG; KOG3327; Eukaryota. DR GeneTree; ENSGT00940000154030; -. DR HOGENOM; CLU_049896_0_0_1; -. DR InParanoid; Q5EBM0; -. DR OMA; ECTSLIP; -. DR OrthoDB; 425602at2759; -. DR PAN-GO; Q5EBM0; 9 GO annotations based on evolutionary models. DR PhylomeDB; Q5EBM0; -. DR BRENDA; 2.7.4.14; 2681. DR PathwayCommons; Q5EBM0; -. DR SABIO-RK; Q5EBM0; -. DR Agora; ENSG00000134326; -. DR BioGRID-ORCS; 129607; 17 hits in 1161 CRISPR screens. DR GenomeRNAi; 129607; -. DR Pharos; Q5EBM0; Tbio. DR PRO; PR:Q5EBM0; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q5EBM0; protein. DR Bgee; ENSG00000134326; Expressed in palpebral conjunctiva and 184 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0036430; F:CMP kinase activity; IEA:RHEA. DR GO; GO:0036431; F:dCMP kinase activity; IEA:RHEA. DR GO; GO:0004798; F:dTMP kinase activity; IBA:GO_Central. DR GO; GO:0120136; F:dUMP kinase activity; IEA:Ensembl. DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IDA:UniProtKB. DR GO; GO:0033862; F:UMP kinase activity; IDA:MGI. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0006233; P:dTDP biosynthetic process; IBA:GO_Central. DR GO; GO:0006235; P:dTTP biosynthetic process; IBA:GO_Central. DR GO; GO:0006227; P:dUDP biosynthetic process; IBA:GO_Central. DR FunFam; 3.40.50.300:FF:001133; UMP-CMP kinase 2, mitochondrial; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR039430; Thymidylate_kin-like_dom. DR InterPro; IPR014505; UMP-CMP_kinase_2. DR PANTHER; PTHR10344; THYMIDYLATE KINASE; 1. DR PANTHER; PTHR10344:SF4; UMP-CMP KINASE 2, MITOCHONDRIAL; 1. DR Pfam; PF02223; Thymidylate_kin; 1. DR PIRSF; PIRSF019736; dTMP_TKRP1; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Coiled coil; Kinase; Mitochondrion; KW Nucleotide-binding; Proteomics identification; Pyrimidine biosynthesis; KW Reference proteome; Transferase; Transit peptide. FT TRANSIT 1..98 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 99..449 FT /note="UMP-CMP kinase 2, mitochondrial" FT /id="PRO_0000331524" FT COILED 380..412 FT /evidence="ECO:0000255" FT BINDING 259..266 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT VAR_SEQ 280..303 FT /note="LLKSPPSCIGQWRKIFDDEPTIIR -> PQPITLCTSGQRTCSNLTLSCCSL FT (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_033238" FT VAR_SEQ 304..449 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_033239" FT VAR_SEQ 332..449 FT /note="YWHSTATYAIATEVSGGLQHLPPAHHPVYQWPEDLLKPDLILLLTVSPEERL FT QRLQGRGMEKTREEAELEANSVFRQKVEMSYQRMENPGCHVVDASPSREKVLQTVLSLI FT QNSFSEP -> SQLGGTLYHPSLHLLGSEVCGTGILDSSHSSQGLE (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_033240" FT VAR_SEQ 410..449 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_033241" FT VARIANT 414 FT /note="Y -> C (in IBGC10; uncertain significance; decreased FT protein abundance; no effect on subcellular location; FT dbSNP:rs1322954088)" FT /evidence="ECO:0000269|PubMed:36443312" FT /id="VAR_090198" FT VARIANT 433 FT /note="K -> R (in dbSNP:rs6712141)" FT /id="VAR_055997" FT CONFLICT 448 FT /note="E -> G (in Ref. 3; AAH89425)" FT /evidence="ECO:0000305" SQ SEQUENCE 449 AA; 49448 MW; 99F382E34332B6DE CRC64; MAFARRLLRG PLSGPLLGRR GVCAGAMAPP RRFVLELPDC TLAHFALGAD APGDADAPDP RLAALLGPPE RSYSLCVPVT PDAGCGARVR AARLHQRLLH QLRRGPFQRC QLLRLLCYCP GGQAGGAQQG FLLRDPLDDP DTRQALLELL GACQEAPRPH LGEFEADPRG QLWQRLWEVQ DGRRLQVGCA QVVPVPEPPL HPVVPDLPSS VVFPDREAAR AVLEECTSFI PEARAVLDLV DQCPKQIQKG KFQVVAIEGL DATGKTTVTQ SVADSLKAVL LKSPPSCIGQ WRKIFDDEPT IIRRAFYSLG NYIVASEIAK ESAKSPVIVD RYWHSTATYA IATEVSGGLQ HLPPAHHPVY QWPEDLLKPD LILLLTVSPE ERLQRLQGRG MEKTREEAEL EANSVFRQKV EMSYQRMENP GCHVVDASPS REKVLQTVLS LIQNSFSEP // ID DJC13_HUMAN Reviewed; 2243 AA. AC O75165; Q3L0T1; Q6PI82; Q6UJ77; Q6ZSW1; Q6ZUT5; Q86XG3; Q96DC1; Q9BWK9; DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 5. DT 28-JAN-2026, entry version 193. DE RecName: Full=DnaJ homolog subfamily C member 13; DE AltName: Full=Required for receptor-mediated endocytosis 8; DE Short=RME-8; GN Name=DNAJC13; Synonyms=KIAA0678, RME8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=16179350; DOI=10.1074/jbc.m505036200; RA Girard M., Poupon V., Blondeau F., McPherson P.S.; RT "The DnaJ-domain protein RME-8 functions in endosomal trafficking."; RL J. Biol. Chem. 280:40135-40143(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-1463. RC TISSUE=Brain; RX PubMed=9734811; DOI=10.1093/dnares/5.3.169; RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., RA Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. X. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:169-176(1998). RN [3] RP SEQUENCE REVISION. RC TISSUE=Aortic endothelium; RA Ohara O., Nagase T., Kikuno R., Ishikawa K., Suyama M.; RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-736 AND 1819-2243. RC TISSUE=Cervix, Placenta, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 617-2243, AND VARIANT SER-1463. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 672-1098. RA Chang H.C., Hull M.J., Mellman I.; RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases. RN [8] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=18256511; DOI=10.1247/csf.07045; RA Fujibayashi A., Taguchi T., Misaki R., Ohtani M., Dohmae N., Takio K., RA Yamada M., Gu J., Yamakami M., Fukuda M., Waguri S., Uchiyama Y., RA Yoshimori T., Sekiguchi K.; RT "Human RME-8 is involved in membrane trafficking through early endosomes."; RL Cell Struct. Funct. 33:35-50(2008). RN [9] RP FUNCTION. RX PubMed=18307993; DOI=10.1016/j.febslet.2008.02.042; RA Girard M., McPherson P.S.; RT "RME-8 regulates trafficking of the epidermal growth factor receptor."; RL FEBS Lett. 582:961-966(2008). RN [10] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-84, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP POSSIBLE INVOLVEMENT IN PARK, VARIANT PARK SER-855, VARIANTS GLN-264; RP ILE-1082 AND LEU-2115, AND CHARACTERIZATION OF VARIANT PARK SER-855. RX PubMed=24218364; DOI=10.1093/hmg/ddt570; RA Vilarino-Guell C., Rajput A., Milnerwood A.J., Shah B., Szu-Tu C., RA Trinh J., Yu I., Encarnacion M., Munsie L.N., Tapia L., Gustavsson E.K., RA Chou P., Tatarnikov I., Evans D.M., Pishotta F.T., Volta M., RA Beccano-Kelly D., Thompson C., Lin M.K., Sherman H.E., Han H.J., RA Guenther B.L., Wasserman W.W., Bernard V., Ross C.J., Appel-Cresswell S., RA Stoessl A.J., Robinson C.A., Dickson D.W., Ross O.A., Wszolek Z.K., RA Aasly J.O., Wu R.M., Hentati F., Gibson R.A., McPherson P.S., Girard M., RA Rajput M., Rajput A.H., Farrer M.J.; RT "DNAJC13 mutations in Parkinson disease."; RL Hum. Mol. Genet. 23:1794-1801(2014). RN [13] RP FUNCTION, INTERACTION WITH WASHC2C, AND SUBCELLULAR LOCATION. RX PubMed=24643499; DOI=10.1242/jcs.144659; RA Freeman C.L., Hesketh G., Seaman M.N.; RT "RME-8 coordinates the activity of the WASH complex with the function of RT the retromer SNX dimer to control endosomal tubulation."; RL J. Cell Sci. 127:2053-2070(2014). RN [14] RP POSSIBLE INVOLVEMENT IN PARK, VARIANTS SER-556; ALA-674; LYS-903; PHE-997; RP SER-1135; GLY-1291; HIS-1516; GLN-1740; SER-2057 AND TRP-2170, AND VARIANTS RP PARK LEU-722; SER-855; GLN-1266 AND MET-1895. RX PubMed=25393719; DOI=10.1002/mds.26064; RA Gustavsson E.K., Trinh J., Guella I., Vilarino-Gueell C., RA Appel-Cresswell S., Stoessl A.J., Tsui J.K., McKeown M., Rajput A., RA Rajput A.H., Aasly J.O., Farrer M.J.; RT "DNAJC13 genetic variants in parkinsonism."; RL Mov. Disord. 30:273-278(2015). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP DISCUSSION ON POSSIBLE INVOLVEMENT IN PARK. RX PubMed=27270108; DOI=10.1038/ng.3589; RA Deng H.X., Shi Y., Yang Y., Ahmeti K.B., Miller N., Huang C., Cheng L., RA Zhai H., Deng S., Nuytemans K., Corbett N.J., Kim M.J., Deng H., Tang B., RA Yang Z., Xu Y., Chan P., Huang B., Gao X.P., Song Z., Liu Z., Fecto F., RA Siddique N., Foroud T., Jankovic J., Ghetti B., Nicholson D.A., Krainc D., RA Melen O., Vance J.M., Pericak-Vance M.A., Ma Y.C., Rajput A.H., RA Siddique T.; RT "Identification of TMEM230 mutations in familial Parkinson's disease."; RL Nat. Genet. 48:733-739(2016). CC -!- FUNCTION: Involved in membrane trafficking through early endosomes, CC such as the early endosome to recycling endosome transport implicated CC in the recycling of transferrin and the early endosome to late endosome CC transport implicated in degradation of EGF and EGFR (PubMed:18256511, CC PubMed:18307993). Involved in the regulation of endosomal membrane CC tubulation and regulates the dynamics of SNX1 on the endosomal CC membrane; via association with WASHC2 may link the WASH complex to the CC retromer SNX-BAR subcomplex (PubMed:24643499). CC {ECO:0000269|PubMed:18256511, ECO:0000269|PubMed:18307993, CC ECO:0000269|PubMed:24643499}. CC -!- SUBUNIT: Interacts with WASHC2C; mediates the association with the WASH CC complex (PubMed:24643499). {ECO:0000269|PubMed:24643499}. CC -!- INTERACTION: CC O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338; CC -!- SUBCELLULAR LOCATION: Early endosome {ECO:0000269|PubMed:18256511}. CC Early endosome membrane {ECO:0000305}; Peripheral membrane protein CC {ECO:0000269|PubMed:18256511}. Endosome membrane CC {ECO:0000269|PubMed:24643499}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:24218364, CC ECO:0000269|PubMed:25393719}. Note=The gene represented in this entry CC may be involved in disease pathogenesis. Genetic variants in DNAJC13 CC (PubMed:24218364, PubMed:25393719) and TMEM230 (PubMed:27270108) have CC been found in the same large multigenerational family with adult-onset CC Parkinson disease. The pathological role of each gene and therefore the CC exact molecular basis of the disease is unclear. CC {ECO:0000305|PubMed:27270108}. CC -!- CAUTION: In human, WASHC2 has undergone evolutionary duplication giving CC rise to highly homologous family members. A WASHC2C construct with CC WASHC2A-specific sequence insertions (of 2 aa and 21 aa length CC resulting in a construct length of 1341 aa similar to WASHC2A length) CC has been used to demonstrate the interaction with WASHC2 CC (PubMed:24643499). {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH43583.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305}; CC Sequence=BAA31653.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86133.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86835.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86835.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY779857; AAV41096.1; -; mRNA. DR EMBL; AB014578; BAA31653.2; ALT_INIT; mRNA. DR EMBL; AC020632; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC020633; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC026374; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000164; AAH00164.2; -; mRNA. DR EMBL; BC009630; AAH09630.1; -; mRNA. DR EMBL; BC040638; AAH40638.1; -; mRNA. DR EMBL; BC043583; AAH43583.1; ALT_SEQ; mRNA. DR EMBL; AK125330; BAC86133.1; ALT_INIT; mRNA. DR EMBL; AK127112; BAC86835.1; ALT_SEQ; mRNA. DR EMBL; AY369172; AAQ57271.1; -; mRNA. DR CCDS; CCDS33857.1; -. DR PIR; T00361; T00361. DR RefSeq; NP_056083.3; NM_015268.4. DR RefSeq; XP_047303776.1; XM_047447820.1. DR AlphaFoldDB; O75165; -. DR SMR; O75165; -. DR BioGRID; 116908; 171. DR FunCoup; O75165; 4068. DR IntAct; O75165; 105. DR MINT; O75165; -. DR STRING; 9606.ENSP00000260818; -. DR GlyGen; O75165; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site). DR iPTMnet; O75165; -. DR MetOSite; O75165; -. DR PhosphoSitePlus; O75165; -. DR SwissPalm; O75165; -. DR BioMuta; DNAJC13; -. DR jPOST; O75165; -. DR MassIVE; O75165; -. DR PaxDb; 9606-ENSP00000260818; -. DR PeptideAtlas; O75165; -. DR ProteomicsDB; 49830; -. DR Pumba; O75165; -. DR Antibodypedia; 51566; 43 antibodies from 19 providers. DR Ensembl; ENST00000260818.11; ENSP00000260818.6; ENSG00000138246.17. DR GeneID; 23317; -. DR KEGG; hsa:23317; -. DR MANE-Select; ENST00000260818.11; ENSP00000260818.6; NM_015268.4; NP_056083.3. DR UCSC; uc003eor.4; human. DR AGR; HGNC:30343; -. DR ClinPGx; PA134947358; -. DR CTD; 23317; -. DR DisGeNET; 23317; -. DR GeneCards; DNAJC13; -. DR HGNC; HGNC:30343; DNAJC13. DR HPA; ENSG00000138246; Low tissue specificity. DR MalaCards; DNAJC13; -. DR MIM; 168600; phenotype. DR MIM; 614334; gene. DR OpenTargets; ENSG00000138246; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000138246; -. DR eggNOG; KOG1789; Eukaryota. DR GeneTree; ENSGT00390000017582; -. DR HOGENOM; CLU_001238_1_0_1; -. DR InParanoid; O75165; -. DR OMA; PQTYSIC; -. DR OrthoDB; 69656at2759; -. DR PAN-GO; O75165; 2 GO annotations based on evolutionary models. DR PhylomeDB; O75165; -. DR PathwayCommons; O75165; -. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; O75165; -. DR Agora; ENSG00000138246; -. DR BioGRID-ORCS; 23317; 78 hits in 1161 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DNAJC13; human. DR GeneWiki; DNAJC13; -. DR GenomeRNAi; 23317; -. DR Pharos; O75165; Tbio. DR PRO; PR:O75165; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; O75165; protein. DR Bgee; ENSG00000138246; Expressed in calcaneal tendon and 209 other cell types or tissues. DR ExpressionAtlas; O75165; baseline and differential. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome. DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB. DR GO; GO:0001649; P:osteoblast differentiation; HDA:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0006898; P:receptor-mediated endocytosis; IBA:GO_Central. DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; IMP:UniProtKB. DR GO; GO:1902954; P:regulation of early endosome to recycling endosome transport; IMP:UniProtKB. DR CDD; cd06257; DnaJ; 1. DR FunFam; 1.10.287.110:FF:000007; DnaJ (Hsp40) homolog, subfamily C, member 13; 1. DR FunFam; 1.25.10.10:FF:000133; DnaJ heat shock protein family (Hsp40) member C13; 1. DR FunFam; 1.25.10.10:FF:000072; dnaJ homolog subfamily C member 13 isoform X2; 1. DR Gene3D; 1.10.287.110; DnaJ domain; 1. DR Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 2. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR001623; DnaJ_domain. DR InterPro; IPR044978; GRV2/DNAJC13. DR InterPro; IPR045802; GRV2/DNAJC13_N. DR InterPro; IPR035445; GYF-like_dom_sf. DR InterPro; IPR025640; GYF_2. DR InterPro; IPR036869; J_dom_sf. DR PANTHER; PTHR36983; DNAJ HOMOLOG SUBFAMILY C MEMBER 13; 1. DR PANTHER; PTHR36983:SF2; DNAJ HOMOLOG SUBFAMILY C MEMBER 13; 1. DR Pfam; PF00226; DnaJ; 1. DR Pfam; PF14237; GYF_2; 1. DR Pfam; PF19432; RME-8_N; 1. DR SMART; SM00271; DnaJ; 1. DR SUPFAM; SSF48371; ARM repeat; 3. DR SUPFAM; SSF46565; Chaperone J-domain; 1. DR SUPFAM; SSF55277; GYF domain; 1. DR PROSITE; PS50076; DNAJ_2; 1. PE 1: Evidence at protein level; KW Acetylation; Chaperone; Disease variant; Endosome; Membrane; KW Neurodegeneration; Parkinson disease; Parkinsonism; Protein transport; KW Proteomics identification; Reference proteome; Transport. FT CHAIN 1..2243 FT /note="DnaJ homolog subfamily C member 13" FT /id="PRO_0000071072" FT DOMAIN 1301..1366 FT /note="J" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00286" FT REGION 1..453 FT /note="Involved in membrane association" FT /evidence="ECO:0000269|PubMed:18256511" FT MOD_RES 84 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT VARIANT 264 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073784" FT VARIANT 556 FT /note="L -> S (in dbSNP:rs749000301)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076716" FT VARIANT 674 FT /note="D -> A (in dbSNP:rs199541720)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076717" FT VARIANT 722 FT /note="V -> L (in PARK; uncertain significance; FT dbSNP:rs146930051)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076718" FT VARIANT 855 FT /note="N -> S (in PARK; uncertain significance; affects FT regulation of endosomal membrane trafficking as indicated FT by accumulation of transferrin in endosomal compartments; FT dbSNP:rs387907571)" FT /evidence="ECO:0000269|PubMed:24218364, FT ECO:0000269|PubMed:25393719" FT /id="VAR_073785" FT VARIANT 903 FT /note="R -> K (in dbSNP:rs141952333)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076719" FT VARIANT 997 FT /note="L -> F (in dbSNP:rs752189478)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076720" FT VARIANT 1082 FT /note="T -> I (in dbSNP:rs202127368)" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073786" FT VARIANT 1135 FT /note="N -> S (in dbSNP:rs751747947)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076721" FT VARIANT 1266 FT /note="R -> Q (in PARK; uncertain significance; FT dbSNP:rs766013346)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076722" FT VARIANT 1291 FT /note="E -> G (in dbSNP:rs61748101)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076723" FT VARIANT 1463 FT /note="A -> S (in dbSNP:rs3762672)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:9734811" FT /id="VAR_047458" FT VARIANT 1487 FT /note="F -> C (in dbSNP:rs4405917)" FT /id="VAR_047459" FT VARIANT 1515 FT /note="P -> S (in dbSNP:rs55825559)" FT /id="VAR_061144" FT VARIANT 1516 FT /note="R -> H (in dbSNP:rs139620588)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076724" FT VARIANT 1740 FT /note="E -> Q (in dbSNP:rs142160751)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076725" FT VARIANT 1895 FT /note="T -> M (in PARK; uncertain significance; FT dbSNP:rs145242123)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076726" FT VARIANT 1995 FT /note="V -> I (in dbSNP:rs10935014)" FT /id="VAR_047460" FT VARIANT 2057 FT /note="A -> S (in dbSNP:rs138693725)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076727" FT VARIANT 2115 FT /note="R -> L (in dbSNP:rs770715465)" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073787" FT VARIANT 2170 FT /note="L -> W (in dbSNP:rs140537885)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076728" FT CONFLICT 476 FT /note="D -> E (in Ref. 2; BAA31653)" FT /evidence="ECO:0000305" FT CONFLICT 562 FT /note="N -> D (in Ref. 5; AAH43583)" FT /evidence="ECO:0000305" FT CONFLICT 1097 FT /note="I -> T (in Ref. 6; BAC86133)" FT /evidence="ECO:0000305" FT CONFLICT 1148 FT /note="T -> I (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 1227 FT /note="Q -> H (in Ref. 2; BAA31653)" FT /evidence="ECO:0000305" FT CONFLICT 1230 FT /note="T -> A (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 1269 FT /note="D -> N (in Ref. 6; BAC86133)" FT /evidence="ECO:0000305" FT CONFLICT 2041 FT /note="L -> P (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 2091 FT /note="T -> A (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" SQ SEQUENCE 2243 AA; 254415 MW; C6D292837DE1F170 CRC64; MNIIRENKDL ACFYTTKHSW RGKYKRVFSV GTHAITTYNP NTLEVTNQWP YGDICSISPV GKGQGTEFNL TFRKGSGKKS ETLKFSTEHR TELLTEALRF RTDFSEGKIT GRRYNCYKHH WSDSRKPVIL EVTPGGFDQI NPATNRVLCS YDYRNIEGFV DLSDYQGGFC ILYGGFSRLH LFASEQREEI IKSAIDHAGN YIGISLRIRK EPLEFEQYLN LRFGKYSTDE SITSLAEFVV QKISPRHSEP VKRVLALTET CLVERDPATY NIATLKPLGE VFALVCDSEN PQLFTIEFIK GQVRKYSSTE RDSLLASLLD GVRASGNRDV CVKMTPTHKG QRWGLLSMPV DEEVESLHLR FLATPPNGNF ADAVFRFNAN ISYSGVLHAV TQDGLFSENK EKLINNAITA LLSQEGDVVA SNAELESQFQ AVRRLVASKA GFLAFTQLPK FRERLGVKVV KALKRSNNGI IHAAVDMLCA LMCPMHDDYD LRQEQLNKAS LLSSKKFLEN LLEKFNSHVD HGTGALVISS LLDFLTFALC APYSETTEGQ QFDMLLEMVA SNGRTLFKLF QHPSMAIIKG AGLVMKAIIE EGDKEIATKM QELALSEGAL PRHLHTAMFT ISSDQRMLTN RQLSRHLVGL WTADNATATN LLKRILPPGL LAYLESSDLV PEKDADRMHV RDNVKIAMDQ YGKFNKVPEW QRLAGKAAKE VEKFAKEKVD LVLMHWRDRM GIAQKENINQ KPVVLRKRRQ RIKIEANWDL FYYRFGQDHA RSNLIWNFKT REELKDTLES EMRAFNIDRE LGSANVISWN HHEFEVKYEC LAEEIKIGDY YLRLLLEEDE NEESGSIKRS YEFFNELYHR FLLTPKVNMK CLCLQALAIV YGRCHEEIGP FTDTRYIIGM LERCTDKLER DRLILFLNKL ILNKKNVKDL MDSNGIRILV DLLTLAHLHV SRATVPLQSN VIEAAPDMKR ESEKEWYFGN ADKERSGPYG FHEMQELWTK GMLNAKTRCW AQGMDGWRPL QSIPQLKWCL LASGQAVLNE TDLATLILNM LITMCGYFPS RDQDNAIIRP LPKVKRLLSD STCLPHIIQL LLTFDPILVE KVAILLYHIM QDNPQLPRLY LSGVFFFIMM YTGSNVLPVA RFLKYTHTKQ AFKSEETKGQ DIFQRSILGH ILPEAMVCYL ENYEPEKFSE IFLGEFDTPE AIWSSEMRRL MIEKIAAHLA DFTPRLQSNT RALYQYCPIP IINYPQLENE LFCNIYYLKQ LCDTLRFPDW PIKDPVKLLK DTLDAWKKEV EKKPPMMSID DAYEVLNLPQ GQGPHDESKI RKAYFRLAQK YHPDKNPEGR DMFEKVNKAY EFLCTKSAKI VDGPDPENII LILKTQSILF NRHKEDLQPY KYAGYPMLIR TITMETSDDL LFSKESPLLP AATELAFHTV NCSALNAEEL RRENGLEVLQ EAFSRCVAVL TRASKPSDMS VQVCGYISKC YSVAAQFEEC REKITEMPSI IKDLCRVLYF GKSIPRVAAL GVECVSSFAV DFWLQTHLFQ AGILWYLLGF LFNYDYTLEE SGIQKSEETN QQEVANSLAK LSVHALSRLG GYLAEEQATP ENPTIRKSLA GMLTPYVARK LAVASVTEIL KMLNSNTESP YLIWNNSTRA ELLEFLESQQ ENMIKKGDCD KTYGSEFVYS DHAKELIVGE IFVRVYNEVP TFQLEVPKAF AASLLDYIGS QAQYLHTFMA ITHAAKVESE QHGDRLPRVE MALEALRNVI KYNPGSESEC IGHFKLIFSL LRVHGAGQVQ QLALEVVNIV TSNQDCVNNI AESMVLSSLL ALLHSLPSSR QLVLETLYAL TSSTKIIKEA MAKGALIYLL DMFCNSTHPQ VRAQTAELFA KMTADKLIGP KVRITLMKFL PSVFMDAMRD NPEAAVHIFE GTHENPELIW NDNSRDKVST TVREMMLEHF KNQQDNPEAN WKLPEDFAVV FGEAEGELAV GGVFLRIFIA QPAWVLRKPR EFLIALLEKL TELLEKNNPH GETLETLTMA TVCLFSAQPQ LADQVPPLGH LPKVIQAMNH RNNAIPKSAI RVIHALSENE LCVRAMASLE TIGPLMNGMK KRADTVGLAC EAINRMFQKE QSELVAQALK ADLVPYLLKL LEGIGLENLD SPAATKAQIV KALKAMTRSL QYGEQVNEIL CRSSVWSAFK DQKHDLFISE SQTAGYLTGP GVAGYLTAGT STSVMSNLPP PVDHEAGDLG YQT // ID GBA1_HUMAN Reviewed; 536 AA. AC P04062; A8K796; B7Z5G2; B7Z6S1; J3KQG4; J3KQK9; Q16545; Q4VX22; Q6I9R6; AC Q9UMJ8; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 09-NOV-2004, sequence version 3. DT 28-JAN-2026, entry version 274. DE RecName: Full=Lysosomal acid glucosylceramidase {ECO:0000305}; DE Short=Lysosomal acid GCase {ECO:0000303|PubMed:24211208}; DE EC=3.2.1.45 {ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204, ECO:0000269|PubMed:9201993}; DE AltName: Full=Acid beta-glucosidase; DE AltName: Full=Alglucerase; DE AltName: Full=Beta-glucocerebrosidase; DE Short=Beta-GC; DE AltName: Full=Beta-glucosylceramidase 1; DE AltName: Full=Cholesterol glucosyltransferase {ECO:0000305|PubMed:24211208}; DE Short=SGTase {ECO:0000303|PubMed:24211208}; DE EC=2.4.1.- {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:32144204}; DE AltName: Full=Cholesteryl-beta-glucosidase {ECO:0000305|PubMed:24211208}; DE EC=3.2.1.- {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:32144204}; DE AltName: Full=D-glucosyl-N-acylsphingosine glucohydrolase; DE AltName: Full=Glucosylceramidase beta 1 {ECO:0000312|HGNC:HGNC:4177}; DE AltName: Full=Imiglucerase; DE AltName: Full=Lysosomal cholesterol glycosyltransferase {ECO:0000305}; DE AltName: Full=Lysosomal galactosylceramidase {ECO:0000305}; DE EC=3.2.1.46 {ECO:0000269|PubMed:32144204}; DE AltName: Full=Lysosomal glycosylceramidase {ECO:0000305}; DE Flags: Precursor; GN Name=GBA1 {ECO:0000312|HGNC:HGNC:4177}; Synonyms=GBA, GC, GLUC; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT). RC TISSUE=Placenta; RX PubMed=3864160; DOI=10.1073/pnas.82.21.7289; RA Sorge J., West C., Westwood B., Beutler E.; RT "Molecular cloning and nucleotide sequence of human glucocerebrosidase RT cDNA."; RL Proc. Natl. Acad. Sci. U.S.A. 82:7289-7293(1985). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), AND VARIANT LEU-298. RC TISSUE=Hepatoma; RX PubMed=3001061; DOI=10.1016/s0021-9258(17)42428-8; RA Tsuji S., Choudary P.V., Martin B.M., Winfield S., Barranger J.A., RA Ginns E.I.; RT "Nucleotide sequence of cDNA containing the complete coding sequence for RT human lysosomal glucocerebrosidase."; RL J. Biol. Chem. 261:50-53(1986). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Liver; RX PubMed=2914709; DOI=10.1016/0888-7543(89)90319-4; RA Horowitz M., Wilder S., Horowitz Z., Reiner O., Gelbart T., Beutler E.; RT "The human glucocerebrosidase gene and pseudogene: structure and RT evolution."; RL Genomics 4:87-96(1989). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Liver; RX PubMed=1572652; DOI=10.1016/0888-7543(92)90311-f; RA Beutler E., West C., Gelbart T.; RT "Polymorphisms in the human glucocerebrosidase gene."; RL Genomics 12:795-800(1992). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND 3), VARIANTS GD ARG-223; RP GLY-230; PRO-235; ARG-241; ILE-252 AND ARG-364, AND VARIANTS GLY-310 AND RP HIS-368. RX PubMed=8294033; DOI=10.1016/0378-1119(93)90497-q; RA Imai K., Nakamura M., Yamada M., Asano A., Yokoyama S., Tsuji S., RA Ginns E.I.; RT "A novel transcript from a pseudogene for human glucocerebrosidase in non- RT Gaucher disease cells."; RL Gene 136:365-368(1993). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9331372; DOI=10.1101/gr.7.10.1020; RA Winfield S.L., Tayebi N., Martin B.M., Ginns E.I., Sidransky E.; RT "Identification of three additional genes contiguous to the RT glucocerebrosidase locus on chromosome 1q21: implications for Gaucher RT disease."; RL Genome Res. 7:1020-1026(1997). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG; 4 AND 5), AND RP VARIANT MET-408. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-11. RX PubMed=3359914; DOI=10.1089/dna.1988.7.107; RA Reiner O., Wigderson M., Horowitz M.; RT "Structural analysis of the human glucocerebrosidase genes."; RL DNA 7:107-116(1988). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-45, AND ALTERNATIVE INITIATION. RX PubMed=3687939; RA Sorge J.A., West C., Kuhl W., Treger L., Beutler E.; RT "The human glucocerebrosidase gene has two functional ATG initiator RT codons."; RL Am. J. Hum. Genet. 41:1016-1024(1987). RN [12] RP PROTEIN SEQUENCE OF 40-44, AND CLEAVAGE OF SIGNAL PEPTIDE AFTER GLY-39. RC TISSUE=Placenta; RA Martin B.M., Murray G.J., Coligan J.E., Raum M., Brady R.O., RA Barranger J.A.; RT "Structural studies of human placental glucocerebrosidase."; RL Fed. Proc. 43:1869-1869(1984). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 403-416. RX PubMed=6091633; DOI=10.1016/0006-291x(84)90268-7; RA Ginns E.I., Choudary P.V., Martin B.M., Winfield S., Stubblefield B., RA Mayor J., Merkle-Lehman D., Murray G.J., Bowers L.A., Barranger J.A.; RT "Isolation of cDNA clones for human beta-glucocerebrosidase using the RT lambda gt11 expression system."; RL Biochem. Biophys. Res. Commun. 123:574-580(1984). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 409-462, AND VARIANT GD1 SER-409. RC TISSUE=Skin; RA Tsuji S., Martin B.M., Barranger J.A., Stubblefield B.K., LaMarca M.E., RA Ginns E.I.; RT "Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in RT Ashkenazic and non-Ashkenazic individuals."; RL Proc. Natl. Acad. Sci. U.S.A. 85:2349-2352(1988). RN [15] RP PROTEIN SEQUENCE OF 469-520. RC TISSUE=Placenta; RX PubMed=3456607; DOI=10.1073/pnas.83.6.1660; RA Dinur T., Osiecki K.M., Legler G., Gatt S., Desnick R.J., Grabowski G.A.; RT "Human acid beta-glucosidase: isolation and amino acid sequence of a RT peptide containing the catalytic site."; RL Proc. Natl. Acad. Sci. U.S.A. 83:1660-1664(1986). RN [16] RP TOPOLOGY. RX PubMed=1848227; DOI=10.1016/s0021-9258(19)67728-8; RA Rijnboutt S., Aerts H.M., Geuze H.J., Tager J.M., Strous G.J.; RT "Mannose 6-phosphate-independent membrane association of cathepsin D, RT glucocerebrosidase, and sphingolipid-activating protein in HepG2 cells."; RL J. Biol. Chem. 266:4862-4868(1991). RN [17] RP MUTAGENESIS OF GLU-379, ACTIVE SITE, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=7908905; DOI=10.1016/s0021-9258(19)78077-6; RA Miao S., McCarter J.D., Grace M.E., Grabowski G.A., Aebersold R., RA Withers S.G.; RT "Identification of Glu340 as the active-site nucleophile in human RT glucocerebrosidase by use of electrospray tandem mass spectrometry."; RL J. Biol. Chem. 269:10975-10978(1994). RN [18] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND ACTIVITY REGULATION. RX PubMed=9201993; DOI=10.1074/jbc.272.27.16862; RA Vaccaro A.M., Tatti M., Ciaffoni F., Salvioli R., Barca A., Scerch C.; RT "Effect of saposins A and C on the enzymatic hydrolysis of liposomal RT glucosylceramide."; RL J. Biol. Chem. 272:16862-16867(1997). RN [19] RP INTERACTION WITH SAPOSIN-C, ACTIVITY REGULATION, AND TOPOLOGY. RX PubMed=10781797; DOI=10.1016/s0014-5793(00)01417-4; RA Salvioli R., Tatti M., Ciaffoni F., Vaccaro A.M.; RT "Further studies on the reconstitution of glucosylceramidase activity by RT Sap C and anionic phospholipids."; RL FEBS Lett. 472:17-21(2000). RN [20] RP GLYCOSYLATION AT ASN-98; ASN-185 AND ASN-309. RX PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [21] RP SUBCELLULAR LOCATION, TOPOLOGY, AND INTERACTION WITH SCARB2. RX PubMed=18022370; DOI=10.1016/j.cell.2007.10.018; RA Reczek D., Schwake M., Schroder J., Hughes H., Blanz J., Jin X., RA Brondyk W., Van Patten S., Edmunds T., Saftig P.; RT "LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent RT targeting of beta-glucocerebrosidase."; RL Cell 131:770-783(2007). RN [22] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Placenta; RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x; RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H., RA Elsaesser H.-P., Mann M., Hasilik A.; RT "Integral and associated lysosomal membrane proteins."; RL Traffic 8:1676-1686(2007). RN [23] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=19279011; DOI=10.1074/jbc.m802790200; RA Kitatani K., Sheldon K., Rajagopalan V., Anelli V., Jenkins R.W., Sun Y., RA Grabowski G.A., Obeid L.M., Hannun Y.A.; RT "Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide RT formation."; RL J. Biol. Chem. 284:12972-12978(2009). RN [24] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-98 AND ASN-309. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [25] RP INTERACTION WITH TCP1, CHARACTERIZATION OF VARIANT GD1 SER-409, AND RP CHARACTERIZATION OF VARIANT GD2 SER-409 AND PRO-483. RX PubMed=21098288; DOI=10.1073/pnas.1014376107; RA Lu J., Chiang J., Iyer R.R., Thompson E., Kaneski C.R., Xu D.S., Yang C., RA Chen M., Hodes R.J., Lonser R.R., Brady R.O., Zhuang Z.; RT "Decreased glucocerebrosidase activity in Gaucher disease parallels RT quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl."; RL Proc. Natl. Acad. Sci. U.S.A. 107:21665-21670(2010). RN [26] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, SUBSTRATE RP SPECIFICITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=24211208; DOI=10.1016/j.bbrc.2013.10.145; RA Akiyama H., Kobayashi S., Hirabayashi Y., Murakami-Murofushi K.; RT "Cholesterol glucosylation is catalyzed by transglucosylation reaction of RT beta-glucosidase 1."; RL Biochem. Biophys. Res. Commun. 441:838-843(2013). RN [28] RP INTERACTION WITH SNCA. RX PubMed=23266198; DOI=10.1016/j.ymgme.2012.11.010; RA Yap T.L., Velayati A., Sidransky E., Lee J.C.; RT "Membrane-bound alpha-synuclein interacts with glucocerebrosidase and RT inhibits enzyme activity."; RL Mol. Genet. Metab. 108:56-64(2013). RN [29] RP INTERACTION WITH GRN. RX PubMed=27789271; DOI=10.1016/j.ebiom.2016.10.010; RA Jian J., Tian Q.Y., Hettinghouse A., Zhao S., Liu H., Wei J., Grunig G., RA Zhang W., Setchell K.D.R., Sun Y., Overkleeft H.S., Chan G.L., Liu C.J.; RT "Progranulin Recruits HSP70 to beta-Glucocerebrosidase and Is Therapeutic RT Against Gaucher Disease."; RL EBioMedicine 13:212-224(2016). RN [30] RP FUNCTION. RX PubMed=27378698; DOI=10.1093/hmg/ddw185; RA Magalhaes J., Gegg M.E., Migdalska-Richards A., Doherty M.K., RA Whitfield P.D., Schapira A.H.; RT "Autophagic lysosome reformation dysfunction in glucocerebrosidase RT deficient cells: relevance to Parkinson disease."; RL Hum. Mol. Genet. 25:3432-3445(2016). RN [31] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND ACTIVITY REGULATION. RX PubMed=26724485; DOI=10.1194/jlr.m064923; RA Marques A.R., Mirzaian M., Akiyama H., Wisse P., Ferraz M.J., Gaspar P., RA Ghauharali-van der Vlugt K., Meijer R., Giraldo P., Alfonso P., Irun P., RA Dahl M., Karlsson S., Pavlova E.V., Cox T.M., Scheij S., Verhoek M., RA Ottenhoff R., van Roomen C.P., Pannu N.S., van Eijk M., Dekker N., RA Boot R.G., Overkleeft H.S., Blommaart E., Hirabayashi Y., Aerts J.M.; RT "Glucosylated cholesterol in mammalian cells and tissues: formation and RT degradation by multiple cellular beta-glucosidases."; RL J. Lipid Res. 57:451-463(2016). RN [32] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=32144204; DOI=10.1074/jbc.ra119.012502; RA Akiyama H., Ide M., Nagatsuka Y., Sayano T., Nakanishi E., Uemura N., RA Yuyama K., Yamaguchi Y., Kamiguchi H., Takahashi R., Aerts J.M.F.G., RA Greimel P., Hirabayashi Y.; RT "Glucocerebrosidases catalyze a transgalactosylation reaction that yields a RT newly-identified brain sterol metabolite, galactosylated cholesterol."; RL J. Biol. Chem. 295:5257-5277(2020). RN [33] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=33361282; DOI=10.1194/jlr.ra120001043; RA Boer D.E., Mirzaian M., Ferraz M.J., Zwiers K.C., Baks M.V., Hazeu M.D., RA Ottenhoff R., Marques A.R.A., Meijer R., Roos J.C.P., Cox T.M., Boot R.G., RA Pannu N., Overkleeft H.S., Artola M., Aerts J.M.; RT "Human glucocerebrosidase mediates formation of xylosyl-cholesterol by RT beta-xylosidase and transxylosidase reactions."; RL J. Lipid Res. 62:100018-100018(2021). RN [34] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=39395789; DOI=10.1016/j.jlr.2024.100670; RA Bannink S., Bila K.O., van Weperen J., Ligthart N.A.M., Ferraz M.J., RA Boot R.G., van der Vliet D., Boer D.E.C., Overkleeft H.S., Artola M., RA Aerts J.M.F.G.; RT "6-O-alkyl 4-methylumbelliferyl-beta-D-glucosides as selective substrates RT for GBA1 in the discovery of glycosylated sterols."; RL J. Lipid Res. 65:100670-100670(2024). RN [35] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 40-536, GLYCOSYLATION AT ASN-58, RP AND DISULFIDE BONDS. RX PubMed=12792654; DOI=10.1038/sj.embor.embor873; RA Dvir H., Harel M., McCarthy A.A., Toker L., Silman I., Futerman A.H., RA Sussman J.L.; RT "X-ray structure of human acid-beta-glucosidase, the defective enzyme in RT Gaucher disease."; RL EMBO Rep. 4:704-709(2003). RN [36] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 40-536 IN COMPLEX WITH SYNTHETIC RP INHIBITOR, AND ACTIVE SITE. RX PubMed=15817452; DOI=10.1074/jbc.m502799200; RA Premkumar L., Sawkar A.R., Boldin-Adamsky S., Toker L., Silman I., RA Kelly J.W., Futerman A.H., Sussman J.L.; RT "X-ray structure of human acid-beta-glucosidase covalently bound to RT conduritol-B-epoxide. Implications for Gaucher disease."; RL J. Biol. Chem. 280:23815-23819(2005). RN [37] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 40-536, CATALYTIC ACTIVITY, RP PATHWAY, CHARACTERIZATION OF VARIANTS GD SER-55; GLN-87; ASN-118; LEU-161; RP VAL-162; VAL-166; ASN-200; PHE-213; PHE-224; GLU-232; GLU-237; LEU-298; RP ILE-303; CYS-343; ILE-362; LYS-365; GLY-381; LYS-388; TRP-392; CYS-402; RP SER-409; VAL-410; HIS-419; LYS-421; ARG-429; LEU-433; SER-436; ASN-438; RP HIS-448; VAL-455; PRO-483; PRO-500; CYS-502 AND PRO-502, CHARACTERIZATION RP OF VARIANT GD2 GLN-159, AND MUTAGENESIS OF CYS-43; CYS-57 AND CYS-62. RX PubMed=16293621; DOI=10.1074/jbc.m511110200; RA Liou B., Kazimierczuk A., Zhang M., Scott C.R., Hegde R.S., Grabowski G.A.; RT "Analyses of variant acid beta-glucosidases: effects of Gaucher disease RT mutations."; RL J. Biol. Chem. 281:4242-4253(2006). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 40-536, AND GLYCOSYLATION AT RP ASN-58; ASN-98 AND ASN-185. RX PubMed=17139081; DOI=10.1107/s0907444906038303; RA Brumshtein B., Wormald M.R., Silman I., Futerman A.H., Sussman J.L.; RT "Structural comparison of differently glycosylated forms of acid-beta- RT glucosidase, the defective enzyme in Gaucher disease."; RL Acta Crystallogr. D 62:1458-1465(2006). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 40-536 IN COMPLEXES WITH RP ISOFAGOMINE, AND SUBCELLULAR LOCATION. RX PubMed=17187079; DOI=10.1038/nchembio850; RA Lieberman R.L., Wustman B.A., Huertas P., Powe A.C. Jr., Pine C.W., RA Khanna R., Schlossmacher M.G., Ringe D., Petsko G.A.; RT "Structure of acid beta-glucosidase with pharmacological chaperone provides RT insight into Gaucher disease."; RL Nat. Chem. Biol. 3:101-107(2007). RN [40] RP REVIEW ON GD VARIANTS. RX PubMed=8118460; DOI=10.1002/humu.1380030102; RA Horowitz M., Zimran A.; RT "Mutations causing Gaucher disease."; RL Hum. Mutat. 3:1-11(1994). RN [41] RP REVIEW ON GD VARIANTS. RX PubMed=8889578; RX DOI=10.1002/(sici)1098-1004(1996)8:3<207::aid-humu2>3.0.co;2-6; RA Beutler E., Gelbart T.; RT "Glucocerebrosidase (Gaucher disease)."; RL Hum. Mutat. 8:207-213(1996). RN [42] RP REVIEW ON GD VARIANTS. RX PubMed=10527671; DOI=10.1006/mgme.1999.2918; RA Tayebi N., Stone D.L., Sidransky E.; RT "Type 2 Gaucher disease: an expanding phenotype."; RL Mol. Genet. Metab. 68:209-219(1999). RN [43] RP VARIANTS GD2 ARG-454 AND PRO-483, AND CHARACTERIZATION OF VARIANTS GD2 RP ARG-454 AND PRO-483. RX PubMed=2464926; RA Wigderson M., Firon N., Horowitz Z., Wilder S., Frishberg Y., Reiner O., RA Horowitz M.; RT "Characterization of mutations in Gaucher patients by cDNA cloning."; RL Am. J. Hum. Genet. 44:365-377(1989). RN [44] RP VARIANTS GD1 LEU-433 AND HIS-448, AND VARIANTS GD3 LEU-433; HIS-448 AND RP VAL-448. RX PubMed=2508065; DOI=10.1093/nar/17.19.7707; RA Theophilus B.D., Latham T., Grabowski G.A., Smith F.I.; RT "Comparison of RNase A, a chemical cleavage and GC-clamped denaturing RT gradient gel electrophoresis for the detection of mutations in exon 9 of RT the human acid beta-glucosidase gene."; RL Nucleic Acids Res. 17:7707-7722(1989). RN [45] RP VARIANT GD TYR-255. RX PubMed=1974409; DOI=10.1111/j.1469-1809.1990.tb00371.x; RA Beutler E., Gelbart T.; RT "Gaucher disease associated with a unique KpnI restriction site: RT identification of the amino-acid substitution."; RL Ann. Hum. Genet. 54:149-153(1990). RN [46] RP VARIANT GD CYS-502, AND CHARACTERIZATION OF VARIANT GD CYS-502. RX PubMed=1972019; DOI=10.1089/dna.1990.9.233; RA Hong C.M., Ohashi T., Yu X.J., Weiler S., Barranger J.A.; RT "Sequence of two alleles responsible for Gaucher disease."; RL DNA Cell Biol. 9:233-241(1990). RN [47] RP VARIANTS GD2 ARG-364 AND GLY-381, AND VARIANT GD1 HIS-448. RX PubMed=2269438; DOI=10.1016/0378-1119(90)90264-r; RA Eyal N., Wilder S., Horowitz M.; RT "Prevalent and rare mutations among Gaucher patients."; RL Gene 96:277-283(1990). RN [48] RP VARIANTS GD1 GLN-196; VAL-348; CYS-351 AND THR-403. RX PubMed=1899336; DOI=10.1089/dna.1991.10.15; RA Latham T.E., Theophilus B.D., Grabowski G.A., Smith F.I.; RT "Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher RT disease patients."; RL DNA Cell Biol. 10:15-21(1991). RN [49] RP VARIANTS GD1 HIS-179; GLN-196 AND LYS-365. RX PubMed=1864608; DOI=10.1007/bf00200914; RA Eyal N., Firon N., Wilder S., Kolodny E.H., Horowitz M.; RT "Three unique base pair changes in a family with Gaucher disease."; RL Hum. Genet. 87:328-332(1991). RN [50] RP VARIANTS GD1 GLN-398 AND CYS-535, AND VARIANT GD3 GLU-464. RX PubMed=1487244; DOI=10.1007/bf00220082; RA Kawame H., Hasegawa Y., Eto Y., Maekawa K.; RT "Rapid identification of mutations in the glucocerebrosidase gene of RT Gaucher disease patients by analysis of single-strand conformation RT polymorphisms."; RL Hum. Genet. 90:294-296(1992). RN [51] RP VARIANTS GD1 ILE-252; LEU-328; ILE-362 AND CYS-502, AND CHARACTERIZATION OF RP VARIANTS GD1 LEU-328; ILE-362 AND CYS-502. RX PubMed=1301953; DOI=10.1002/humu.1380010513; RA He G.S., Grace M.E., Grabowski G.A.; RT "Gaucher disease: four rare alleles encoding F213I, P289L, T323I, and R463C RT in type 1 variants."; RL Hum. Mutat. 1:423-427(1992). RN [52] RP VARIANTS GD HIS-251 AND SER-517, AND VARIANTS GD1 SER-161 AND HIS-535. RX PubMed=8432537; DOI=10.1006/geno.1993.1035; RA Beutler E., Gelbart T., West C.; RT "Identification of six new Gaucher disease mutations."; RL Genomics 15:203-205(1993). RN [53] RP VARIANT GD1 HIS-535. RX PubMed=7916532; DOI=10.1002/ajmg.1320510216; RA Choy F.Y.M., Wei C., Applegarth D.A., McGillivray B.C.; RT "DNA analysis of an uncommon missense mutation in a Gaucher disease patient RT of Jewish-Polish-Russian descent."; RL Am. J. Med. Genet. 51:156-160(1994). RN [54] RP VARIANT GD2 ASN-438. RX PubMed=8112750; DOI=10.1007/bf00210614; RA Beutler E., Gelbart T.; RT "Two new Gaucher disease mutations."; RL Hum. Genet. 93:209-210(1994). RN [55] RP VARIANTS GD SER-409 AND CYS-457. RX PubMed=8076951; DOI=10.1007/bf00208292; RA Tuteja R., Tuteja N., Lilliu F., Bembi B., Galanello R., Cao A., RA Baralle F.E.; RT "Y418C: a novel mutation in exon 9 of the glucocerebrosidase gene of a RT patient with Gaucher disease creates a new Bgl I site."; RL Hum. Genet. 94:314-315(1994). RN [56] RP VARIANTS GD1 SER-409 AND VAL-456. RX PubMed=7915932; DOI=10.1093/hmg/3.5.821; RA Choy F.Y., Wei C., Applegarth D.A., Yong S.L.; RT "A new missense mutation in glucocerebrosidase exon 9 of a non-Jewish RT Caucasian type 1 Gaucher disease patient."; RL Hum. Mol. Genet. 3:821-823(1994). RN [57] RP VARIANT GD2 ARG-483. RX PubMed=7981693; DOI=10.1093/hmg/3.7.1183; RA Uchiyama A., Tomatsu S., Kondo N., Suzuki Y., Shimozawa N., Fukuda S., RA Sukegawa K., Taki N., Inamori H., Orii T.; RT "New Gaucher disease mutations in exon 10: a novel L444R mutation produces RT a new NciI site the same as L444P."; RL Hum. Mol. Genet. 3:1183-1184(1994). RN [58] RP CHARACTERIZATION OF VARIANT GD TYR-255, CHARACTERIZATION OF VARIANTS GD1 RP LEU-328; ILE-362; THR-403; SER-409; LEU-433; HIS-448; PRO-483; PRO-495 AND RP CYS-502, CHARACTERIZATION OF VARIANT GD2 ARG-454, CHARACTERIZATION OF RP VARIANT GD3 VAL-448, AND MUTAGENESIS OF ASP-482 AND ASN-501. RX PubMed=8294487; DOI=10.1016/s0021-9258(17)42166-1; RA Grace M.E., Newman K.M., Scheinker V., Berg-Fussman A., Grabowski G.A.; RT "Analysis of human acid beta-glucosidase by site-directed mutagenesis and RT heterologous expression."; RL J. Biol. Chem. 269:2283-2291(1994). RN [59] RP VARIANTS GD1 ASP-215; THR-221; ARG-241; GLN-296; CYS-324; GLY-417 AND RP ASN-419. RX PubMed=8790604; DOI=10.1007/bf03403534; RA Beutler E., Demina A., Gelbart T.; RT "Glucocerebrosidase mutations in Gaucher disease."; RL Mol. Med. 1:82-92(1994). RN [60] RP VARIANTS GD1 ILE-82 AND TRP-87. RX PubMed=7655857; DOI=10.1006/bcmd.1995.0004; RA Beutler E., Gelbart T., Demina A., Zimran A., LeCoutre P.; RT "Five new Gaucher disease mutations."; RL Blood Cells Mol. Dis. 21:20-24(1995). RN [61] RP VARIANTS GD1 ARG-305; HIS-354 AND ASP-357. RX PubMed=8547070; DOI=10.1111/j.1365-2141.1995.tb05298.x; RA Walley A.J., Ellis I., Harris A.; RT "Three unrelated Gaucher's disease patients with three novel point RT mutations in the glucocerebrosidase gene (P266R, D315H and A318D)."; RL Br. J. Haematol. 91:330-332(1995). RN [62] RP VARIANTS GD SER-409; HIS-448; PRO-483 AND CYS-502. RX PubMed=7627184; DOI=10.1002/humu.1380050406; RA Cormand B., Vilageliu L., Burguera J.M., Balcells S., Gonzalez-Duarte R., RA Grinberg D., Chabas A.; RT "Gaucher disease in Spanish patients: analysis of eight mutations."; RL Hum. Mutat. 5:303-309(1995). RN [63] RP VARIANT GD2 SER-217. RX PubMed=7627192; DOI=10.1002/humu.1380050414; RA Choy F.Y.M., Wei C.; RT "Identification of a new mutation (P178S) in an African-American patient RT with type 2 Gaucher disease."; RL Hum. Mutat. 5:345-347(1995). RN [64] RP VARIANTS GD1 SER-409 AND PRO-483, VARIANTS GD2 HIS-448; PRO-483 AND RP CYS-502, AND VARIANTS GD3 HIS-448 AND PRO-483. RX PubMed=8598642; DOI=10.1007/bf02436006; RA Michelakakis H., Dimitriou E., Van Weely S., Boot R.G., Mavridou I., RA Verhoek M., Aerts J.M.; RT "Characterization of glucocerebrosidase in Greek Gaucher disease patients: RT mutation analysis and biochemical studies."; RL J. Inherit. Metab. Dis. 18:609-615(1995). RN [65] RP VARIANT GD HIS-448. RX PubMed=7475546; DOI=10.1016/s0140-6736(95)91688-1; RA Abrahamov A., Elstein D., Gross-Tsur V., Farber B., Glaser Y., RA Hadas-Halpern I., Ronen S., Tafakjdi M., Horowitz M., Zimran A.; RT "Gaucher's disease variant characterised by progressive calcification of RT heart valves and unique genotype."; RL Lancet 346:1000-1003(1995). RN [66] RP CHARACTERIZATION OF VARIANTS GD1 SER-409; VAL-456 AND HIS-535, AND RP CHARACTERIZATION OF VARIANT GD2 PRO-483. RX PubMed=9240741; RX DOI=10.1002/(sici)1096-8628(19961028)65:3<184::aid-ajmg3>3.0.co;2-q; RA Choy F.Y., Wei C., Levin D.; RT "Gaucher disease: functional expression of the normal glucocerebrosidase RT and Gaucher T1366G and G1604A alleles in Baculovirus-transfected Spodoptera RT frugiperda cells."; RL Am. J. Med. Genet. 65:184-189(1996). RN [67] RP VARIANTS GD SER-409; LEU-426; LEU-433 AND PRO-483. RX PubMed=8937765; DOI=10.1111/j.1399-0004.1996.tb02352.x; RA Morar B., Lane A.B.; RT "The molecular characterization of Gaucher disease in South Africa."; RL Clin. Genet. 50:78-84(1996). RN [68] RP VARIANTS GD LEU-54; GLU-85 AND SER-227. RX PubMed=8829654; RX DOI=10.1002/(sici)1098-1004(1996)7:3<214::aid-humu5>3.0.co;2-a; RA Kim J.-W., Liou B.B., Lai M.-Y., Ponce E., Grabowski G.A.; RT "Gaucher disease: identification of three new mutations in the Korean and RT Chinese (Taiwanese) populations."; RL Hum. Mutat. 7:214-218(1996). RN [69] RP VARIANTS GD HIS-352 AND GLN-398. RX PubMed=8829663; RX DOI=10.1002/(sici)1098-1004(1996)7:3<272::aid-humu14>3.0.co;2-#; RA Cormand B., Vilageliu L., Balcells S., Gonzalez-Duatre R., Chabas A., RA Grinberg D.; RT "Two novel (1098insA and Y313H) and one rare (R359Q) mutations detected in RT exon 8 of the beta-glucocerebrosidase gene in Gaucher's disease patients."; RL Hum. Mutat. 7:272-274(1996). RN [70] RP VARIANT GD1 THR-435. RX PubMed=8889591; RX DOI=10.1002/(sici)1098-1004(1996)8:3<280::aid-humu15>3.0.co;2-z; RA Amaral O., Pinto E., Fortuna M., Lacerda L., Sa Miranda M.C.; RT "Type 1 Gaucher disease: identification of N396T and prevalence of RT glucocerebrosidase mutations in the Portuguese."; RL Hum. Mutat. 8:280-281(1996). RN [71] RP VARIANTS GD3 LEU-437 AND ILE-530. RX PubMed=8780099; DOI=10.1212/wnl.46.4.1102; RA Seeman P.J.V., Finckh U., Hoeppner J., Lakner V., Liebisch I., Grau G., RA Rolfs A.; RT "Two new missense mutations in a non-Jewish Caucasian family with type 3 RT Gaucher disease."; RL Neurology 46:1102-1107(1996). RN [72] RP VARIANTS GD LEU-414 AND THR-441. RX PubMed=9182788; RX DOI=10.1002/(sici)1096-8628(19970627)70:4<437::aid-ajmg19>3.0.co;2-i; RA Cormand B., Grinberg D., Gort L., Fiumara A., Barone R., Vilageliu L., RA Chabas A.; RT "Two new mild homozygous mutations in Gaucher disease patients: clinical RT signs and biochemical analyses."; RL Am. J. Med. Genet. 70:437-443(1997). RN [73] RP VARIANTS GD VAL-76; GLU-85; TRP-87; TRP-159; SER-227; ILE-252 AND PRO-483. RX PubMed=9217217; RX DOI=10.1002/(sici)1096-8628(19970808)71:2<172::aid-ajmg10>3.0.co;2-b; RA Choy F.Y.M., Humphries M.L., Shi H.; RT "Identification of two novel and four uncommon missense mutations among RT Chinese Gaucher disease patients."; RL Am. J. Med. Genet. 71:172-178(1997). RN [74] RP VARIANT GD1 TRP-87. RX PubMed=9295080; RX DOI=10.1002/(sici)1096-8628(19971003)72:1<77::aid-ajmg16>3.0.co;2-r; RA Rockah R., Narinsky R., Hatskelzon L., Frisch A.; RT "Type I Gaucher disease due to homozygosity for the 259T mutation in a RT Bedouin patient."; RL Am. J. Med. Genet. 72:77-78(1997). RN [75] RP VARIANT GD2 LYS-501. RX PubMed=9279145; DOI=10.1136/adc.77.1.17; RA Hatton C.E., Cooper A., Whitehouse C., Wraith J.E.; RT "Mutation analysis in 46 British and Irish patients with Gaucher's RT disease."; RL Arch. Dis. Child. 77:17-22(1997). RN [76] RP VARIANTS GD1 TRP-87; GLU-234; ASN-310; LEU-391 AND SER-409, VARIANTS GD2 RP ARG-241 AND ILE-252, CHARACTERIZATION OF VARIANTS GD1 TRP-87; GLU-234; RP ASN-310; LEU-391 AND SER-409, AND CHARACTERIZATION OF VARIANT GD2 ARG-241. RX PubMed=9153297; DOI=10.1172/jci119437; RA Grace M.E., Desnick R.J., Pastores G.M.; RT "Identification and expression of acid beta-glucosidase mutations causing RT severe type 1 and neurologic type 2 Gaucher disease in non-Jewish RT patients."; RL J. Clin. Invest. 99:2530-2537(1997). RN [77] RP VARIANTS GD VAL-228; ILE-252; GLY-405; HIS-448; GLN-452; PRO-483 AND RP CYS-535. RX PubMed=9061570; DOI=10.1023/a:1005313724361; RA Ida H., Rennert O.M., Kawame H., Maekawa K., Eto Y.; RT "Mutation prevalence among 47 unrelated Japanese patients with Gaucher RT disease: identification of four novel mutations."; RL J. Inherit. Metab. Dis. 20:67-73(1997). RN [78] RP VARIANT GD3C HIS-448. RX PubMed=9040001; DOI=10.1136/jmg.34.2.175; RA Uyama E., Uchino M., Ida H., Eto Y., Owada M.; RT "D409H/D409H genotype in Gaucher-like disease."; RL J. Med. Genet. 34:175-175(1997). RN [79] RP VARIANTS GD LEU-198; THR-380; ASN-405 AND ARG-432, AND VARIANT GD2 LEU-146. RX PubMed=9554454; DOI=10.1159/000040815; RA Demina A., Beutler E.; RT "Six new Gaucher disease mutations."; RL Acta Haematol. 99:80-82(1998). RN [80] RP VARIANTS GD1 TRP-87; THR-158; TRP-159; PRO-209; LYS-227; PRO-276; ILE-342; RP PRO-363; SER-409; SER-416; PRO-483; PRO-485 AND CYS-502, AND VARIANTS GD3 RP LEU-433 AND PRO-483. RX PubMed=9683600; DOI=10.1086/301969; RA Germain D.P., Puech J.-P., Caillaud C., Kahn A., Poenaru L.; RT "Exhaustive screening of the acid beta-glucosidase gene, by fluorescence- RT assisted mismatch analysis using universal primers: mutation profile and RT genotype/phenotype correlations in Gaucher disease."; RL Am. J. Hum. Genet. 63:415-427(1998). RN [81] RP VARIANT GD2 TYR-513. RX PubMed=9637431; RX DOI=10.1002/(sici)1096-8628(19980616)78:1<92::aid-ajmg19>3.3.co;2-8; RA Choy F.Y.M., Humphries M.L., Ben-Yoseph Y.; RT "Gaucher type 2 disease: identification of a novel transversion mutation in RT a French-Irish patient."; RL Am. J. Med. Genet. 78:92-93(1998). RN [82] RP VARIANTS GD1 TRP-87; TRP-159; SER-200; ARG-241; ASP-304; CYS-324; SER-409; RP ASN-438; ILE-450 AND PRO-483, AND VARIANT GD2 HIS-448. RX PubMed=9856561; RX DOI=10.1002/(sici)1096-8628(19981204)80:4<343::aid-ajmg8>3.0.co;2-w; RA Cormand B., Harboe T.L., Gort L., Campoy C., Blanco M., Chamoles N., RA Chabas A., Vilageliu L., Grinberg D.; RT "Mutation analysis of Gaucher disease patients from Argentina: high RT prevalence of the RecNciI mutation."; RL Am. J. Med. Genet. 80:343-351(1998). RN [83] RP VARIANTS GD. RX PubMed=9516376; DOI=10.1006/bcmd.1998.0165; RA Beutler E., Gelbart T.; RT "Hematologically important mutations: Gaucher disease."; RL Blood Cells Mol. Dis. 24:2-8(1998). RN [84] RP VARIANTS GD2 LYS-80; CYS-170 AND PRO-483. RX PubMed=9851895; DOI=10.1006/bcmd.1998.0210; RA Sinclair G., Choy F.Y.M., Humphries L.; RT "A novel complex allele and two new point mutations in type 2 (acute RT neuronopathic) Gaucher disease."; RL Blood Cells Mol. Dis. 24:420-427(1998). RN [85] RP VARIANT GD GLY-392. RX PubMed=9650766; DOI=10.1111/j.1399-0004.1998.tb02697.x; RA Parenti G., Filocamo M., Titomanlio L., Rizzolo G., Silvestro E., RA Perretti A., Gatti R., Andria G.; RT "A novel mutation of the beta-glucocerebrosidase gene associated with RT neurologic manifestations in three sibs."; RL Clin. Genet. 53:281-285(1998). RN [86] RP VARIANTS GD1 GLU-152; PRO-173; LEU-430 AND HIS-451, AND VARIANTS GD2 RP GLU-428 AND ILE-431. RX PubMed=9554746; RX DOI=10.1002/(sici)1098-1004(1998)11:4<295::aid-humu7>3.0.co;2-6; RA Cormand B., Grinberg D., Gort L., Chabas A., Vilageliu L.; RT "Molecular analysis and clinical findings in the Spanish Gaucher disease RT population: putative haplotype of the N370S ancestral chromosome."; RL Hum. Mutat. 11:295-305(1998). RN [87] RP VARIANTS GD1 GLY-230 AND SER-409. RX PubMed=10206680; RX DOI=10.1002/(sici)1098-1004(1998)11:5<411::aid-humu11>3.0.co;2-2; RA Choy F.Y.M., Humphries M.L., Ben-Yoseph Y.; RT "A novel mutation (V191G) in a German-British type 1 Gaucher disease RT patient."; RL Hum. Mutat. 11:411-412(1998). RN [88] RP VARIANTS GD1 SER-409 AND LEU-440. RX PubMed=10340647; RX DOI=10.1002/(sici)1096-8628(19990604)84:4<334::aid-ajmg5>3.3.co;2-g; RA Wasserstein M.P., Martignetti J.A., Zeitlin R., Lumerman H., Solomon M., RA Grace M.E., Desnick R.J.; RT "Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: RT identification and expression of a novel acid beta-glucosidase mutation."; RL Am. J. Med. Genet. 84:334-339(1999). RN [89] RP VARIANT GD1 CYS-244, VARIANTS GD2 ILE-252 AND PRO-483, AND VARIANTS GD3 RP ARG-241; HIS-448 AND PRO-483. RX PubMed=10360404; RX DOI=10.1002/(sici)1096-8628(19990611)84:5<484::aid-ajmg14>3.0.co;2-w; RA Choy F.Y.M., Wong K., Shi H.P.; RT "Glucocerebrosidase mutations among Chinese neuronopathic and non- RT neuronopathic Gaucher disease patients."; RL Am. J. Med. Genet. 84:484-486(1999). RN [90] RP VARIANTS GD. RX PubMed=10744424; RA Hodanov K., Hrebicek M., Cervenkov M., Mrzov L., Veprekov L., Zemen J.; RT "Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher RT patients: mutation profile and description of six novel mutant alleles."; RL Blood Cells Mol. Dis. 25:287-298(1999). RN [91] RP VARIANTS GDPL ARG-350 AND PHE-437. RX PubMed=10352942; DOI=10.1038/sj.ejhg.5200315; RA Stone D.L., van Diggelen O.P., de Klerk J.B.C., Gaillard J.L.J., RA Niermeijer M.F., Willemsen R., Tayebi N., Sidransky E.; RT "Is the perinatal lethal form of Gaucher disease more common than classic RT type 2 Gaucher disease?"; RL Eur. J. Hum. Genet. 7:505-509(1999). RN [92] RP VARIANTS GD PRO-173; TRP-234; SER-409; SER-416; HIS-448 AND PRO-483. RX PubMed=10447266; RX DOI=10.1002/(sici)1098-1004(1999)14:1<88::aid-humu16>3.0.co;2-e; RA Sarria A.J., Giraldo P., Perez-Calvo J.I., Pocovi M.; RT "Detection of three rare (G377S, T134P and 1451delAC), and two novel RT mutations (G195W and Rec[1263del55;1342G>C]] in Spanish Gaucher disease RT patients."; RL Hum. Mutat. 14:88-88(1999). RN [93] RP VARIANTS GD1 TRP-87; ASN-118; THR-129; ASP-156; GLN-159; TRP-159; LEU-170; RP ILE-173; CYS-209; PRO-209; SER-227; PRO-235; ARG-241; ILE-252; GLN-296; RP CYS-324; LYS-365; THR-380; MET-408; SER-409; SER-416; LEU-433; TYR-438; RP HIS-448; PRO-483 AND CYS-502, VARIANT GD2 GLN-159, AND VARIANTS GD3 RP THR-229; HIS-448; PRO-483 AND CYS-502. RX PubMed=10796875; DOI=10.1086/302925; RA Koprivica V., Stone D.L., Park J.K., Callahan M., Frisch A., Cohen I.J., RA Tayebi N., Sidransky E.; RT "Analysis and classification of 304 mutant alleles in patients with type 1 RT and type 3 Gaucher disease."; RL Am. J. Hum. Genet. 66:1777-1786(2000). RN [94] RP VARIANTS GD2 LEU-170; LYS-227; GLU-229; PRO-235; GLN-294; GLN-296; LEU-298; RP HIS-324 AND CYS-343. RX PubMed=10649495; RX DOI=10.1002/(sici)1098-1004(200002)15:2<181::aid-humu7>3.0.co;2-s; RA Stone D.L., Tayebi N., Orvisky E., Stubblefield B., Madike V., RA Sidransky E.; RT "Glucocerebrosidase gene mutations in patients with type 2 Gaucher RT disease."; RL Hum. Mutat. 15:181-188(2000). RN [95] RP VARIANTS GD2 ARG-223 AND PRO-483. RX PubMed=10679038; DOI=10.1007/s100240050023; RA Choy F.Y., Wong K., Vallance H.D., Baldwin V.; RT "Novel point mutation (W184R) in neonatal type 2 Gaucher disease."; RL Pediatr. Dev. Pathol. 3:180-183(2000). RN [96] RP VARIANTS GD SER-55 AND HIS-448. RX PubMed=11992489; DOI=10.1002/ajmg.10385; RA Bodamer O.A.F., Church H.J., Cooper A., Wraith J.E., Scott C.R., RA Scaglia F.; RT "Variant Gaucher disease characterized by dysmorphic features, absence of RT cardiovascular involvement, laryngospasm, and compound heterozygosity for a RT novel mutation (D409H/C16S)."; RL Am. J. Med. Genet. 109:328-331(2002). RN [97] RP VARIANT LYS-365. RX PubMed=11903352; DOI=10.1034/j.1399-0004.2002.610106.x; RA Park J.K., Tayebi N., Stubblefield B.K., LaMarca M.E., MacKenzie J.J., RA Stone D.L., Sidransky E.; RT "The E326K mutation and Gaucher disease: mutation or polymorphism?"; RL Clin. Genet. 61:32-34(2002). RN [98] RP VARIANT GD GLU-175, VARIANT GDPL LEU-290, VARIANTS GD1 PRO-201 AND SER-409, RP VARIANT GD2 GLU-237, AND VARIANTS GD3 CYS-244; SER-416; PHE-441 AND RP HIS-448. RX PubMed=11933202; DOI=10.1002/humu.9024; RA Orvisky E., Park J.K., Parker A., Walker J.M., Martin B.M., RA Stubblefield B.K., Uyama E., Tayebi N., Sidransky E.; RT "The identification of eight novel glucocerebrosidase (GBA) mutations in RT patients with Gaucher disease."; RL Hum. Mutat. 19:458-459(2002). RN [99] RP VARIANTS GD1 THR-198; CYS-209; PRO-209; ARG-241; ILE-252; CYS-324; HIS-324; RP CYS-351; ASN-438; HIS-448; CYS-457; PRO-485 AND ARG-490, VARIANTS GD2 RP CYS-170; PRO-235; ARG-241; ARG-270 AND ILE-400, AND VARIANTS GD3 LEU-146; RP SER-227; ARG-241; ILE-252; CYS-324; GLY-392 AND HIS-448. RX PubMed=12204005; DOI=10.1002/humu.9058; RA Filocamo M., Mazzotti R., Stroppiano M., Seri M., Giona F., Parenti G., RA Regis S., Corsolini F., Zoboli S., Gatti R.; RT "Analysis of the glucocerebrosidase gene and mutation profile in 144 RT Italian Gaucher patients."; RL Hum. Mutat. 20:234-235(2002). RN [100] RP VARIANT MET-408. RX PubMed=12694238; DOI=10.1034/j.1399-0004.2003.00055.x; RA Walker J.M., Lwin A., Tayebi N., LaMarca M.E., Orvisky E., Sidransky E.; RT "Glucocerebrosidase mutation T369M appears to be another polymorphism."; RL Clin. Genet. 63:237-238(2003). RN [101] RP POSSIBLE INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=12847165; DOI=10.1212/01.wnl.0000072482.70963.d7; RA Bembi B., Zambito Marsala S., Sidransky E., Ciana G., Carrozzi M., RA Zorzon M., Martini C., Gioulis M., Pittis M.G., Capus L.; RT "Gaucher's disease with Parkinson's disease: clinical and pathological RT aspects."; RL Neurology 61:99-101(2003). RN [102] RP VARIANT GD SER-55. RX PubMed=15292921; DOI=10.1038/sj.ejhg.5201251; RA Church H.J., Cooper A., Stewart F., Thornton C.M., Wraith J.E.; RT "Homozygous loss of a cysteine residue in the glucocerebrosidase gene RT results in Gaucher's disease with a hydropic phenotype."; RL Eur. J. Hum. Genet. 12:975-978(2004). RN [103] RP VARIANTS GD2 GLN-294 AND HIS-448. RX PubMed=15690354; DOI=10.1002/ajmg.a.30316; RA Filocamo M., Grossi S., Stroppiano M., Tortori-Donati P., Regis S., RA Allegri A., Di Rocco M.; RT "Homozygosity for a non-pseudogene complex glucocerebrosidase allele as RT cause of an atypical neuronopathic form of Gaucher disease."; RL Am. J. Med. Genet. A 134A:95-96(2005). RN [104] RP CHARACTERIZATION OF VARIANT GD SER-409. RX PubMed=15826241; DOI=10.1042/bj20050325; RA Salvioli R., Tatti M., Scarpa S., Moavero S.M., Ciaffoni F., Felicetti F., RA Kaneski C.R., Brady R.O., Vaccaro A.M.; RT "The N370S (Asn370->Ser) mutation affects the capacity of RT glucosylceramidase to interact with anionic phospholipid-containing RT membranes and saposin C."; RL Biochem. J. 390:95-103(2005). RN [105] RP CHARACTERIZATION OF VARIANTS GD HIS-179 AND GLN-196, CATALYTIC ACTIVITY, RP AND FUNCTION. RX PubMed=15916907; DOI=10.1016/j.bcmd.2005.03.006; RA Ron I., Dagan A., Gatt S., Pasmanik-Chor M., Horowitz M.; RT "Use of fluorescent substrates for characterization of Gaucher disease RT mutations."; RL Blood Cells Mol. Dis. 35:57-65(2005). RN [106] RP VARIANTS GD1 ASN-63; SER-158; TRP-159; CYS-170; LEU-221; GLU-230; ARG-241; RP CYS-324; SER-409; ASN-438; LEU-440; HIS-448; CYS-457; ASP-460; PRO-483 AND RP ARG-490, AND CHARACTERIZATION OF VARIANTS GD1 ASN-63; SER-158; LEU-221; RP GLU-230; ASP-460 AND ARG-490. RX PubMed=15605411; DOI=10.1002/humu.9301; RA Miocic S., Filocamo M., Dominissini S., Montalvo A.L., Vlahovicek K., RA Deganuto M., Mazzotti R., Cariati R., Bembi B., Pittis M.G.; RT "Identification and functional characterization of five novel mutant RT alleles in 58 Italian patients with Gaucher disease type 1."; RL Hum. Mutat. 25:100-100(2005). RN [107] RP POSSIBLE INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=16148263; DOI=10.1212/01.wnl.0000176987.47875.28; RA Aharon-Peretz J., Badarny S., Rosenbaum H., Gershoni-Baruch R.; RT "Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype- RT genotype correlation."; RL Neurology 65:1460-1461(2005). RN [108] RP INVOLVEMENT OF VARIANT GD PRO-483 IN SUSCEPTIBILITY TO PARKINSON DISEASE. RX PubMed=17620502; DOI=10.1001/archneur.64.7.1056; RA Tan E.K., Tong J., Fook-Chong S., Yih Y., Wong M.C., Pavanni R., Zhao Y.; RT "Glucocerebrosidase mutations and risk of Parkinson disease in Chinese RT patients."; RL Arch. Neurol. 64:1056-1058(2007). RN [109] RP INVOLVEMENT OF VARIANTS GD SER-409 AND PRO-483 IN SUSCEPTIBILITY TO RP PARKINSON DISEASE. RX PubMed=18332251; DOI=10.1001/archneurol.2007.68; RA Mata I.F., Samii A., Schneer S.H., Roberts J.W., Griffith A., Leis B.C., RA Schellenberg G.D., Sidransky E., Bird T.D., Leverenz J.B., Tsuang D., RA Zabetian C.P.; RT "Glucocerebrosidase gene mutations: a risk factor for Lewy body RT disorders."; RL Arch. Neurol. 65:379-382(2008). RN [110] RP INVOLVEMENT IN PARKINSON DISEASE, AND VARIANTS GLU-46; CYS-170; GLU-232; RP GLN-296; SER-409; ALA-419; HIS-448; ASN-482; PRO-483; PRO-495; LEU-497 AND RP CYS-502. RX PubMed=19286695; DOI=10.1093/brain/awp044; RA Neumann J., Bras J., Deas E., O'Sullivan S.S., Parkkinen L., Lachmann R.H., RA Li A., Holton J., Guerreiro R., Paudel R., Segarane B., Singleton A., RA Lees A., Hardy J., Houlden H., Revesz T., Wood N.W.; RT "Glucocerebrosidase mutations in clinical and pathologically proven RT Parkinson's disease."; RL Brain 132:1783-1794(2009). RN [111] RP INVOLVEMENT OF VARIANTS GD SER-409 AND PRO-483 IN SUSCEPTIBILITY TO RP PARKINSON DISEASE. RX PubMed=19846850; DOI=10.1056/nejmoa0901281; RA Sidransky E., Nalls M.A., Aasly J.O., Aharon-Peretz J., Annesi G., RA Barbosa E.R., Bar-Shira A., Berg D., Bras J., Brice A., Chen C.M., RA Clark L.N., Condroyer C., De Marco E.V., Durr A., Eblan M.J., Fahn S., RA Farrer M.J., Fung H.C., Gan-Or Z., Gasser T., Gershoni-Baruch R., RA Giladi N., Griffith A., Gurevich T., Januario C., Kropp P., Lang A.E., RA Lee-Chen G.J., Lesage S., Marder K., Mata I.F., Mirelman A., Mitsui J., RA Mizuta I., Nicoletti G., Oliveira C., Ottman R., Orr-Urtreger A., RA Pereira L.V., Quattrone A., Rogaeva E., Rolfs A., Rosenbaum H., RA Rozenberg R., Samii A., Samaddar T., Schulte C., Sharma M., Singleton A., RA Spitz M., Tan E.K., Tayebi N., Toda T., Troiano A.R., Tsuji S., RA Wittstock M., Wolfsberg T.G., Wu Y.R., Zabetian C.P., Zhao Y., RA Ziegler S.G.; RT "Multicenter analysis of glucocerebrosidase mutations in Parkinson's RT disease."; RL N. Engl. J. Med. 361:1651-1661(2009). RN [112] RP VARIANTS GD1 VAL-289; GLY-301 AND GLU-486. RX PubMed=22658918; DOI=10.1016/j.ymgme.2012.05.006; RA Duran R., McNeill A., Mehta A., Hughes D., Cox T., Deegan P., RA Schapira A.H., Hardy J.; RT "Novel pathogenic mutations in the glucocerebrosidase locus."; RL Mol. Genet. Metab. 106:495-497(2012). RN [113] RP VARIANTS GD1 LEU-266 AND SER-347. RX PubMed=24577513; DOI=10.1007/s00277-014-2036-x; RA Machaczka M., Klimkowska M.; RT "Novel heterozygous c.798C>G and c.1040T>G mutations in the GBA1 gene are RT associated with a severe phenotype of Gaucher disease type 1."; RL Ann. Hematol. 93:1787-1789(2014). RN [114] RP VARIANTS GD1 SER-198; THR-284; SER-351; LYS-365; ARG-405; ASN-419 AND RP CYS-420, CHARACTERIZATION OF VARIANTS GD1 SER-198; THR-284; SER-351; RP LYS-365; ARG-405; SER-409; ASN-419 AND CYS-420, VARIANTS GD2 ILE-227 AND RP LYS-274, CHARACTERIZATION OF VARIANTS GD2 ILE-227 AND LYS-274, VARIANTS GD3 RP SER-227 AND ARG-304, AND CHARACTERIZATION OF VARIANTS GD3 SER-227 AND RP ARG-304. RX PubMed=24022302; DOI=10.1038/ejhg.2013.182; RA Malini E., Grossi S., Deganuto M., Rosano C., Parini R., Dominisini S., RA Cariati R., Zampieri S., Bembi B., Filocamo M., Dardis A.; RT "Functional analysis of 11 novel GBA alleles."; RL Eur. J. Hum. Genet. 22:511-516(2014). RN [115] RP VARIANT GD1 TRP-62. RX PubMed=24434810; DOI=10.1016/j.gene.2014.01.015; RA Jack A., Amato D., Morris G., Choy F.Y.; RT "Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified RT in Type 1 Gaucher patients heterozygous for N370S."; RL Gene 538:84-87(2014). RN [116] RP VARIANT PRO-363. RX PubMed=26528954; DOI=10.1002/ana.24553; RG International Parkinsonism Genetics Network; RA Olgiati S., Quadri M., Fang M., Rood J.P., Saute J.A., Chien H.F., RA Bouwkamp C.G., Graafland J., Minneboo M., Breedveld G.J., Zhang J., RA Verheijen F.W., Boon A.J., Kievit A.J., Jardim L.B., Mandemakers W., RA Barbosa E.R., Rieder C.R., Leenders K.L., Wang J., Bonifati V.; RT "DNAJC6 mutations associated with early-onset Parkinson's disease."; RL Ann. Neurol. 79:244-256(2016). RN [117] RP VARIANT GD2 ARG-350, AND VARIANTS GD1 SER-409; SER-416; ARG-483; PRO-483 RP AND PRO-495. RX PubMed=27825739; DOI=10.1016/j.bcmd.2016.10.013; RA Basgalupp S.P., Siebert M., Vairo F.P.E., Chami A.M., Pinto L.L.C., RA Carvalho G.D.S., Schwartz I.V.D.; RT "Use of a multiplex ligation-dependent probe amplification method for the RT detection of deletions/duplications in the GBA1 gene in Gaucher disease RT patients."; RL Blood Cells Mol. Dis. 68:17-20(2018). RN [118] RP VARIANTS GD1 GLN-87; LEU-120; HIS-155; TRP-159; SER-174; PRO-214; ARG-223; RP ARG-241; ILE-252; ILE-270; GLN-294; ASN-322; VAL-348; ARG-350; SER-409; RP HIS-448; PRO-483; TYR-501; LYS-521 AND CYS-535, VARIANTS GD2 TRP-159; RP ARG-241; GLN-294; HIS-448 AND PRO-483, AND VARIANTS GD3 CYS-147; GLN-294; RP HIS-448 AND PRO-483. RX PubMed=32547927; DOI=10.1016/j.ymgmr.2020.100614; RA Dimitriou E., Moraitou M., Cozar M., Serra-Vinardell J., Vilageliu L., RA Grinberg D., Mavridou I., Michelakakis H.; RT "Gaucher disease: Biochemical and molecular findings in 141 patients RT diagnosed in Greece."; RL Mol. Genet. Metab. Rep. 24:100614-100614(2020). RN [119] RP CHARACTERIZATION OF VARIANT GD3 VAL-448. RX PubMed=34106956; DOI=10.1371/journal.pone.0252325; RA Polinski N.K., Martinez T.N., Gorodinsky A., Gareus R., Sasner M., RA Herberth M., Switzer R., Ahmad S.O., Cosden M., Kandebo M., Drolet R.E., RA Buckett P.D., Shan W., Chen Y., Pellegrino L.J., Ellsworth G.D., RA Dungan L.B., Hirst W.D., Clark S.W., Dave K.D.; RT "Decreased glucocerebrosidase activity and substrate accumulation of RT glycosphingolipids in a novel GBA1 D409V knock-in mouse model."; RL PLoS ONE 16:e0252325-e0252325(2021). RN [120] RP VARIANTS GD1 LEU-414 AND HIS-448. RX PubMed=36776904; DOI=10.3389/fped.2023.1092645; RA Liu Q., Shen Z., Pan H., Ma S., Xiong F., He F.; RT "The molecular mechanism of Gaucher disease caused by compound heterozygous RT mutations in GBA1 gene."; RL Front. Pediatr. 11:1092645-1092645(2023). CC -!- FUNCTION: Glucosylceramidase that catalyzes, within the lysosomal CC compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta- CC D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as CC N-acylsphing-4-enine) and glucose (PubMed:15916907, PubMed:24211208, CC PubMed:32144204, PubMed:39395789, PubMed:9201993). Plays a central role CC in the degradation of complex lipids and the turnover of cellular CC membranes (PubMed:27378698). Through the production of ceramides, CC participates in the PKC-activated salvage pathway of ceramide formation CC (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through CC a transglucosylation reaction where glucose is transferred from GlcCer CC to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). CC GlcCer containing mono-unsaturated fatty acids (such as beta-D- CC glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose CC donors for cholesterol glucosylation when compared with GlcCer CC containing same chain length of saturated fatty acids (such as beta-D- CC glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under CC specific conditions, may alternatively catalyze the reverse reaction, CC transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide CC (Probable) (PubMed:26724485). Can also hydrolyze cholesteryl 3-beta-D- CC glucoside producing glucose and cholesterol (PubMed:24211208, CC PubMed:26724485, PubMed:39395789). Catalyzes the hydrolysis of CC galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N- CC acylsphing-4-enine), as well as the transfer of galactose between CC GalCers and cholesterol in vitro, but with lower activity than with CC GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, CC xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4- CC enine) is not a good substrate for hydrolysis, however it is a good CC xylose donor for transxylosylation activity to form cholesteryl 3-beta- CC D-xyloside (PubMed:33361282). Can also metabolize plant glycosyl CC phytosterols such as glucosylstigmasterol (PubMed:39395789). CC {ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:19279011, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:27378698, ECO:0000269|PubMed:32144204, CC ECO:0000269|PubMed:33361282, ECO:0000269|PubMed:39395789, CC ECO:0000269|PubMed:9201993, ECO:0000305|PubMed:32144204}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = an N- CC acylsphing-4-enine + D-glucose; Xref=Rhea:RHEA:13269, CC ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, ChEBI:CHEBI:22801, CC ChEBI:CHEBI:52639; EC=3.2.1.45; CC Evidence={ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204, CC ECO:0000269|PubMed:9201993}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13270; CC Evidence={ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H2O = an CC N-acylsphing-4-enine + D-galactose; Xref=Rhea:RHEA:14297, CC ChEBI:CHEBI:4139, ChEBI:CHEBI:15377, ChEBI:CHEBI:18390, CC ChEBI:CHEBI:52639; EC=3.2.1.46; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14298; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=cholesteryl 3-beta-D-glucoside + H2O = cholesterol + D- CC glucose; Xref=Rhea:RHEA:11956, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:16113, ChEBI:CHEBI:17495; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:33361282, CC ECO:0000269|PubMed:39395789}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11957; CC Evidence={ECO:0000269|PubMed:33361282, ECO:0000269|PubMed:39395789, CC ECO:0000305|PubMed:24211208}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + cholesterol CC = cholesteryl 3-beta-D-glucoside + an N-acylsphing-4-enine; CC Xref=Rhea:RHEA:58264, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:22801, ChEBI:CHEBI:52639; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58265; CC Evidence={ECO:0000269|PubMed:32144204, ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58266; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine + CC cholesterol = N-(9Z-octadecenoyl)-sphing-4-enine + cholesteryl 3- CC beta-D-glucoside; Xref=Rhea:RHEA:58324, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:17495, ChEBI:CHEBI:77996, ChEBI:CHEBI:139140; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58325; CC Evidence={ECO:0000269|PubMed:32144204, ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58326; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1')-N-hexadecanoylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-glucoside + N-hexadecanoylsphing- CC 4-enine; Xref=Rhea:RHEA:58316, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72959, ChEBI:CHEBI:84716; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58317; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58318; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-octanoylsphing-4E-enine + cholesterol = N- CC octanoylsphing-4-enine + cholesteryl 3-beta-D-glucoside; CC Xref=Rhea:RHEA:70303, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:45815, ChEBI:CHEBI:65222; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70304; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70305; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-dodecanoylsphing-4-enine + cholesterol = N- CC dodecanoylsphing-4-enine + cholesteryl 3-beta-D-glucoside; CC Xref=Rhea:RHEA:70307, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72956, ChEBI:CHEBI:76297; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70308; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70309; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1)-N-octadecanoylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-glucoside + N-octadecanoylsphing- CC 4-enine; Xref=Rhea:RHEA:70311, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72961, ChEBI:CHEBI:84719; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70312; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70313; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1')-N-(15Z-tetracosenoyl)-sphing-4-enine CC + cholesterol = N-(15Z-tetracosenoyl)-sphing-4-enine + cholesteryl 3- CC beta-D-glucoside; Xref=Rhea:RHEA:70315, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:17495, ChEBI:CHEBI:74450, ChEBI:CHEBI:76302; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70316; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70317; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-galactoside + an N-acylsphing-4- CC enine; Xref=Rhea:RHEA:70235, ChEBI:CHEBI:16113, ChEBI:CHEBI:18390, CC ChEBI:CHEBI:52639, ChEBI:CHEBI:189066; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70236; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70237; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol CC = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine; CC Xref=Rhea:RHEA:70255, ChEBI:CHEBI:16113, ChEBI:CHEBI:72956, CC ChEBI:CHEBI:73432, ChEBI:CHEBI:189066; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70256; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70257; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine + cholesterol = CC cholesteryl 3-beta-D-xyloside + an N-acylsphing-4-enine; CC Xref=Rhea:RHEA:70239, ChEBI:CHEBI:16113, ChEBI:CHEBI:52639, CC ChEBI:CHEBI:189067, ChEBI:CHEBI:189068; CC Evidence={ECO:0000269|PubMed:33361282}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70240; CC Evidence={ECO:0000269|PubMed:33361282}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-xylosyl-(1<->1')-N-(9Z-octadecenoyl)-sphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-xyloside + N-(9Z-octadecenoyl)- CC sphing-4-enine; Xref=Rhea:RHEA:70251, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:77996, ChEBI:CHEBI:189067, ChEBI:CHEBI:189081; CC Evidence={ECO:0000269|PubMed:33361282}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70252; CC Evidence={ECO:0000269|PubMed:33361282}; CC -!- CATALYTIC ACTIVITY: CC Reaction=stigmasteryl 3-beta-D-glucoside + H2O = stigmasterol + D- CC glucose; Xref=Rhea:RHEA:62028, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:28824, ChEBI:CHEBI:68383; CC Evidence={ECO:0000269|PubMed:39395789}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62029; CC Evidence={ECO:0000269|PubMed:39395789}; CC -!- ACTIVITY REGULATION: Synergistically activated by saposin-A and CC saposin-C, two saposin peptides produced by proteolytic processing of CC prosaposin/PSAP (PubMed:9201993). Saposin-C activates GBA1 through its CC recruitment to membranes (PubMed:10781797, PubMed:9201993). The CC membrane structure and composition in anionic phospholipids are also CC important for the activation (PubMed:10781797, PubMed:9201993). CC Activated by PKC in the salvage pathway of ceramide formation CC (PubMed:19279011). Inhibited by conduritol B epoxide/CBE CC (PubMed:24211208, PubMed:26724485). {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:19279011, ECO:0000269|PubMed:24211208, CC ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:9201993}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 5.3. {ECO:0000269|PubMed:24211208}; CC Temperature dependence: CC Optimum temperature is 43 degrees Celsius. CC {ECO:0000269|PubMed:24211208}; CC -!- PATHWAY: Steroid metabolism; cholesterol metabolism. CC {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485}. CC -!- PATHWAY: Sphingolipid metabolism. {ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:9201993}. CC -!- SUBUNIT: Interacts with saposin-C (PubMed:10781797). Interacts with CC SCARB2 (PubMed:18022370). Interacts with TCP1 (PubMed:21098288). May CC interacts with SNCA; this interaction may inhibit the CC glucosylceramidase activity (PubMed:23266198). Interacts with GRN; this CC interaction prevents aggregation of GBA1-SCARB2 complex via interaction CC with HSPA1A upon stress (PubMed:27789271). CC {ECO:0000269|PubMed:10781797, ECO:0000269|PubMed:18022370, CC ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:23266198, CC ECO:0000269|PubMed:27789271}. CC -!- INTERACTION: CC P04062; P17987: TCP1; NbExp=2; IntAct=EBI-1564609, EBI-356553; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17187079, CC ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370}; Peripheral CC membrane protein {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:1848227}; Lumenal side CC {ECO:0000269|PubMed:18022370}. Note=Interaction with saposin-C promotes CC membrane association (PubMed:10781797). Targeting to lysosomes occurs CC through an alternative MPR-independent mechanism via SCARB2 CC (PubMed:18022370). {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:18022370}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=5; CC Name=Long; CC IsoId=P04062-1; Sequence=Displayed; CC Name=Short; CC IsoId=P04062-2; Sequence=VSP_018800; CC Name=3; CC IsoId=P04062-3; Sequence=VSP_025216, VSP_025217, VSP_025218; CC Name=4; CC IsoId=P04062-4; Sequence=VSP_054655; CC Name=5; CC IsoId=P04062-5; Sequence=VSP_054656; CC -!- DISEASE: Gaucher disease (GD) [MIM:230800]: An autosomal recessive CC lysosomal storage disease due to deficient activity of lysosomal beta- CC glucocerebrosidase, and characterized by accumulation of CC glucosylceramide in the reticulo-endothelial system. GD is a CC multisystem disease historically divided into three main subtypes on CC the basis of the presence of neurologic involvement, age at onset and CC progression rate: type 1 is the non-neuropathic form, type 2 is the CC acute neuropathic form with early onset and rapid neurologic CC deterioration, type 3 is the chronic neuropathic form with slow CC progression of neurologic features. GD shows a marked phenotypic CC diversity ranging from adult asymptomatic forms, at the mild end, to CC perinatal lethal forms at the severe end of the disease spectrum. CC Formal diagnosis of Gaucher disease is based on the measurement of CC glucocerebrosidase levels in circulating leukocytes and molecular CC genetic analysis. {ECO:0000269|PubMed:10352942, CC ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10744424, CC ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, CC ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:15826241, CC ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:17620502, ECO:0000269|PubMed:18332251, CC ECO:0000269|PubMed:1972019, ECO:0000269|PubMed:1974409, CC ECO:0000269|PubMed:19846850, ECO:0000269|PubMed:7475546, CC ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7627192, CC ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8294033, CC ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8432537, CC ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:8829663, CC ECO:0000269|PubMed:8937765, ECO:0000269|PubMed:9061570, CC ECO:0000269|PubMed:9182788, ECO:0000269|PubMed:9217217, CC ECO:0000269|PubMed:9516376, ECO:0000269|PubMed:9554454, CC ECO:0000269|PubMed:9650766}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 1 (GD1) [MIM:230800]: A form of Gaucher CC disease, an autosomal recessive lysosomal storage disease due to CC deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD1 is characterized by hepatosplenomegaly with CC consequent anemia and thrombopenia, and bone involvement. The central CC nervous system is not involved. {ECO:0000269|PubMed:10206680, CC ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:10360404, CC ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, CC ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:1301953, CC ECO:0000269|PubMed:1487244, ECO:0000269|PubMed:15605411, CC ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:1899336, CC ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:22658918, CC ECO:0000269|PubMed:2269438, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:24434810, ECO:0000269|PubMed:24577513, CC ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:27825739, CC ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:36776904, CC ECO:0000269|PubMed:7655857, ECO:0000269|PubMed:7915932, CC ECO:0000269|PubMed:7916532, ECO:0000269|PubMed:8294487, CC ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:8547070, CC ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8790604, CC ECO:0000269|PubMed:8829663, ECO:0000269|PubMed:8889591, CC ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9153297, CC ECO:0000269|PubMed:9240741, ECO:0000269|PubMed:9295080, CC ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9683600, CC ECO:0000269|PubMed:9856561, ECO:0000269|Ref.14}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 2 (GD2) [MIM:230900]: The most severe form of CC Gaucher disease, an autosomal recessive lysosomal storage disease due CC to deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD2 is an acute neuronopathic form that manifests CC soon after birth, with death generally occurring before patients reach CC two years of age. Clinical features include hepatosplenomegaly, CC developmental regression, growth arrest, and rapidly progressing CC neurologic deterioration. {ECO:0000269|PubMed:10360404, CC ECO:0000269|PubMed:10649495, ECO:0000269|PubMed:10679038, CC ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, CC ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15690354, CC ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:21098288, CC ECO:0000269|PubMed:2269438, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:2464926, ECO:0000269|PubMed:27825739, CC ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:7627192, CC ECO:0000269|PubMed:7981693, ECO:0000269|PubMed:8112750, CC ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8598642, CC ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9240741, CC ECO:0000269|PubMed:9279145, ECO:0000269|PubMed:9554454, CC ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9637431, CC ECO:0000269|PubMed:9851895, ECO:0000269|PubMed:9856561}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Gaucher disease 3 (GD3) [MIM:231000]: A form of Gaucher CC disease, an autosomal recessive lysosomal storage disease due to CC deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD3 is a subacute neuronopathic form characterized CC by later onset and slower progression compared to Gaucher disease 2. CC {ECO:0000269|PubMed:10360404, ECO:0000269|PubMed:10796875, CC ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:12204005, CC ECO:0000269|PubMed:1487244, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:32547927, CC ECO:0000269|PubMed:34106956, ECO:0000269|PubMed:8294487, CC ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8780099, CC ECO:0000269|PubMed:9683600}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 3C (GD3C) [MIM:231005]: A variant of subacute CC neuronopathic Gaucher disease 3 associated with cardiovascular CC calcifications. {ECO:0000269|PubMed:9040001}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease perinatal lethal (GDPL) [MIM:608013]: Distinct CC form of Gaucher disease type 2, characterized by fetal onset. Hydrops CC fetalis, in utero fetal death and neonatal distress are prominent CC features. When hydrops is absent, neurologic involvement begins in the CC first week and leads to death within 3 months. Hepatosplenomegaly is a CC major sign, and is associated with ichthyosis, arthrogryposis, and CC facial dysmorphism. {ECO:0000269|PubMed:10352942, CC ECO:0000269|PubMed:11933202}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Perinatal lethal Gaucher CC disease is associated with non-immune hydrops fetalis, a generalized CC edema of the fetus with fluid accumulation in the body cavities due to CC non-immune causes. Non-immune hydrops fetalis is not a diagnosis in CC itself but a symptom, a feature of many genetic disorders, and the end- CC stage of a wide variety of disorders. {ECO:0000269|PubMed:10352942}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12847165, CC ECO:0000269|PubMed:16148263, ECO:0000269|PubMed:17620502, CC ECO:0000269|PubMed:18332251, ECO:0000269|PubMed:19286695, CC ECO:0000269|PubMed:19846850}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC -!- PHARMACEUTICAL: Available under the names Ceredase and Cerenzyme CC (Genzyme). Used to treat Gaucher disease. CC -!- MISCELLANEOUS: [Isoform Long]: Major isoform. CC {ECO:0000269|PubMed:3687939}. CC -!- MISCELLANEOUS: [Isoform Short]: Produced by alternative initiation from CC a downstream AUG. Two to three times less protein is produced from this CC downstream AUG. {ECO:0000269|PubMed:3687939}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 30 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Ceredase; Note=Clinical information on Ceredase; CC URL="https://www.rxlist.com/ceredase-drug.htm"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M16328; AAA35873.1; -; mRNA. DR EMBL; K02920; AAA35877.1; -; mRNA. DR EMBL; J03059; AAC63056.1; -; Genomic_DNA. DR EMBL; D13286; BAA02545.1; -; mRNA. DR EMBL; D13287; BAA02546.1; -; mRNA. DR EMBL; AF023268; AAC51820.1; -; Genomic_DNA. DR EMBL; AK291911; BAF84600.1; -; mRNA. DR EMBL; AK298900; BAH12898.1; -; mRNA. DR EMBL; AK300829; BAH13357.1; -; mRNA. DR EMBL; AL713999; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC003356; AAH03356.1; -; mRNA. DR EMBL; M19285; AAA35880.1; -; mRNA. DR EMBL; M18916; AAA35878.1; ALT_SEQ; Genomic_DNA. DR EMBL; M18917; AAA35879.1; ALT_SEQ; Genomic_DNA. DR EMBL; M20248; AAA35874.1; -; Genomic_DNA. DR EMBL; M20282; AAA35876.1; -; Genomic_DNA. DR CCDS; CCDS1102.1; -. [P04062-1] DR CCDS; CCDS53373.1; -. [P04062-4] DR CCDS; CCDS53374.1; -. [P04062-5] DR PIR; A94068; EUHUGC. DR PIR; I52980; I52980. DR PIR; I67792; I67792. DR RefSeq; NP_000148.2; NM_000157.4. [P04062-1] DR RefSeq; NP_001005741.1; NM_001005741.3. [P04062-1] DR RefSeq; NP_001005742.1; NM_001005742.3. [P04062-1] DR RefSeq; NP_001165282.1; NM_001171811.2. [P04062-4] DR RefSeq; NP_001165283.1; NM_001171812.2. [P04062-5] DR PDB; 1OGS; X-ray; 2.00 A; A/B=40-536. DR PDB; 1Y7V; X-ray; 2.40 A; A/B=40-536. DR PDB; 2F61; X-ray; 2.50 A; A/B=40-536. DR PDB; 2J25; X-ray; 2.90 A; A/B=40-536. DR PDB; 2NSX; X-ray; 2.11 A; A/B/C/D=40-536. DR PDB; 2NT0; X-ray; 1.79 A; A/B/C/D=40-536. DR PDB; 2NT1; X-ray; 2.30 A; A/B/C/D=40-536. DR PDB; 2V3D; X-ray; 1.96 A; A/B=40-536. DR PDB; 2V3E; X-ray; 2.00 A; A/B=40-536. DR PDB; 2V3F; X-ray; 1.95 A; A/B=40-536. DR PDB; 2VT0; X-ray; 2.15 A; A/B=40-536. DR PDB; 2WCG; X-ray; 2.30 A; A/B=40-536. DR PDB; 2WKL; X-ray; 2.70 A; A/B=40-536. DR PDB; 2XWD; X-ray; 2.66 A; A/B=40-536. DR PDB; 2XWE; X-ray; 2.31 A; A/B=40-536. DR PDB; 3GXD; X-ray; 2.50 A; A/B/C/D=40-536. DR PDB; 3GXF; X-ray; 2.40 A; A/B/C/D=40-536. DR PDB; 3GXI; X-ray; 1.84 A; A/B/C/D=40-536. DR PDB; 3GXM; X-ray; 2.20 A; A/B/C/D=40-536. DR PDB; 3KE0; X-ray; 2.70 A; A/B=40-536. DR PDB; 3KEH; X-ray; 2.80 A; A/B=40-536. DR PDB; 3RIK; X-ray; 2.48 A; A/B/C/D=40-536. DR PDB; 3RIL; X-ray; 2.40 A; A/B/C/D=40-536. DR PDB; 5LVX; X-ray; 2.20 A; A/B/C/D=40-536. DR PDB; 6MOZ; X-ray; 2.10 A; A/B=40-536. DR PDB; 6Q1N; X-ray; 2.53 A; A/B=40-536. DR PDB; 6Q1P; X-ray; 2.80 A; A/B=40-536. DR PDB; 6Q6K; X-ray; 1.92 A; A/B=40-536. DR PDB; 6Q6L; X-ray; 1.81 A; A/B=40-536. DR PDB; 6Q6N; X-ray; 1.63 A; A/B=40-536. DR PDB; 6T13; X-ray; 1.85 A; A/B/C/D=1-536. DR PDB; 6TJJ; X-ray; 1.59 A; AAA/BBB=40-536. DR PDB; 6TJK; X-ray; 1.56 A; AAA/BBB=40-536. DR PDB; 6TJQ; X-ray; 1.41 A; BBB=40-536. DR PDB; 6TN1; X-ray; 0.98 A; AAA=40-536. DR PDB; 6YTP; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6YTR; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6YUT; X-ray; 1.76 A; AAA/BBB=40-536. DR PDB; 6YV3; X-ray; 1.80 A; AAA/BBB=40-536. DR PDB; 6Z39; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6Z3I; X-ray; 1.80 A; BBB=40-536. DR PDB; 7NWV; X-ray; 1.86 A; AAA/BBB=40-536. DR PDB; 8AWK; X-ray; 1.58 A; AAA=40-536. DR PDB; 8AWR; X-ray; 1.49 A; AAA=40-536. DR PDB; 8AX3; X-ray; 1.59 A; A/B=40-536. DR PDB; 8P3E; X-ray; 1.75 A; A/B=40-536. DR PDB; 8P41; X-ray; 1.83 A; A/B=40-536. DR PDB; 9ENA; X-ray; 1.70 A; A=40-536. DR PDB; 9F9Z; X-ray; 2.28 A; A=40-536. DR PDB; 9FA3; X-ray; 1.36 A; A=1-536. DR PDB; 9FA6; X-ray; 1.49 A; A=1-536. DR PDB; 9FAD; X-ray; 1.80 A; A=1-536. DR PDB; 9FAL; X-ray; 1.39 A; A=1-536. DR PDB; 9FAY; X-ray; 1.40 A; A=1-536. DR PDB; 9FAZ; X-ray; 1.63 A; A=1-536. DR PDB; 9FB2; X-ray; 1.14 A; A=1-536. DR PDB; 9FDI; X-ray; 1.41 A; A=1-536. DR PDB; 9FJF; EM; 3.70 A; B=40-536. DR PDBsum; 1OGS; -. DR PDBsum; 1Y7V; -. DR PDBsum; 2F61; -. DR PDBsum; 2J25; -. DR PDBsum; 2NSX; -. DR PDBsum; 2NT0; -. DR PDBsum; 2NT1; -. DR PDBsum; 2V3D; -. DR PDBsum; 2V3E; -. DR PDBsum; 2V3F; -. DR PDBsum; 2VT0; -. DR PDBsum; 2WCG; -. DR PDBsum; 2WKL; -. DR PDBsum; 2XWD; -. DR PDBsum; 2XWE; -. DR PDBsum; 3GXD; -. DR PDBsum; 3GXF; -. DR PDBsum; 3GXI; -. DR PDBsum; 3GXM; -. DR PDBsum; 3KE0; -. DR PDBsum; 3KEH; -. DR PDBsum; 3RIK; -. DR PDBsum; 3RIL; -. DR PDBsum; 5LVX; -. DR PDBsum; 6MOZ; -. DR PDBsum; 6Q1N; -. DR PDBsum; 6Q1P; -. DR PDBsum; 6Q6K; -. DR PDBsum; 6Q6L; -. DR PDBsum; 6Q6N; -. DR PDBsum; 6T13; -. DR PDBsum; 6TJJ; -. DR PDBsum; 6TJK; -. DR PDBsum; 6TJQ; -. DR PDBsum; 6TN1; -. DR PDBsum; 6YTP; -. DR PDBsum; 6YTR; -. DR PDBsum; 6YUT; -. DR PDBsum; 6YV3; -. DR PDBsum; 6Z39; -. DR PDBsum; 6Z3I; -. DR PDBsum; 7NWV; -. DR PDBsum; 8AWK; -. DR PDBsum; 8AWR; -. DR PDBsum; 8AX3; -. DR PDBsum; 8P3E; -. DR PDBsum; 8P41; -. DR PDBsum; 9ENA; -. DR PDBsum; 9F9Z; -. DR PDBsum; 9FA3; -. DR PDBsum; 9FA6; -. DR PDBsum; 9FAD; -. DR PDBsum; 9FAL; -. DR PDBsum; 9FAY; -. DR PDBsum; 9FAZ; -. DR PDBsum; 9FB2; -. DR PDBsum; 9FDI; -. DR PDBsum; 9FJF; -. DR AlphaFoldDB; P04062; -. DR EMDB; EMD-50502; -. DR EMDB; EMD-50936; -. DR EMDB; EMD-50937; -. DR EMDB; EMD-50938; -. DR SMR; P04062; -. DR BioGRID; 108899; 144. DR CORUM; P04062; -. DR DIP; DIP-38645N; -. DR FunCoup; P04062; 516. DR IntAct; P04062; 72. DR MINT; P04062; -. DR STRING; 9606.ENSP00000314508; -. DR BindingDB; P04062; -. DR ChEMBL; CHEMBL2179; -. DR DrugBank; DB08321; (1S,2S,3R,6R)-4-(hydroxymethyl)-6-(octylamino)cyclohex-4-ene-1,2,3-triol. DR DrugBank; DB08283; (2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOL. DR DrugBank; DB04545; Afegostat. DR DrugBank; DB03740; N-acetyl-alpha-D-glucosamine. DR DrugBank; DB03106; scyllo-inositol. DR DrugBank; DB06720; Velaglucerase alfa. DR DrugCentral; P04062; -. DR SwissLipids; SLP:000001387; -. DR Allergome; 8244; Hom s Glucocerebrosidase. DR CAZy; GH30; Glycoside Hydrolase Family 30. DR GlyConnect; 1271; 26 N-Linked glycans (4 sites). DR GlyCosmos; P04062; 6 sites, 29 glycans. DR GlyGen; P04062; 8 sites, 35 N-linked glycans (4 sites), 1 O-linked glycan (2 sites). DR iPTMnet; P04062; -. DR MetOSite; P04062; -. DR PhosphoSitePlus; P04062; -. DR SwissPalm; P04062; -. DR BioMuta; GBA; -. DR DMDM; 55584151; -. DR jPOST; P04062; -. DR MassIVE; P04062; -. DR PaxDb; 9606-ENSP00000314508; -. DR PeptideAtlas; P04062; -. DR ProteomicsDB; 51642; -. [P04062-1] DR ProteomicsDB; 51643; -. [P04062-2] DR ProteomicsDB; 51644; -. [P04062-3] DR Pumba; P04062; -. DR ABCD; P04062; 7 sequenced antibodies. DR Antibodypedia; 1678; 510 antibodies from 33 providers. DR DNASU; 2629; -. DR Ensembl; ENST00000327247.9; ENSP00000314508.5; ENSG00000177628.17. [P04062-1] DR Ensembl; ENST00000368373.8; ENSP00000357357.3; ENSG00000177628.17. [P04062-1] DR Ensembl; ENST00000427500.7; ENSP00000402577.2; ENSG00000177628.17. [P04062-5] DR Ensembl; ENST00000428024.3; ENSP00000397986.2; ENSG00000177628.17. [P04062-4] DR GeneID; 2629; -. DR KEGG; hsa:2629; -. DR MANE-Select; ENST00000368373.8; ENSP00000357357.3; NM_000157.4; NP_000148.2. DR UCSC; uc001fjh.4; human. [P04062-1] DR AGR; HGNC:4177; -. DR ClinPGx; PA28591; -. DR CTD; 2629; -. DR DisGeNET; 2629; -. DR GeneCards; GBA1; -. DR GeneReviews; GBA1; -. DR HGNC; HGNC:4177; GBA1. DR HPA; ENSG00000177628; Low tissue specificity. DR MalaCards; GBA1; -. DR MIM; 168600; phenotype. DR MIM; 230800; phenotype. DR MIM; 230900; phenotype. DR MIM; 231000; phenotype. DR MIM; 231005; phenotype. DR MIM; 606463; gene. DR MIM; 608013; phenotype. DR OpenTargets; ENSG00000177628; -. DR Orphanet; 85212; Fetal Gaucher disease. DR Orphanet; 77259; Gaucher disease type 1. DR Orphanet; 77260; Gaucher disease type 2. DR Orphanet; 77261; Gaucher disease type 3. DR Orphanet; 2072; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000177628; -. DR eggNOG; KOG2566; Eukaryota. DR GeneTree; ENSGT00390000009464; -. DR HOGENOM; CLU_014379_1_2_1; -. DR InParanoid; P04062; -. DR OMA; FGGIAWH; -. DR OrthoDB; 2160638at2759; -. DR PAN-GO; P04062; 2 GO annotations based on evolutionary models. DR PhylomeDB; P04062; -. DR BRENDA; 3.2.1.45; 2681. DR PathwayCommons; P04062; -. DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SignaLink; P04062; -. DR SIGNOR; P04062; -. DR UniPathway; UPA00296; -. DR Agora; ENSG00000177628; -. DR BioGRID-ORCS; 2629; 10 hits in 1162 CRISPR screens. DR ChiTaRS; GBA; human. DR EvolutionaryTrace; P04062; -. DR GeneWiki; Glucocerebrosidase; -. DR GenomeRNAi; 2629; -. DR Pharos; P04062; Tclin. DR PRO; PR:P04062; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P04062; protein. DR Bgee; ENSG00000177628; Expressed in stromal cell of endometrium and 101 other cell types or tissues. DR ExpressionAtlas; P04062; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; ISS:BHF-UCL. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IMP:ARUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB. DR GO; GO:0008422; F:beta-glucosidase activity; IDA:MGI. DR GO; GO:0004336; F:galactosylceramidase activity; IEA:UniProtKB-EC. DR GO; GO:0004348; F:glucosylceramidase activity; IDA:UniProtKB. DR GO; GO:0046527; F:glucosyltransferase activity; IDA:UniProtKB. DR GO; GO:0005124; F:scavenger receptor binding; IPI:ARUK-UCL. DR GO; GO:0005102; F:signaling receptor binding; ISS:BHF-UCL. DR GO; GO:0050295; F:steryl-beta-glucosidase activity; IDA:UniProtKB. DR GO; GO:0019882; P:antigen processing and presentation; IEA:Ensembl. DR GO; GO:1905037; P:autophagosome organization; IEA:Ensembl. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1901805; P:beta-glucoside catabolic process; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0048469; P:cell maturation; IEA:Ensembl. DR GO; GO:0009267; P:cellular response to starvation; IEA:Ensembl. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IMP:BHF-UCL. DR GO; GO:0046513; P:ceramide biosynthetic process; IMP:BHF-UCL. DR GO; GO:0021694; P:cerebellar Purkinje cell layer formation; IEA:Ensembl. DR GO; GO:0008203; P:cholesterol metabolic process; IDA:UniProtKB. DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl. DR GO; GO:0061436; P:establishment of skin barrier; IEA:Ensembl. DR GO; GO:0006680; P:glucosylceramide catabolic process; IDA:UniProtKB. DR GO; GO:0009247; P:glycolipid biosynthetic process; IDA:UniProtKB. DR GO; GO:0071425; P:hematopoietic stem cell proliferation; IEA:Ensembl. DR GO; GO:0048872; P:homeostasis of number of cells; IEA:Ensembl. DR GO; GO:0006955; P:immune response; IEA:Ensembl. DR GO; GO:0019915; P:lipid storage; IEA:Ensembl. DR GO; GO:0072676; P:lymphocyte migration; IEA:Ensembl. DR GO; GO:1905146; P:lysosomal protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0007040; P:lysosome organization; IMP:UniProtKB. DR GO; GO:0014004; P:microglia differentiation; IEA:Ensembl. DR GO; GO:0061518; P:microglial cell proliferation; IEA:Ensembl. DR GO; GO:0000423; P:mitophagy; IEA:Ensembl. DR GO; GO:0061744; P:motor behavior; IEA:Ensembl. DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:BHF-UCL. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IMP:BHF-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051248; P:negative regulation of protein metabolic process; IEA:Ensembl. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:1904457; P:positive regulation of neuronal action potential; IMP:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0021859; P:pyramidal neuron differentiation; IEA:Ensembl. DR GO; GO:1905165; P:regulation of lysosomal protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0032006; P:regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:0022904; P:respiratory electron transport chain; IEA:Ensembl. DR GO; GO:0071548; P:response to dexamethasone; IEA:Ensembl. DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl. DR GO; GO:0009268; P:response to pH; IEA:Ensembl. DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl. DR GO; GO:0097066; P:response to thyroid hormone; IEA:Ensembl. DR GO; GO:0046512; P:sphingosine biosynthetic process; IMP:BHF-UCL. DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl. DR GO; GO:0023021; P:termination of signal transduction; IMP:BHF-UCL. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR FunFam; 3.20.20.80:FF:000030; Lysosomal acid glucosylceramidase; 1. DR Gene3D; 3.20.20.80; Glycosidases; 1. DR InterPro; IPR017853; GH. DR InterPro; IPR033452; GH30_C. DR InterPro; IPR001139; Glyco_hydro_30. DR InterPro; IPR033453; Glyco_hydro_30_TIM-barrel. DR PANTHER; PTHR11069; GLUCOSYLCERAMIDASE; 1. DR PANTHER; PTHR11069:SF33; LYSOSOMAL ACID GLUCOSYLCERAMIDASE; 1. DR Pfam; PF02055; Glyco_hydro_30; 1. DR Pfam; PF17189; Glyco_hydro_30C; 1. DR PRINTS; PR00843; GLHYDRLASE30. DR SUPFAM; SSF51445; (Trans)glycosidases; 1. DR SUPFAM; SSF51011; Glycosyl hydrolase domain; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Alternative splicing; KW Cholesterol metabolism; Direct protein sequencing; Disease variant; KW Disulfide bond; Gaucher disease; Glycoprotein; Glycosidase; KW Glycosyltransferase; Hydrolase; Ichthyosis; Lipid metabolism; Lysosome; KW Membrane; Neurodegeneration; Parkinson disease; Parkinsonism; KW Pharmaceutical; Proteomics identification; Reference proteome; Signal; KW Sphingolipid metabolism; Steroid metabolism; Sterol metabolism; KW Transferase. FT SIGNAL 1..39 FT /evidence="ECO:0000269|Ref.12" FT CHAIN 40..536 FT /note="Lysosomal acid glucosylceramidase" FT /id="PRO_0000012177" FT ACT_SITE 274 FT /note="Proton donor" FT /evidence="ECO:0000269|PubMed:15817452" FT ACT_SITE 379 FT /note="Nucleophile" FT /evidence="ECO:0000269|PubMed:15817452" FT CARBOHYD 58 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0000269|PubMed:17139081" FT CARBOHYD 98 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:17139081, ECO:0000269|PubMed:19159218" FT CARBOHYD 185 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:17139081" FT CARBOHYD 309 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:19159218" FT CARBOHYD 501 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 43..55 FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0007744|PDB:1OGS" FT DISULFID 57..62 FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0007744|PDB:1OGS" FT VAR_SEQ 1..161 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025216" FT VAR_SEQ 1..87 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054655" FT VAR_SEQ 1..20 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000303|PubMed:3001061, FT ECO:0000303|PubMed:3864160" FT /id="VSP_018800" FT VAR_SEQ 103..151 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054656" FT VAR_SEQ 422..423 FT /note="LA -> PS (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025217" FT VAR_SEQ 425..536 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025218" FT VARIANT 46 FT /note="K -> E (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs142761046)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063066" FT VARIANT 54 FT /note="V -> L (in GD; dbSNP:rs121908302)" FT /evidence="ECO:0000269|PubMed:8829654" FT /id="VAR_003255" FT VARIANT 55 FT /note="C -> S (in GD; neuronopathic and perinatal lethal FT forms; loss of glucosylceramidase activity; FT dbSNP:rs773007510)" FT /evidence="ECO:0000269|PubMed:11992489, FT ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:16293621" FT /id="VAR_032394" FT VARIANT 62 FT /note="C -> W (in GD1)" FT /evidence="ECO:0000269|PubMed:24434810" FT /id="VAR_081188" FT VARIANT 63 FT /note="D -> N (in GD1; very low glucosylceramidase FT activity)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032395" FT VARIANT 76 FT /note="F -> V (in GD)" FT /evidence="ECO:0000269|PubMed:9217217" FT /id="VAR_003256" FT VARIANT 80 FT /note="E -> K (in GD2)" FT /evidence="ECO:0000269|PubMed:9851895" FT /id="VAR_009033" FT VARIANT 82 FT /note="T -> I (in GD1; dbSNP:rs1141811)" FT /evidence="ECO:0000269|PubMed:7655857" FT /id="VAR_003257" FT VARIANT 85 FT /note="G -> E (in GD; dbSNP:rs77829017)" FT /evidence="ECO:0000269|PubMed:8829654, FT ECO:0000269|PubMed:9217217" FT /id="VAR_003258" FT VARIANT 87 FT /note="R -> Q (in GD1; decreased glucosylceramidase FT activity; 20% of normal activity; dbSNP:rs78769774)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:32547927" FT /id="VAR_032197" FT VARIANT 87 FT /note="R -> W (in GD1; decreased glucosylceramidase FT activity; dbSNP:rs1141814)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:7655857, ECO:0000269|PubMed:9153297, FT ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9295080, FT ECO:0000269|PubMed:9683600, ECO:0000269|PubMed:9856561" FT /id="VAR_003259" FT VARIANT 92 FT /note="M -> T (in dbSNP:rs1141815)" FT /id="VAR_032396" FT VARIANT 118 FT /note="K -> N (in GD1; mild; decreased glucosylceramidase FT activity; 8% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs121908312)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621" FT /id="VAR_003260" FT VARIANT 120 FT /note="F -> L (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088437" FT VARIANT 129 FT /note="A -> T (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032397" FT VARIANT 146 FT /note="S -> L (in GD2 and GD3; dbSNP:rs758447515)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9554454" FT /id="VAR_009034" FT VARIANT 147 FT /note="Y -> C (in GD3)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088438" FT VARIANT 152 FT /note="G -> E (in GD1)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003261" FT VARIANT 155 FT /note="Y -> H (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088439" FT VARIANT 156 FT /note="N -> D (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032398" FT VARIANT 158 FT /note="I -> S (in GD1; very low glucosylceramidase FT activity; dbSNP:rs77834747)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032399" FT VARIANT 158 FT /note="I -> T (in GD1; dbSNP:rs77834747)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003262" FT VARIANT 159 FT /note="R -> Q (in GD1 and GD2; decreased glucosylceramidase FT activity; 13% of normal activity; dbSNP:rs79653797)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621" FT /id="VAR_003263" FT VARIANT 159 FT /note="R -> W (in GD1 and GD2; dbSNP:rs439898)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9683600, FT ECO:0000269|PubMed:9856561" FT /id="VAR_003264" FT VARIANT 161 FT /note="P -> L (in GD; decreased glucosylceramidase FT activity; 16% of normal activity; dbSNP:rs79637617)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032198" FT VARIANT 161 FT /note="P -> S (in GD1; dbSNP:rs121908299)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003265" FT VARIANT 162 FT /note="M -> V (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation; FT dbSNP:rs377325220)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032199" FT VARIANT 166 FT /note="D -> V (in GD; decreased glucosylceramidase FT activity; 9% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs79796061)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032200" FT VARIANT 170 FT /note="R -> C (in GD1 and GD2; also found in a patient with FT Parkinson disease; dbSNP:rs398123530)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:9851895" FT /id="VAR_009035" FT VARIANT 170 FT /note="R -> L (in GD1 and GD2; dbSNP:rs80356763)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875" FT /id="VAR_009036" FT VARIANT 173 FT /note="T -> I (in GD1; dbSNP:rs78657146)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032400" FT VARIANT 173 FT /note="T -> P (in GD1; dbSNP:rs1441909908)" FT /evidence="ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:9554746" FT /id="VAR_003266" FT VARIANT 174 FT /note="Y -> S (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088440" FT VARIANT 175 FT /note="A -> E (in GD; dbSNP:rs79660787)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032401" FT VARIANT 179 FT /note="D -> H (in GD1; decreased glucosylceramide catabolic FT process; dbSNP:rs147138516)" FT /evidence="ECO:0000269|PubMed:15916907, FT ECO:0000269|PubMed:1864608" FT /id="VAR_003267" FT VARIANT 196 FT /note="K -> Q (in GD1; decreased protein abundance; FT decreased glucosylceramide catabolic process; FT dbSNP:rs121908297)" FT /evidence="ECO:0000269|PubMed:15916907, FT ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:1899336" FT /id="VAR_003268" FT VARIANT 198 FT /note="P -> L (in GD; dbSNP:rs80222298)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009037" FT VARIANT 198 FT /note="P -> S (in GD1; decreased glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081189" FT VARIANT 198 FT /note="P -> T (in GD1)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032402" FT VARIANT 200 FT /note="I -> N (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs77933015)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032201" FT VARIANT 200 FT /note="I -> S (in GD1; dbSNP:rs77933015)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010059" FT VARIANT 201 FT /note="H -> P (in GD1; dbSNP:rs76500263)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032403" FT VARIANT 209 FT /note="R -> C (in GD1; dbSNP:rs398123532)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005" FT /id="VAR_032404" FT VARIANT 209 FT /note="R -> P (in GD1; dbSNP:rs749416070)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:9683600" FT /id="VAR_003269" FT VARIANT 213 FT /note="L -> F (in GD; decreased glucosylceramidase FT activity; 12% of normal activity; dbSNP:rs374591570)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032202" FT VARIANT 214 FT /note="L -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088441" FT VARIANT 215 FT /note="A -> D (in GD1)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003270" FT VARIANT 217 FT /note="P -> S (in GD2)" FT /evidence="ECO:0000269|PubMed:7627192" FT /id="VAR_003271" FT VARIANT 221 FT /note="P -> L (in GD1; very low glucosylceramidase FT activity; dbSNP:rs80205046)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032405" FT VARIANT 221 FT /note="P -> T (in GD1; dbSNP:rs866075757)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003272" FT VARIANT 223 FT /note="W -> R (in GD1 and GD2; dbSNP:rs61748906)" FT /evidence="ECO:0000269|PubMed:10679038, FT ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:8294033" FT /id="VAR_003273" FT VARIANT 224 FT /note="L -> F (in GD; decreased glucosylceramidase FT activity; 4% of normal activity; increases susceptibility FT to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032203" FT VARIANT 227 FT /note="N -> I (in GD2; decreased glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081190" FT VARIANT 227 FT /note="N -> K (in GD1 and GD2; dbSNP:rs381418)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003275" FT VARIANT 227 FT /note="N -> S (in GD1 and GD3; decreased glucosylceramide FT catabolic process; dbSNP:rs364897)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:9217217" FT /id="VAR_003274" FT VARIANT 228 FT /note="G -> V (in GD; dbSNP:rs78911246)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010060" FT VARIANT 229 FT /note="A -> E (in GD2; dbSNP:rs75636769)" FT /evidence="ECO:0000269|PubMed:10649495" FT /id="VAR_009038" FT VARIANT 229 FT /note="A -> T (in GD3)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032406" FT VARIANT 230 FT /note="V -> E (in GD1; very low glucosylceramidase FT activity; dbSNP:rs381427)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032407" FT VARIANT 230 FT /note="V -> G (in GD1; dbSNP:rs381427)" FT /evidence="ECO:0000269|PubMed:10206680, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003276" FT VARIANT 232 FT /note="G -> E (in GD; also found in a patient with FT Parkinson disease; decreased glucosylceramidase activity; FT 7% of normal activity; dbSNP:rs1376479747)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695" FT /id="VAR_032204" FT VARIANT 234 FT /note="G -> E (in GD1; severely decreased FT glucosylceramidase activity; dbSNP:rs74462743)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_003277" FT VARIANT 234 FT /note="G -> W (in GD)" FT /evidence="ECO:0000269|PubMed:10447266" FT /id="VAR_009039" FT VARIANT 235 FT /note="S -> P (in GD1 and GD2; dbSNP:rs1064644)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003278" FT VARIANT 237 FT /note="K -> E (in GD2; severe; loss of glucosylceramidase FT activity; increases susceptibility to proteolytic FT degradation; dbSNP:rs773409311)" FT /evidence="ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:16293621" FT /id="VAR_032205" FT VARIANT 241 FT /note="G -> R (in GD1, GD2 and GD3; severely decreased FT glucosylceramidase activity; dbSNP:rs409652)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:8790604, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9856561" FT /id="VAR_003279" FT VARIANT 244 FT /note="Y -> C (in GD1 and GD3; dbSNP:rs76026102)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:11933202" FT /id="VAR_010062" FT VARIANT 251 FT /note="Y -> H (in GD; uncertain significance; FT dbSNP:rs121908300)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003280" FT VARIANT 252 FT /note="F -> I (in GD1, GD2 and GD3; dbSNP:rs381737)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:1301953, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:9061570, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9217217" FT /id="VAR_003281" FT VARIANT 255 FT /note="F -> Y (in GD; loss of glucosylceramidase activity;; FT dbSNP:rs74500255)" FT /evidence="ECO:0000269|PubMed:1974409, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003282" FT VARIANT 266 FT /note="F -> L (in GD1)" FT /evidence="ECO:0000269|PubMed:24577513" FT /id="VAR_081191" FT VARIANT 270 FT /note="T -> I (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088442" FT VARIANT 270 FT /note="T -> R (in GD2; dbSNP:rs76725886)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032408" FT VARIANT 274 FT /note="E -> K (in GD2; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081192" FT VARIANT 276 FT /note="S -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003283" FT VARIANT 284 FT /note="P -> T (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081193" FT VARIANT 289 FT /note="G -> V (in GD1; dbSNP:rs878853321)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081194" FT VARIANT 290 FT /note="F -> L (in GDPL; dbSNP:rs121908313)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032409" FT VARIANT 294 FT /note="H -> Q (in GD1, GD2 and GD3; associated in cis with FT H-448 in all patients analyzed; uncertain significance; FT dbSNP:rs367968666)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:15690354, ECO:0000269|PubMed:32547927" FT /id="VAR_009040" FT VARIANT 296 FT /note="R -> Q (in GD1 and GD2; also found in a patient with FT Parkinson disease; dbSNP:rs78973108)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:8790604" FT /id="VAR_003284" FT VARIANT 298 FT /note="F -> L (in GD and GD2; decreased glucosylceramidase FT activity; 4% of normal activity)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:3001061" FT /id="VAR_009041" FT VARIANT 301 FT /note="R -> G (in GD1)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081195" FT VARIANT 303 FT /note="L -> I (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs1296507371)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032206" FT VARIANT 304 FT /note="G -> D (in GD1; dbSNP:rs80116658)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010063" FT VARIANT 304 FT /note="G -> R (in GD3; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081196" FT VARIANT 305 FT /note="P -> R (in GD1; dbSNP:rs79215220)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003285" FT VARIANT 310 FT /note="S -> G (in dbSNP:rs1057942)" FT /evidence="ECO:0000269|PubMed:8294033" FT /id="VAR_032410" FT VARIANT 310 FT /note="S -> N (in GD1; severely decreased FT glucosylceramidase activity; less than 5% of normal FT activity; dbSNP:rs74731340)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_010064" FT VARIANT 322 FT /note="D -> N (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088443" FT VARIANT 324 FT /note="R -> C (in GD1 and GD3; dbSNP:rs765633380)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:8790604, ECO:0000269|PubMed:9856561" FT /id="VAR_003286" FT VARIANT 324 FT /note="R -> H (in GD1 and GD2; dbSNP:rs79696831)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:12204005" FT /id="VAR_009042" FT VARIANT 328 FT /note="P -> L (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs121908298)" FT /evidence="ECO:0000269|PubMed:1301953, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003287" FT VARIANT 342 FT /note="K -> I (in GD1; dbSNP:rs77714449)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003288" FT VARIANT 343 FT /note="Y -> C (in GD2; decreased glucosylceramidase FT activity; 16% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs77321207)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:16293621" FT /id="VAR_009043" FT VARIANT 347 FT /note="I -> S (in GD1)" FT /evidence="ECO:0000269|PubMed:24577513" FT /id="VAR_081197" FT VARIANT 348 FT /note="A -> V (in GD1; dbSNP:rs78396650)" FT /evidence="ECO:0000269|PubMed:1899336, FT ECO:0000269|PubMed:32547927" FT /id="VAR_003289" FT VARIANT 350 FT /note="H -> R (in GDPL, GD1 and GD2; dbSNP:rs78198234)" FT /evidence="ECO:0000269|PubMed:10352942, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927" FT /id="VAR_009044" FT VARIANT 351 FT /note="W -> C (in GD1; dbSNP:rs121908304)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:1899336" FT /id="VAR_003290" FT VARIANT 351 FT /note="W -> S (in GD1; loss of glucosylceramide catabolic FT process; dbSNP:rs1553217294)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081198" FT VARIANT 352 FT /note="Y -> H (in GD)" FT /evidence="ECO:0000269|PubMed:8829663" FT /id="VAR_003291" FT VARIANT 354 FT /note="D -> H (in GD1; uncertain significance; FT dbSNP:rs398123526)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003292" FT VARIANT 357 FT /note="A -> D (in GD1; uncertain significance; FT dbSNP:rs78188205)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003293" FT VARIANT 362 FT /note="T -> I (in GD1; decreased glucosylceramidase FT activity; 4-6% of normal activity; dbSNP:rs76539814)" FT /evidence="ECO:0000269|PubMed:1301953, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:8294487" FT /id="VAR_003294" FT VARIANT 363 FT /note="L -> P (in GD1; uncertain significance; also found FT in a patient with Parkinson disease; uncertain FT significance; dbSNP:rs1178732315)" FT /evidence="ECO:0000269|PubMed:26528954, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003295" FT VARIANT 364 FT /note="G -> R (in GD2; dbSNP:rs121908305)" FT /evidence="ECO:0000269|PubMed:2269438, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003296" FT VARIANT 365 FT /note="E -> K (in GD1; benign; decreased glucosylceramidase FT activity; 42% of normal activity; dbSNP:rs2230288)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:11903352, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:24022302" FT /id="VAR_003297" FT VARIANT 368 FT /note="R -> H (in dbSNP:rs1064648)" FT /evidence="ECO:0000269|PubMed:8294033" FT /id="VAR_032411" FT VARIANT 380 FT /note="A -> T (in GD1; dbSNP:rs781306264)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:9554454" FT /id="VAR_009045" FT VARIANT 381 FT /note="C -> G (in GD2; loss of glucosylceramidase activity; FT dbSNP:rs121908306)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:2269438" FT /id="VAR_003298" FT VARIANT 388 FT /note="E -> K (in GD; decreased glucosylceramidase FT activity; 12% of normal activity; dbSNP:rs1161552095)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032207" FT VARIANT 391 FT /note="V -> L (in GD1; decreased glucosylceramidase FT activity; dbSNP:rs398123527)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_010065" FT VARIANT 392 FT /note="R -> G (in GD and GD3; dbSNP:rs121908308)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9650766" FT /id="VAR_010066" FT VARIANT 392 FT /note="R -> W (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs121908308)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032208" FT VARIANT 398 FT /note="R -> Q (in GD1; mild; dbSNP:rs74979486)" FT /evidence="ECO:0000269|PubMed:1487244, FT ECO:0000269|PubMed:8829663" FT /id="VAR_003299" FT VARIANT 400 FT /note="M -> I (in GD2; uncertain significance; FT dbSNP:rs149487315)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032412" FT VARIANT 402 FT /note="Y -> C (in GD; decreased glucosylceramidase FT activity; 8% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs76228122)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032209" FT VARIANT 403 FT /note="S -> T (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs121908307)" FT /evidence="ECO:0000269|PubMed:1899336, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003300" FT VARIANT 405 FT /note="S -> G (in GD)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010067" FT VARIANT 405 FT /note="S -> N (in GD; dbSNP:rs1392291885)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009046" FT VARIANT 405 FT /note="S -> R (in GD1; loss of glucosylceramide catabolic FT process; dbSNP:rs75528494)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081199" FT VARIANT 408 FT /note="T -> M (in GD1; likely benign; dbSNP:rs75548401)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12694238, ECO:0000269|PubMed:14702039" FT /id="VAR_003301" FT VARIANT 409 FT /note="N -> S (in GD1; risk factor for Parkinson disease; FT increased proteasomal degradation; decreased protein FT abundance; decreased glucosylceramide catabolic process; FT decreased glucosylceramidase activity; 23% of normal FT activity when expressed in a heterologous system; alters FT interaction with saposin-C; dbSNP:rs76763715)" FT /evidence="ECO:0000269|PubMed:10206680, FT ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:15826241, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:18332251, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:19846850, FT ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7915932, FT ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9240741, FT ECO:0000269|PubMed:9683600, ECO:0000269|PubMed:9856561, FT ECO:0000269|Ref.14" FT /id="VAR_003302" FT VARIANT 410 FT /note="L -> V (in GD; decreased glucosylceramidase FT activity; 15% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs121908314)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032210" FT VARIANT 414 FT /note="V -> L (in GD and GD1; mild; dbSNP:rs398123528)" FT /evidence="ECO:0000269|PubMed:36776904, FT ECO:0000269|PubMed:9182788" FT /id="VAR_010068" FT VARIANT 416 FT /note="G -> S (in GD1 and GD3; dbSNP:rs121908311)" FT /evidence="ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:9683600" FT /id="VAR_003303" FT VARIANT 417 FT /note="W -> G (in GD1; dbSNP:rs1450426641)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003304" FT VARIANT 419 FT /note="D -> A (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs77284004)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_003305" FT VARIANT 419 FT /note="D -> H (in GD; decreased glucosylceramidase FT activity; 4% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032211" FT VARIANT 419 FT /note="D -> N (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:8790604" FT /id="VAR_003306" FT VARIANT 420 FT /note="W -> C (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081200" FT VARIANT 421 FT /note="N -> K (in GD; decreased glucosylceramidase FT activity; 22% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032212" FT VARIANT 426 FT /note="P -> L (in GD; dbSNP:rs1057519357 and FT dbSNP:rs994723035)" FT /evidence="ECO:0000269|PubMed:8937765" FT /id="VAR_010069" FT VARIANT 428 FT /note="G -> E (in GD2)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003307" FT VARIANT 429 FT /note="G -> R (in GD; decreased glucosylceramidase FT activity; 17% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032213" FT VARIANT 430 FT /note="P -> L (in GD1; dbSNP:rs76910485)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003308" FT VARIANT 431 FT /note="N -> I (in GD2; dbSNP:rs77738682)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003309" FT VARIANT 432 FT /note="W -> R (in GD)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009047" FT VARIANT 433 FT /note="V -> L (in GD1 and GD3; severe; decreased FT glucosylceramidase activity; 12% of normal activity; FT dbSNP:rs80356769)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:2508065, FT ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003310" FT VARIANT 435 FT /note="N -> T (in GD1; mild; dbSNP:rs75385858)" FT /evidence="ECO:0000269|PubMed:8889591" FT /id="VAR_003311" FT VARIANT 436 FT /note="F -> S (in GD; decreased glucosylceramidase FT activity; 6% of normal activity; alters protein stability FT and increases susceptibility to proteolytic degradation; FT dbSNP:rs75243000)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032214" FT VARIANT 437 FT /note="V -> F (in GDPL; dbSNP:rs121908310)" FT /evidence="ECO:0000269|PubMed:10352942" FT /id="VAR_009048" FT VARIANT 437 FT /note="V -> L (in GD3; dbSNP:rs121908310)" FT /evidence="ECO:0000269|PubMed:8780099" FT /id="VAR_010070" FT VARIANT 438 FT /note="D -> N (in GD1 and GD2; decreased glucosylceramidase FT activity; 14% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs1553217009)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:8112750, ECO:0000269|PubMed:9856561" FT /id="VAR_003312" FT VARIANT 438 FT /note="D -> Y (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032413" FT VARIANT 440 FT /note="P -> L (in GD1; dbSNP:rs74598136)" FT /evidence="ECO:0000269|PubMed:10340647, FT ECO:0000269|PubMed:15605411" FT /id="VAR_010071" FT VARIANT 441 FT /note="I -> F (in GD3)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032414" FT VARIANT 441 FT /note="I -> T (in GD; mild; dbSNP:rs75564605)" FT /evidence="ECO:0000269|PubMed:9182788" FT /id="VAR_010072" FT VARIANT 448 FT /note="D -> H (in GD1, GD2, GD3 and GD3C; associated in cis FT with Q-294 in some patients; at homozygosity it causes FT GD3C; also found in a patient with Parkinson disease; loss FT of glucosylceramidase activity; alters protein stability; FT dbSNP:rs1064651)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:15690354, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:2269438, FT ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:36776904, ECO:0000269|PubMed:7475546, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:9040001, FT ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9856561" FT /id="VAR_003313" FT VARIANT 448 FT /note="D -> V (in GD3; loss of glucosylceramidase activity; FT results in glycosphingolipid accumulation in brain and FT liver of a knockin mouse model due to impaired FT glucosylceramidase activity; dbSNP:rs77369218)" FT /evidence="ECO:0000269|PubMed:2508065, FT ECO:0000269|PubMed:34106956, ECO:0000269|PubMed:8294487" FT /id="VAR_003314" FT VARIANT 450 FT /note="F -> I (in GD1; dbSNP:rs1553216985)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010073" FT VARIANT 451 FT /note="Y -> H (in GD1)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003315" FT VARIANT 452 FT /note="K -> Q (in GD)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010074" FT VARIANT 454 FT /note="P -> R (in GD2; loss of glucosylceramidase activity; FT dbSNP:rs121908295)" FT /evidence="ECO:0000269|PubMed:2464926, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003316" FT VARIANT 455 FT /note="M -> V (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032215" FT VARIANT 456 FT /note="F -> V (in GD1; severely decreased FT glucosylceramidase activity; 3% of normal activity when FT expressed in a heterologous system)" FT /evidence="ECO:0000269|PubMed:7915932, FT ECO:0000269|PubMed:9240741" FT /id="VAR_003317" FT VARIANT 457 FT /note="Y -> C (in GD and GD1; dbSNP:rs74752878)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:8076951" FT /id="VAR_003318" FT VARIANT 460 FT /note="G -> D (in GD1; associated in cis with R-490; loss FT of glucosylceramidase activity)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032415" FT VARIANT 464 FT /note="K -> E (in GD3; severe; uncertain significance)" FT /evidence="ECO:0000269|PubMed:1487244" FT /id="VAR_003319" FT VARIANT 482 FT /note="D -> N (likely benign; found in a patient with FT Parkinson disease; dbSNP:rs75671029)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063067" FT VARIANT 483 FT /note="L -> P (in GD1, GD2 and GD3; risk factor for FT Parkinson disease; gene conversion; alters protein FT stability; increased proteasomal degradation; decreased FT protein abundance; very low glucosylceramide catabolic FT process; severe decrease of glucosylceramidase activity; 3% FT of normal activity when expressed in a heterologous system; FT dbSNP:rs421016)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10679038, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:2464926, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9217217, FT ECO:0000269|PubMed:9240741, ECO:0000269|PubMed:9683600, FT ECO:0000269|PubMed:9851895, ECO:0000269|PubMed:9856561" FT /id="VAR_003321" FT VARIANT 483 FT /note="L -> R (in GD1 and GD2; dbSNP:rs421016)" FT /evidence="ECO:0000269|PubMed:27825739, FT ECO:0000269|PubMed:7981693" FT /id="VAR_003320" FT VARIANT 485 FT /note="A -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003322" FT VARIANT 486 FT /note="V -> E (in GD1)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081201" FT VARIANT 490 FT /note="H -> R (in GD1; associated in cis with D-460; FT uncertain significance; no effect on glucosylceramidase FT activity; dbSNP:rs76071730)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411" FT /id="VAR_032416" FT VARIANT 495 FT /note="A -> P (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs368060)" FT /evidence="ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:8294487" FT /id="VAR_003323" FT VARIANT 497 FT /note="V -> L" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063068" FT VARIANT 500 FT /note="L -> P (in GD; decreased glucosylceramidase FT activity; 10% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs1362103320)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032216" FT VARIANT 501 FT /note="N -> K (in GD2)" FT /evidence="ECO:0000269|PubMed:9279145" FT /id="VAR_009049" FT VARIANT 501 FT /note="N -> Y (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088444" FT VARIANT 502 FT /note="R -> C (in GD1 and GD2; also found in patients with FT Parkinson disease; no effect on protein abundance; FT decreased glucosylceramidase activity; dbSNP:rs80356771)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:1301953, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:1972019, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:9683600" FT /id="VAR_003324" FT VARIANT 502 FT /note="R -> P (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032217" FT VARIANT 509 FT /note="L -> P" FT /id="VAR_003325" FT VARIANT 513 FT /note="D -> Y (in GD2)" FT /evidence="ECO:0000269|PubMed:9637431" FT /id="VAR_009050" FT VARIANT 517 FT /note="G -> S (in GD; dbSNP:rs121908301)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003326" FT VARIANT 521 FT /note="T -> K (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088445" FT VARIANT 530 FT /note="T -> I (in GD3; dbSNP:rs78016673)" FT /evidence="ECO:0000269|PubMed:8780099" FT /id="VAR_010075" FT VARIANT 535 FT /note="R -> C (in GD1; mild; dbSNP:rs747506979)" FT /evidence="ECO:0000269|PubMed:1487244, FT ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:9061570" FT /id="VAR_003327" FT VARIANT 535 FT /note="R -> H (in GD1; decreased glucosylceramidase FT activity; 7% of normal activity when expressed in a FT heterologous system; dbSNP:rs75822236)" FT /evidence="ECO:0000269|PubMed:7916532, FT ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:9240741" FT /id="VAR_003328" FT MUTAGEN 43 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 57 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 62 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 379 FT /note="E->G: 1000-fold decreases of glucosylceramidase FT activity." FT /evidence="ECO:0000269|PubMed:7908905" FT MUTAGEN 482 FT /note="D->E: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 482 FT /note="D->G: Decreased glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 482 FT /note="D->S: Severe decrease of glucosylceramidase FT activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 501 FT /note="N->D: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 501 FT /note="N->Q: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT CONFLICT 176 FT /note="D -> G (in Ref. 7; BAH13357)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="N -> R (in Ref. 5; BAA02546)" FT /evidence="ECO:0000305" FT CONFLICT 470 FT /note="S -> I (in Ref. 15; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 534 FT /note="R -> H (in Ref. 1; AAA35873)" FT /evidence="ECO:0000305" FT STRAND 44..46 FT /evidence="ECO:0007829|PDB:6Q1P" FT STRAND 49..52 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 54..57 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 75..82 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 88..94 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 96..98 FT /evidence="ECO:0007829|PDB:6Q6N" FT STRAND 102..116 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 119..123 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 126..133 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 137..148 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 150..153 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 157..163 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 166..170 FT /evidence="ECO:0007829|PDB:6Q6N" FT STRAND 177..179 FT /evidence="ECO:0007829|PDB:6Q6K" FT HELIX 190..193 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 196..206 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 212..218 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 222..224 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 225..227 FT /evidence="ECO:0007829|PDB:6Q1N" FT STRAND 228..233 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 236..238 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 243..261 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 267..271 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 275..279 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:3GXF" FT HELIX 292..301 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 303..308 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 311..314 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 315..323 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 324..326 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 329..335 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 346..350 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 354..356 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 359..362 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 363..369 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 373..379 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 385..388 FT /evidence="ECO:0007829|PDB:6MOZ" FT HELIX 396..411 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 414..422 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:3KEH" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6Q1N" FT STRAND 440..444 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 445..447 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 449..452 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 471..479 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 482..489 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 495..501 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 507..513 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 514..516 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 517..523 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 527..533 FT /evidence="ECO:0007829|PDB:8AX3" SQ SEQUENCE 536 AA; 59716 MW; FA1E15684344A0E6 CRC64; MEFSSPSREE CPKPLSRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT YCDSFDPPTF PALGTFSRYE STRSGRRMEL SMGPIQANHT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV PMASCDFSIR TYTYADTPDD FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA RDLGPTLANS THHNVRLLML DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM QYSHSIITNL LYHVVGWTDW NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ // ID GRN_HUMAN Reviewed; 593 AA. AC P28799; D3DX55; P23781; P23782; P23783; P23784; Q53HQ8; Q53Y88; Q540U8; AC Q9BWE7; Q9H8S1; Q9UCH0; DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2005, sequence version 2. DT 28-JAN-2026, entry version 244. DE RecName: Full=Progranulin {ECO:0000303|PubMed:16862116}; DE Short=PGRN {ECO:0000303|PubMed:16862116}; DE AltName: Full=Acrogranin {ECO:0000250|UniProtKB:P28798}; DE AltName: Full=Epithelin precursor {ECO:0000303|PubMed:1618805}; DE AltName: Full=Glycoprotein of 88 Kda {ECO:0000250|UniProtKB:P28798}; DE Short=GP88; DE Short=Glycoprotein 88; DE AltName: Full=Granulin precursor {ECO:0000303|PubMed:1542665}; DE AltName: Full=PC cell-derived growth factor {ECO:0000250|UniProtKB:P28798}; DE Short=PCDGF {ECO:0000303|Ref.4}; DE AltName: Full=Proepithelin {ECO:0000303|PubMed:12526812, ECO:0000303|PubMed:1618805}; DE Short=PEPI {ECO:0000303|PubMed:12526812}; DE Contains: DE RecName: Full=Paragranulin; DE Contains: DE RecName: Full=Granulin-1; DE AltName: Full=Granulin G; DE Contains: DE RecName: Full=Granulin-2; DE AltName: Full=Granulin F; DE Contains: DE RecName: Full=Granulin-3; DE AltName: Full=Epithelin-2 {ECO:0000250|UniProtKB:P23785}; DE AltName: Full=Granulin B; DE Contains: DE RecName: Full=Granulin-4; DE AltName: Full=Epithelin-1 {ECO:0000250|UniProtKB:P23785}; DE AltName: Full=Granulin A; DE Contains: DE RecName: Full=Granulin-5; DE AltName: Full=Granulin C; DE Contains: DE RecName: Full=Granulin-6; DE AltName: Full=Granulin D; DE Contains: DE RecName: Full=Granulin-7; DE AltName: Full=Granulin E; DE Flags: Precursor; GN Name=GRN {ECO:0000312|HGNC:HGNC:4601}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND SEQUENCE REVISION. RX PubMed=1417868; DOI=10.1016/0006-291x(92)92349-3; RA Bhandari V., Bateman A.; RT "Structure and chromosomal location of the human granulin gene."; RL Biochem. Biophys. Res. Commun. 188:57-63(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Kidney; RX PubMed=1618805; DOI=10.1016/s0021-9258(18)42382-4; RA Plowman G.D., Green J.M., Neubauer M.G., Buckley S.D., McDonald V.L., RA Todaro G.J., Shoyab M.; RT "The epithelin precursor encodes two proteins with opposing activities on RT epithelial cell growth."; RL J. Biol. Chem. 267:13073-13078(1992). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Bone marrow; RX PubMed=1542665; DOI=10.1073/pnas.89.5.1715; RA Bhandari V., Palfree R.G.E., Bateman A.; RT "Isolation and sequence of the granulin precursor cDNA from human bone RT marrow reveals tandem cysteine-rich granulin domains."; RL Proc. Natl. Acad. Sci. U.S.A. 89:1715-1719(1992). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Lu R., Tian C., Serrero G.; RT "PCDGF sequence from lambda phage human Jurkat T cell cDNA library RT (Clontech)."; RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RA Yu W., Gibbs R.A.; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Ovary; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Adipose tissue; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Cervix, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP PROTEIN SEQUENCE OF 51-62; 122-131; 351-357; 361-367; 435-446 AND 517-526, RP INTERACTION WITH SLPI, PROTEOLYTIC CLEAVAGE, AND FUNCTION. RX PubMed=12526812; DOI=10.1016/s0092-8674(02)01141-8; RA Zhu J., Nathan C., Jin W., Sim D., Ashcroft G.S., Wahl S.M., Lacomis L., RA Erdjument-Bromage H., Tempst P., Wright C.D., Ding A.; RT "Conversion of proepithelin to epithelins: roles of SLPI and elastase in RT host defense and wound repair."; RL Cell 111:867-878(2002). RN [12] RP PROTEIN SEQUENCE OF 206-233; 281-336; 364-396 AND 442-447. RC TISSUE=Leukocyte; RX PubMed=2268320; DOI=10.1016/s0006-291x(05)80908-8; RA Bateman A., Belcourt D.R., Bennett H.P., Lazure C., Solomon S.; RT "Granulins, a novel class of peptide from leukocytes."; RL Biochem. Biophys. Res. Commun. 173:1161-1168(1990). RN [13] RP PROTEIN SEQUENCE OF 281-295. RX PubMed=8471426; DOI=10.1038/bjc.1993.127; RA Kardana A., Bagshawe K.D., Coles B., Read D., Taylor M.; RT "Characterisation of UGP and its relationship with beta-core fragment."; RL Br. J. Cancer 67:686-692(1993). RN [14] RP INVOLVEMENT IN FTD2. RX PubMed=16862116; DOI=10.1038/nature05016; RA Baker M., Mackenzie I.R., Pickering-Brown S.M., Gass J., Rademakers R., RA Lindholm C., Snowden J., Adamson J., Sadovnick A.D., Rollinson S., RA Cannon A., Dwosh E., Neary D., Melquist S., Richardson A., Dickson D., RA Berger Z., Eriksen J., Robinson T., Zehr C., Dickey C.A., Crook R., RA McGowan E., Mann D., Boeve B., Feldman H., Hutton M.; RT "Mutations in progranulin cause tau-negative frontotemporal dementia linked RT to chromosome 17."; RL Nature 442:916-919(2006). RN [15] RP FUNCTION. RX PubMed=18378771; DOI=10.1083/jcb.200712039; RA Van Damme P., Van Hoecke A., Lambrechts D., Vanacker P., Bogaert E., RA van Swieten J., Carmeliet P., Van Den Bosch L., Robberecht W.; RT "Progranulin functions as a neurotrophic factor to regulate neurite RT outgrowth and enhance neuronal survival."; RL J. Cell Biol. 181:37-41(2008). RN [16] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-265. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [17] RP GLYCOSYLATION AT ASN-118; ASN-265; ASN-368 AND ASN-530. RX PubMed=20188224; DOI=10.1016/j.jprot.2010.02.013; RA Songsrirote K., Li Z., Ashford D., Bateman A., Thomas-Oates J.; RT "Development and application of mass spectrometric methods for the analysis RT of progranulin N-glycosylation."; RL J. Proteomics 73:1479-1490(2010). RN [18] RP INTERACTION WITH SORT1, AND SUBCELLULAR LOCATION. RX PubMed=21092856; DOI=10.1016/j.neuron.2010.09.034; RA Hu F., Padukkavidana T., Vaegter C.B., Brady O.A., Zheng Y., RA Mackenzie I.R., Feldman H.H., Nykjaer A., Strittmatter S.M.; RT "Sortilin-mediated endocytosis determines levels of the frontotemporal RT dementia protein, progranulin."; RL Neuron 68:654-667(2010). RN [19] RP INVOLVEMENT IN CLN11. RX PubMed=22608501; DOI=10.1016/j.ajhg.2012.04.021; RA Smith K.R., Damiano J., Franceschetti S., Carpenter S., Canafoglia L., RA Morbin M., Rossi G., Pareyson D., Mole S.E., Staropoli J.F., Sims K.B., RA Lewis J., Lin W.L., Dickson D.W., Dahl H.H., Bahlo M., Berkovic S.F.; RT "Strikingly different clinicopathological phenotypes determined by RT progranulin-mutation dosage."; RL Am. J. Hum. Genet. 90:1102-1107(2012). RN [20] RP SUBUNIT. RX PubMed=23364791; DOI=10.1074/jbc.m112.441949; RA Nguyen A.D., Nguyen T.A., Cenik B., Yu G., Herz J., Walther T.C., RA Davidson W.S., Farese R.V. Jr.; RT "Secreted progranulin is a homodimer and is not a component of high density RT lipoproteins (HDL)."; RL J. Biol. Chem. 288:8627-8635(2013). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [22] RP INTERACTION WITH PSAP, AND SUBCELLULAR LOCATION. RX PubMed=26370502; DOI=10.1083/jcb.201502029; RA Zhou X., Sun L., Bastos de Oliveira F., Qi X., Brown W.J., Smolka M.B., RA Sun Y., Hu F.; RT "Prosaposin facilitates sortilin-independent lysosomal trafficking of RT progranulin."; RL J. Cell Biol. 210:991-1002(2015). RN [23] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [24] RP INTERACTION WITH GBA1 AND HSPA1A. RX PubMed=27789271; DOI=10.1016/j.ebiom.2016.10.010; RA Jian J., Tian Q.Y., Hettinghouse A., Zhao S., Liu H., Wei J., Grunig G., RA Zhang W., Setchell K.D.R., Sun Y., Overkleeft H.S., Chan G.L., Liu C.J.; RT "Progranulin Recruits HSP70 to beta-Glucocerebrosidase and Is Therapeutic RT Against Gaucher Disease."; RL EBioMedicine 13:212-224(2016). RN [25] RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION. RX PubMed=28073925; DOI=10.1093/hmg/ddx011; RA Tanaka Y., Suzuki G., Matsuwaki T., Hosokawa M., Serrano G., Beach T.G., RA Yamanouchi K., Hasegawa M., Nishihara M.; RT "Progranulin regulates lysosomal function and biogenesis through RT acidification of lysosomes."; RL Hum. Mol. Genet. 26:969-988(2017). RN [26] RP FUNCTION, AND INTERACTION WITH CTSD. RX PubMed=28453791; DOI=10.1093/hmg/ddx162; RA Beel S., Moisse M., Damme M., De Muynck L., Robberecht W., RA Van Den Bosch L., Saftig P., Van Damme P.; RT "Progranulin functions as a cathepsin D chaperone to stimulate axonal RT outgrowth in vivo."; RL Hum. Mol. Genet. 26:2850-2863(2017). RN [27] RP PROTEOLYTIC CLEAVAGE BY CTSL AND ELANE, IDENTIFICATION BY MASS RP SPECTROMETRY, AND SUBCELLULAR LOCATION. RX PubMed=28743268; DOI=10.1186/s13024-017-0196-6; RA Lee C.W., Stankowski J.N., Chew J., Cook C.N., Lam Y.W., Almeida S., RA Carlomagno Y., Lau K.F., Prudencio M., Gao F.B., Bogyo M., Dickson D.W., RA Petrucelli L.; RT "The lysosomal protein cathepsin L is a progranulin protease."; RL Mol. Neurodegener. 12:55-55(2017). RN [28] RP FUNCTION, INTERACTION WITH PSAP AND SORT1, AND SUBCELLULAR LOCATION. RX PubMed=28541286; DOI=10.1038/ncomms15277; RA Zhou X., Sun L., Bracko O., Choi J.W., Jia Y., Nana A.L., Brady O.A., RA Hernandez J.C.C., Nishimura N., Seeley W.W., Hu F.; RT "Impaired prosaposin lysosomal trafficking in frontotemporal lobar RT degeneration due to progranulin mutations."; RL Nat. Commun. 8:15277-15277(2017). RN [29] RP STRUCTURE BY NMR OF 284-311. RX PubMed=10715107; DOI=10.1021/bi992130u; RA Tolkatchev D., Ng A., Vranken W., Ni F.; RT "Design and solution structure of a well-folded stack of two beta-hairpins RT based on the amino-terminal fragment of human granulin A."; RL Biochemistry 39:2878-2886(2000). RN [30] RP STRUCTURE BY NMR OF 123-179; 281-337 AND 364-417, AND DISULFIDE BONDS. RX PubMed=18359860; DOI=10.1110/ps.073295308; RA Tolkatchev D., Malik S., Vinogradova A., Wang P., Chen Z., Xu P., RA Bennett H.P., Bateman A., Ni F.; RT "Structure dissection of human progranulin identifies well-folded RT granulin/epithelin modules with unique functional activities."; RL Protein Sci. 17:711-724(2008). RN [31] RP VARIANT FTD2 ASP-9. RX PubMed=16983685; DOI=10.1002/ana.20963; RA Mukherjee O., Pastor P., Cairns N.J., Chakraverty S., Kauwe J.S.K., RA Shears S., Behrens M.I., Budde J., Hinrichs A.L., Norton J., Levitch D., RA Taylor-Reinwald L., Gitcho M., Tu P.-H., Tenenholz Grinberg L., RA Liscic R.M., Armendariz J., Morris J.C., Goate A.M.; RT "HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin- RT positive, tau-negative inclusions caused by a missense mutation in the RT signal peptide of progranulin."; RL Ann. Neurol. 60:314-322(2006). RN [32] RP CHARACTERIZATION OF VARIANT FTD2 ASP-9. RX PubMed=18183624; DOI=10.1002/humu.20681; RA Mukherjee O., Wang J., Gitcho M., Chakraverty S., Taylor-Reinwald L., RA Shears S., Kauwe J.S.K., Norton J., Levitch D., Bigio E.H., Hatanpaa K.J., RA White C.L., Morris J.C., Cairns N.J., Goate A.; RT "Molecular characterization of novel progranulin (GRN) mutations in RT frontotemporal dementia."; RL Hum. Mutat. 29:512-521(2008). RN [33] RP VARIANTS TRP-19; TRP-55; THR-69; ASN-119 DEL; TYR-120; MET-182; SER-221; RP LEU-275; ASN-376; LEU-398; GLN-433; ALA-515 AND HIS-564. RX PubMed=20020531; DOI=10.1002/humu.21152; RA Guerreiro R.J., Washecka N., Hardy J., Singleton A.; RT "A thorough assessment of benign genetic variability in GRN and MAPT."; RL Hum. Mutat. 31:E1126-E1140(2010). CC -!- FUNCTION: Secreted protein that acts as a key regulator of lysosomal CC function and as a growth factor involved in inflammation, wound healing CC and cell proliferation (PubMed:12526812, PubMed:18378771, CC PubMed:28073925, PubMed:28453791, PubMed:28541286). Regulates protein CC trafficking to lysosomes, and also the activity of lysosomal enzymes CC (PubMed:28453791, PubMed:28541286). Also facilitates the acidification CC of lysosomes, causing degradation of mature CTSD by CTSB CC (PubMed:28073925). In addition, functions as a wound-related growth CC factor that acts directly on dermal fibroblasts and endothelial cells CC to promote division, migration and the formation of capillary-like CC tubule structures (By similarity). Also promotes epithelial cell CC proliferation by blocking TNF-mediated neutrophil activation preventing CC release of oxidants and proteases (PubMed:12526812). Moreover, CC modulates inflammation in neurons by preserving neurons survival, CC axonal outgrowth and neuronal integrity (PubMed:18378771). CC {ECO:0000250|UniProtKB:P28798, ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:18378771, ECO:0000269|PubMed:28073925, CC ECO:0000269|PubMed:28453791, ECO:0000269|PubMed:28541286}. CC -!- FUNCTION: [Granulin-4]: Promotes proliferation of the epithelial cell CC line A431 in culture. CC -!- FUNCTION: [Granulin-3]: Inhibits epithelial cell proliferation and CC induces epithelial cells to secrete IL-8. CC {ECO:0000269|PubMed:12526812}. CC -!- FUNCTION: [Granulin-7]: Stabilizes CTSD through interaction with CTSD CC leading to maintain its aspartic-type peptidase activity. CC {ECO:0000269|PubMed:28453791}. CC -!- SUBUNIT: Progranulin is secreted as a homodimer (PubMed:23364791). CC Interacts with SLPI; interaction protects progranulin from proteolysis CC (PubMed:12526812). Interacts (via region corresponding to granulin-7 CC peptide) with CTSD; stabilizes CTSD and increases its proteolytic CC activity (PubMed:28453791). Interacts (via region corresponding to CC granulin-7 peptide) with SORT1; this interaction mediates endocytosis CC and lysosome delivery of progranulin; interaction occurs at the CC neuronal cell surface in a stressed nervous system (PubMed:21092856). CC Interacts with PSAP; facilitates lysosomal delivery of progranulin from CC the extracellular space and the biosynthetic pathway (PubMed:26370502). CC Forms a complex with PSAP and M6PR; PSAP bridges the binding between CC progranulin and M6PR (PubMed:26370502). Forms a complex with PSAP and CC SORT1; progranulin bridges the interaction between PSAP and SORT1; CC facilitates lysosomal targeting of PSAP via SORT1; interaction enhances CC PSAP uptake in primary cortical neurons (PubMed:28541286). Interacts CC (via regions corresponding to granulin-2 and granulin-7 peptides) with CC GBA1; this interaction prevents aggregation of GBA1-SCARB2 complex via CC interaction with HSPA1A upon stress (PubMed:27789271). Interacts (via CC region corresponding to granulin-7 peptide) with HSPA1A; mediates CC recruitment of HSPA1A to GBA1 and prevents GBA1 aggregation in response CC to stress (PubMed:27789271). {ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:21092856, ECO:0000269|PubMed:23364791, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:27789271, CC ECO:0000269|PubMed:28453791, ECO:0000269|PubMed:28541286}. CC -!- INTERACTION: CC P28799; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-747754, EBI-10173507; CC P28799; Q9UIJ7: AK3; NbExp=3; IntAct=EBI-747754, EBI-3916527; CC P28799; Q9NYG5: ANAPC11; NbExp=3; IntAct=EBI-747754, EBI-2130187; CC P28799; Q8N6T3: ARFGAP1; NbExp=3; IntAct=EBI-747754, EBI-716933; CC P28799; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-747754, EBI-10694449; CC P28799; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-747754, EBI-14199987; CC P28799; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-747754, EBI-25843552; CC P28799; Q6XD76: ASCL4; NbExp=3; IntAct=EBI-747754, EBI-10254793; CC P28799; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-747754, EBI-9089489; CC P28799; Q8IXM2: BACC1; NbExp=3; IntAct=EBI-747754, EBI-4280811; CC P28799; P46379-2: BAG6; NbExp=3; IntAct=EBI-747754, EBI-10988864; CC P28799; Q16611: BAK1; NbExp=3; IntAct=EBI-747754, EBI-519866; CC P28799; Q14457: BECN1; NbExp=3; IntAct=EBI-747754, EBI-949378; CC P28799; Q96LC9: BMF; NbExp=3; IntAct=EBI-747754, EBI-3919268; CC P28799; Q9GZL8: BPESC1; NbExp=3; IntAct=EBI-747754, EBI-25861458; CC P28799; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-747754, EBI-2837444; CC P28799; Q9Y297: BTRC; NbExp=3; IntAct=EBI-747754, EBI-307461; CC P28799; Q8TAB5: C1orf216; NbExp=3; IntAct=EBI-747754, EBI-747505; CC P28799; Q6P5X5: C22orf39; NbExp=3; IntAct=EBI-747754, EBI-7317823; CC P28799; Q6P5X5-2: C22orf39; NbExp=3; IntAct=EBI-747754, EBI-10692329; CC P28799; Q53FE4: C4orf17; NbExp=3; IntAct=EBI-747754, EBI-715110; CC P28799; O00555: CACNA1A; NbExp=2; IntAct=EBI-747754, EBI-766279; CC P28799; Q96NX5: CAMK1G; NbExp=3; IntAct=EBI-747754, EBI-3920838; CC P28799; O75808: CAPN15; NbExp=3; IntAct=EBI-747754, EBI-6149008; CC P28799; Q8N5R6: CCDC33; NbExp=3; IntAct=EBI-747754, EBI-740841; CC P28799; P50750-2: CDK9; NbExp=3; IntAct=EBI-747754, EBI-12029902; CC P28799; O14646-2: CHD1; NbExp=3; IntAct=EBI-747754, EBI-10961487; CC P28799; Q9BRJ6: CHLSN; NbExp=3; IntAct=EBI-747754, EBI-751612; CC P28799; Q9Y3D0: CIAO2B; NbExp=3; IntAct=EBI-747754, EBI-744045; CC P28799; Q99967: CITED2; NbExp=3; IntAct=EBI-747754, EBI-937732; CC P28799; Q9Y240: CLEC11A; NbExp=3; IntAct=EBI-747754, EBI-3957044; CC P28799; Q9H2X3: CLEC4M; NbExp=2; IntAct=EBI-747754, EBI-1391211; CC P28799; Q96DZ5: CLIP3; NbExp=3; IntAct=EBI-747754, EBI-12823145; CC P28799; Q16740: CLPP; NbExp=3; IntAct=EBI-747754, EBI-1056029; CC P28799; Q9BT09: CNPY3; NbExp=3; IntAct=EBI-747754, EBI-2835965; CC P28799; Q6PJW8-3: CNST; NbExp=3; IntAct=EBI-747754, EBI-25836090; CC P28799; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-747754, EBI-350590; CC P28799; Q9UGL9: CRCT1; NbExp=3; IntAct=EBI-747754, EBI-713677; CC P28799; Q02930-3: CREB5; NbExp=3; IntAct=EBI-747754, EBI-10192698; CC P28799; Q49AN0: CRY2; NbExp=3; IntAct=EBI-747754, EBI-2212355; CC P28799; P01040: CSTA; NbExp=3; IntAct=EBI-747754, EBI-724303; CC P28799; P07339: CTSD; NbExp=4; IntAct=EBI-747754, EBI-2115097; CC P28799; P42830: CXCL5; NbExp=3; IntAct=EBI-747754, EBI-12175919; CC P28799; Q8TB03: CXorf38; NbExp=3; IntAct=EBI-747754, EBI-12024320; CC P28799; P00167: CYB5A; NbExp=3; IntAct=EBI-747754, EBI-1047284; CC P28799; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-747754, EBI-3867333; CC P28799; Q16643: DBN1; NbExp=5; IntAct=EBI-747754, EBI-351394; CC P28799; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-747754, EBI-25842815; CC P28799; Q9P1A6-3: DLGAP2; NbExp=3; IntAct=EBI-747754, EBI-12019838; CC P28799; Q07687: DLX2; NbExp=3; IntAct=EBI-747754, EBI-3908234; CC P28799; Q9NQL9: DMRT3; NbExp=3; IntAct=EBI-747754, EBI-9679045; CC P28799; P49184: DNASE1L1; NbExp=3; IntAct=EBI-747754, EBI-20894690; CC P28799; Q16610: ECM1; NbExp=3; IntAct=EBI-747754, EBI-947964; CC P28799; O75530-2: EED; NbExp=3; IntAct=EBI-747754, EBI-11132357; CC P28799; O60841: EIF5B; NbExp=3; IntAct=EBI-747754, EBI-928530; CC P28799; Q6UXG2-3: ELAPOR1; NbExp=3; IntAct=EBI-747754, EBI-12920100; CC P28799; Q8TE68-3: EPS8L1; NbExp=3; IntAct=EBI-747754, EBI-21574901; CC P28799; Q9H6S3: EPS8L2; NbExp=3; IntAct=EBI-747754, EBI-3940939; CC P28799; O15540: FABP7; NbExp=3; IntAct=EBI-747754, EBI-10697159; CC P28799; Q9UNN5: FAF1; NbExp=3; IntAct=EBI-747754, EBI-718246; CC P28799; Q6SJ93: FAM111B; NbExp=3; IntAct=EBI-747754, EBI-6309082; CC P28799; Q96AQ9: FAM131C; NbExp=4; IntAct=EBI-747754, EBI-741921; CC P28799; Q5HYJ3-3: FAM76B; NbExp=6; IntAct=EBI-747754, EBI-11956087; CC P28799; Q17RN3: FAM98C; NbExp=3; IntAct=EBI-747754, EBI-5461838; CC P28799; Q8IZU1: FAM9A; NbExp=3; IntAct=EBI-747754, EBI-8468186; CC P28799; Q9NW38: FANCL; NbExp=3; IntAct=EBI-747754, EBI-2339898; CC P28799; Q53R41: FASTKD1; NbExp=3; IntAct=EBI-747754, EBI-3957005; CC P28799; Q8NFZ0: FBH1; NbExp=3; IntAct=EBI-747754, EBI-724767; CC P28799; Q9UBX5: FBLN5; NbExp=3; IntAct=EBI-747754, EBI-947897; CC P28799; P15976-2: GATA1; NbExp=3; IntAct=EBI-747754, EBI-9090198; CC P28799; P23769-2: GATA2; NbExp=3; IntAct=EBI-747754, EBI-21856389; CC P28799; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-747754, EBI-8799578; CC P28799; P10075: GLI4; NbExp=3; IntAct=EBI-747754, EBI-14061927; CC P28799; O76003: GLRX3; NbExp=9; IntAct=EBI-747754, EBI-374781; CC P28799; Q9Y223-2: GNE; NbExp=6; IntAct=EBI-747754, EBI-11975289; CC P28799; Q9HBQ8: GOLGA2P5; NbExp=3; IntAct=EBI-747754, EBI-22000587; CC P28799; Q7Z602: GPR141; NbExp=3; IntAct=EBI-747754, EBI-21649723; CC P28799; Q9Y4H4: GPSM3; NbExp=3; IntAct=EBI-747754, EBI-347538; CC P28799; O75409: H2AP; NbExp=3; IntAct=EBI-747754, EBI-6447217; CC P28799; Q6NXT2: H3-5; NbExp=3; IntAct=EBI-747754, EBI-2868501; CC P28799; P68431: H3C12; NbExp=3; IntAct=EBI-747754, EBI-79722; CC P28799; A8K0U2: hCG_2001421; NbExp=3; IntAct=EBI-747754, EBI-25843825; CC P28799; Q03014: HHEX; NbExp=3; IntAct=EBI-747754, EBI-747421; CC P28799; P49639: HOXA1; NbExp=18; IntAct=EBI-747754, EBI-740785; CC P28799; P09017: HOXC4; NbExp=3; IntAct=EBI-747754, EBI-3923226; CC P28799; P98160: HSPG2; NbExp=3; IntAct=EBI-747754, EBI-947664; CC P28799; P22692: IGFBP4; NbExp=3; IntAct=EBI-747754, EBI-2831948; CC P28799; Q14005-2: IL16; NbExp=3; IntAct=EBI-747754, EBI-17178971; CC P28799; Q9NXX0: ILF3; NbExp=3; IntAct=EBI-747754, EBI-743980; CC P28799; Q9UNL4: ING4; NbExp=3; IntAct=EBI-747754, EBI-2866661; CC P28799; Q8IXL9: IQCF2; NbExp=3; IntAct=EBI-747754, EBI-10238842; CC P28799; Q9Y6F6-3: IRAG1; NbExp=3; IntAct=EBI-747754, EBI-25840037; CC P28799; Q86U28: ISCA2; NbExp=3; IntAct=EBI-747754, EBI-10258659; CC P28799; Q14145: KEAP1; NbExp=3; IntAct=EBI-747754, EBI-751001; CC P28799; Q12756: KIF1A; NbExp=3; IntAct=EBI-747754, EBI-2679809; CC P28799; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-747754, EBI-2796400; CC P28799; P57682: KLF3; NbExp=4; IntAct=EBI-747754, EBI-8472267; CC P28799; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-747754, EBI-714379; CC P28799; O76011: KRT34; NbExp=3; IntAct=EBI-747754, EBI-1047093; CC P28799; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-747754, EBI-11959885; CC P28799; Q9BYS1: KRTAP1-5; NbExp=3; IntAct=EBI-747754, EBI-11741292; CC P28799; P60409: KRTAP10-7; NbExp=3; IntAct=EBI-747754, EBI-10172290; CC P28799; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-747754, EBI-10171774; CC P28799; Q8IUC1: KRTAP11-1; NbExp=3; IntAct=EBI-747754, EBI-1052037; CC P28799; P59990: KRTAP12-1; NbExp=3; IntAct=EBI-747754, EBI-10210845; CC P28799; Q52LG2: KRTAP13-2; NbExp=3; IntAct=EBI-747754, EBI-11953846; CC P28799; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-747754, EBI-10241252; CC P28799; Q3LI76: KRTAP15-1; NbExp=3; IntAct=EBI-747754, EBI-11992140; CC P28799; Q3SYF9: KRTAP19-7; NbExp=3; IntAct=EBI-747754, EBI-10241353; CC P28799; Q6PEX3: KRTAP26-1; NbExp=8; IntAct=EBI-747754, EBI-3957672; CC P28799; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-747754, EBI-3958099; CC P28799; Q3LI64: KRTAP6-1; NbExp=3; IntAct=EBI-747754, EBI-12111050; CC P28799; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-747754, EBI-11962084; CC P28799; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-747754, EBI-10261141; CC P28799; Q14847-2: LASP1; NbExp=3; IntAct=EBI-747754, EBI-9088686; CC P28799; O95447: LCA5L; NbExp=3; IntAct=EBI-747754, EBI-8473670; CC P28799; Q5T7P2: LCE1A; NbExp=3; IntAct=EBI-747754, EBI-11962058; CC P28799; Q5T7P3: LCE1B; NbExp=3; IntAct=EBI-747754, EBI-10245913; CC P28799; Q5T752: LCE1D; NbExp=3; IntAct=EBI-747754, EBI-11741311; CC P28799; Q5T753: LCE1E; NbExp=3; IntAct=EBI-747754, EBI-11955335; CC P28799; Q5TA79: LCE2A; NbExp=3; IntAct=EBI-747754, EBI-10246607; CC P28799; O14633: LCE2B; NbExp=3; IntAct=EBI-747754, EBI-11478468; CC P28799; Q5TA82: LCE2D; NbExp=3; IntAct=EBI-747754, EBI-10246750; CC P28799; Q5T5A8: LCE3C; NbExp=3; IntAct=EBI-747754, EBI-10245291; CC P28799; Q5T5B0: LCE3E; NbExp=3; IntAct=EBI-747754, EBI-10245456; CC P28799; Q5TA78: LCE4A; NbExp=4; IntAct=EBI-747754, EBI-10246358; CC P28799; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-747754, EBI-10258746; CC P28799; Q68G74: LHX8; NbExp=3; IntAct=EBI-747754, EBI-8474075; CC P28799; A2RU56: LOC401296; NbExp=3; IntAct=EBI-747754, EBI-9088215; CC P28799; Q96JB6: LOXL4; NbExp=3; IntAct=EBI-747754, EBI-749562; CC P28799; Q14693: LPIN1; NbExp=3; IntAct=EBI-747754, EBI-5278370; CC P28799; Q6Q4G3-4: LVRN; NbExp=3; IntAct=EBI-747754, EBI-25862057; CC P28799; Q9UDY8-2: MALT1; NbExp=3; IntAct=EBI-747754, EBI-12056869; CC P28799; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-747754, EBI-373144; CC P28799; Q99683: MAP3K5; NbExp=3; IntAct=EBI-747754, EBI-476263; CC P28799; P61244-4: MAX; NbExp=3; IntAct=EBI-747754, EBI-25848049; CC P28799; O95243-2: MBD4; NbExp=3; IntAct=EBI-747754, EBI-6448717; CC P28799; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-747754, EBI-16439278; CC P28799; P41218: MNDA; NbExp=3; IntAct=EBI-747754, EBI-2829677; CC P28799; Q86VF5-3: MOGAT3; NbExp=3; IntAct=EBI-747754, EBI-25840143; CC P28799; Q9Y2R5: MRPS17; NbExp=3; IntAct=EBI-747754, EBI-1046443; CC P28799; O43196-4: MSH5; NbExp=3; IntAct=EBI-747754, EBI-25860238; CC P28799; Q8IXL7-2: MSRB3; NbExp=3; IntAct=EBI-747754, EBI-10699187; CC P28799; Q96A32: MYL11; NbExp=3; IntAct=EBI-747754, EBI-1390771; CC P28799; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-747754, EBI-3446748; CC P28799; O15069: NACAD; NbExp=3; IntAct=EBI-747754, EBI-7108375; CC P28799; Q99608: NDN; NbExp=3; IntAct=EBI-747754, EBI-718177; CC P28799; Q9P032: NDUFAF4; NbExp=3; IntAct=EBI-747754, EBI-2606839; CC P28799; Q12986: NFX1; NbExp=3; IntAct=EBI-747754, EBI-2130062; CC P28799; Q8N5V2: NGEF; NbExp=3; IntAct=EBI-747754, EBI-718372; CC P28799; Q9UBE8: NLK; NbExp=7; IntAct=EBI-747754, EBI-366978; CC P28799; Q96AM0: NLRP1; NbExp=3; IntAct=EBI-747754, EBI-25860999; CC P28799; Q6IAD4: NOTCH1; NbExp=3; IntAct=EBI-747754, EBI-25860267; CC P28799; Q14995: NR1D2; NbExp=3; IntAct=EBI-747754, EBI-6144053; CC P28799; Q7Z417: NUFIP2; NbExp=10; IntAct=EBI-747754, EBI-1210753; CC P28799; O43482: OIP5; NbExp=3; IntAct=EBI-747754, EBI-536879; CC P28799; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-747754, EBI-1058491; CC P28799; P32242: OTX1; NbExp=10; IntAct=EBI-747754, EBI-740446; CC P28799; Q15077: P2RY6; NbExp=3; IntAct=EBI-747754, EBI-10235794; CC P28799; P07237: P4HB; NbExp=4; IntAct=EBI-747754, EBI-395883; CC P28799; O75781-2: PALM; NbExp=3; IntAct=EBI-747754, EBI-16399860; CC P28799; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-747754, EBI-17159452; CC P28799; Q86SE9-2: PCGF5; NbExp=3; IntAct=EBI-747754, EBI-25861637; CC P28799; O15534: PER1; NbExp=3; IntAct=EBI-747754, EBI-2557276; CC P28799; Q96FX8: PERP; NbExp=3; IntAct=EBI-747754, EBI-17183069; CC P28799; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-747754, EBI-12339509; CC P28799; Q9BWX1: PHF7; NbExp=3; IntAct=EBI-747754, EBI-4307517; CC P28799; A2BDE7: PHLDA1; NbExp=3; IntAct=EBI-747754, EBI-14084211; CC P28799; O75925: PIAS1; NbExp=3; IntAct=EBI-747754, EBI-629434; CC P28799; Q9BZM1: PLA2G12A; NbExp=3; IntAct=EBI-747754, EBI-3916751; CC P28799; Q58EX7-2: PLEKHG4; NbExp=3; IntAct=EBI-747754, EBI-21503705; CC P28799; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-747754, EBI-12891828; CC P28799; Q9Y342: PLLP; NbExp=3; IntAct=EBI-747754, EBI-3919291; CC P28799; Q8TBJ4: PLPPR1; NbExp=3; IntAct=EBI-747754, EBI-18063495; CC P28799; Q9H1D9: POLR3F; NbExp=3; IntAct=EBI-747754, EBI-710067; CC P28799; Q12837: POU4F2; NbExp=6; IntAct=EBI-747754, EBI-17236143; CC P28799; P09565: PP9974; NbExp=3; IntAct=EBI-747754, EBI-10196507; CC P28799; P54646: PRKAA2; NbExp=3; IntAct=EBI-747754, EBI-1383852; CC P28799; O43741: PRKAB2; NbExp=4; IntAct=EBI-747754, EBI-1053424; CC P28799; P11908: PRPS2; NbExp=3; IntAct=EBI-747754, EBI-4290895; CC P28799; P07602: PSAP; NbExp=6; IntAct=EBI-747754, EBI-716699; CC P28799; P40306: PSMB10; NbExp=3; IntAct=EBI-747754, EBI-603329; CC P28799; P28062-2: PSMB8; NbExp=3; IntAct=EBI-747754, EBI-372312; CC P28799; Q8TBK9: PTMA; NbExp=3; IntAct=EBI-747754, EBI-1056327; CC P28799; Q8WUK0: PTPMT1; NbExp=3; IntAct=EBI-747754, EBI-7199479; CC P28799; Q14671: PUM1; NbExp=3; IntAct=EBI-747754, EBI-948453; CC P28799; Q7Z7K5: PXN; NbExp=3; IntAct=EBI-747754, EBI-25841978; CC P28799; P47897: QARS1; NbExp=3; IntAct=EBI-747754, EBI-347462; CC P28799; Q96PK6: RBM14; NbExp=3; IntAct=EBI-747754, EBI-954272; CC P28799; Q96PM5-4: RCHY1; NbExp=3; IntAct=EBI-747754, EBI-21252376; CC P28799; Q8TCX5: RHPN1; NbExp=3; IntAct=EBI-747754, EBI-746325; CC P28799; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-747754, EBI-25829984; CC P28799; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-747754, EBI-749039; CC P28799; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-747754, EBI-2130308; CC P28799; Q9H0X6: RNF208; NbExp=3; IntAct=EBI-747754, EBI-751555; CC P28799; P62244: RPS15A; NbExp=3; IntAct=EBI-747754, EBI-347895; CC P28799; Q66K80: RUSC1-AS1; NbExp=3; IntAct=EBI-747754, EBI-10248967; CC P28799; Q8N488: RYBP; NbExp=3; IntAct=EBI-747754, EBI-752324; CC P28799; Q969E2: SCAMP4; NbExp=3; IntAct=EBI-747754, EBI-4403649; CC P28799; P34741: SDC2; NbExp=3; IntAct=EBI-747754, EBI-1172957; CC P28799; P60896: SEM1; NbExp=3; IntAct=EBI-747754, EBI-79819; CC P28799; Q9NTN9-3: SEMA4G; NbExp=3; IntAct=EBI-747754, EBI-9089805; CC P28799; Q14141: SEPTIN6; NbExp=3; IntAct=EBI-747754, EBI-745901; CC P28799; Q13530: SERINC3; NbExp=3; IntAct=EBI-747754, EBI-1045571; CC P28799; O43765: SGTA; NbExp=7; IntAct=EBI-747754, EBI-347996; CC P28799; Q9NUL5-3: SHFL; NbExp=3; IntAct=EBI-747754, EBI-22000547; CC P28799; O60902-3: SHOX2; NbExp=3; IntAct=EBI-747754, EBI-9092164; CC P28799; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-747754, EBI-358545; CC P28799; O15198-2: SMAD9; NbExp=3; IntAct=EBI-747754, EBI-12273450; CC P28799; P49901: SMCP; NbExp=3; IntAct=EBI-747754, EBI-750494; CC P28799; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-747754, EBI-9845742; CC P28799; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-747754, EBI-538492; CC P28799; Q99523: SORT1; NbExp=3; IntAct=EBI-747754, EBI-1057058; CC P28799; Q6RVD6: SPATA8; NbExp=3; IntAct=EBI-747754, EBI-8635958; CC P28799; P20155: SPINK2; NbExp=3; IntAct=EBI-747754, EBI-10200479; CC P28799; Q8N865: SPMIP4; NbExp=3; IntAct=EBI-747754, EBI-10174456; CC P28799; Q7Z698: SPRED2; NbExp=3; IntAct=EBI-747754, EBI-7082156; CC P28799; O43597: SPRY2; NbExp=3; IntAct=EBI-747754, EBI-742487; CC P28799; Q9C004: SPRY4; NbExp=3; IntAct=EBI-747754, EBI-354861; CC P28799; Q6PJ21: SPSB3; NbExp=3; IntAct=EBI-747754, EBI-3937206; CC P28799; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-747754, EBI-357085; CC P28799; Q8NBJ7: SUMF2; NbExp=3; IntAct=EBI-747754, EBI-723091; CC P28799; Q17RD7-3: SYT16; NbExp=3; IntAct=EBI-747754, EBI-25861603; CC P28799; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-747754, EBI-745958; CC P28799; P17735: TAT; NbExp=3; IntAct=EBI-747754, EBI-12046643; CC P28799; Q86VP1: TAX1BP1; NbExp=3; IntAct=EBI-747754, EBI-529518; CC P28799; P62380: TBPL1; NbExp=3; IntAct=EBI-747754, EBI-716225; CC P28799; Q8IYN2: TCEAL8; NbExp=3; IntAct=EBI-747754, EBI-2116184; CC P28799; Q13569: TDG; NbExp=3; IntAct=EBI-747754, EBI-348333; CC P28799; P28347-2: TEAD1; NbExp=3; IntAct=EBI-747754, EBI-12151837; CC P28799; Q8NA77: TEX19; NbExp=3; IntAct=EBI-747754, EBI-13323487; CC P28799; O60830: TIMM17B; NbExp=3; IntAct=EBI-747754, EBI-2372529; CC P28799; Q04724: TLE1; NbExp=3; IntAct=EBI-747754, EBI-711424; CC P28799; Q08117-2: TLE5; NbExp=3; IntAct=EBI-747754, EBI-11741437; CC P28799; Q8N0U2: TMEM61; NbExp=3; IntAct=EBI-747754, EBI-25830583; CC P28799; Q53NU3: tmp_locus_54; NbExp=3; IntAct=EBI-747754, EBI-10242677; CC P28799; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-747754, EBI-25831574; CC P28799; P19438: TNFRSF1A; NbExp=4; IntAct=EBI-747754, EBI-299451; CC P28799; P20333: TNFRSF1B; NbExp=5; IntAct=EBI-747754, EBI-358983; CC P28799; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-747754, EBI-17716262; CC P28799; Q9BVS5: TRMT61B; NbExp=3; IntAct=EBI-747754, EBI-3197877; CC P28799; Q96Q11-3: TRNT1; NbExp=3; IntAct=EBI-747754, EBI-25861172; CC P28799; Q9Y3Q8: TSC22D4; NbExp=3; IntAct=EBI-747754, EBI-739485; CC P28799; O14817: TSPAN4; NbExp=3; IntAct=EBI-747754, EBI-8652667; CC P28799; Q9Y5U2: TSSC4; NbExp=3; IntAct=EBI-747754, EBI-717229; CC P28799; Q99614: TTC1; NbExp=3; IntAct=EBI-747754, EBI-742074; CC P28799; Q5W5X9-3: TTC23; NbExp=3; IntAct=EBI-747754, EBI-9090990; CC P28799; Q5VYS8-5: TUT7; NbExp=3; IntAct=EBI-747754, EBI-9088812; CC P28799; Q9BRU9: UTP23; NbExp=3; IntAct=EBI-747754, EBI-5457544; CC P28799; Q6EMK4: VASN; NbExp=3; IntAct=EBI-747754, EBI-10249550; CC P28799; P45880: VDAC2; NbExp=3; IntAct=EBI-747754, EBI-354022; CC P28799; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-747754, EBI-2850578; CC P28799; Q8NEZ2-2: VPS37A; NbExp=3; IntAct=EBI-747754, EBI-10270911; CC P28799; P58304: VSX2; NbExp=3; IntAct=EBI-747754, EBI-6427899; CC P28799; Q9NZC7-5: WWOX; NbExp=3; IntAct=EBI-747754, EBI-12040603; CC P28799; Q8IY57-5: YAF2; NbExp=3; IntAct=EBI-747754, EBI-12111538; CC P28799; O95070: YIF1A; NbExp=3; IntAct=EBI-747754, EBI-2799703; CC P28799; P25490: YY1; NbExp=4; IntAct=EBI-747754, EBI-765538; CC P28799; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-747754, EBI-25842419; CC P28799; Q9NTW7: ZFP64; NbExp=3; IntAct=EBI-747754, EBI-711679; CC P28799; Q15776: ZKSCAN8; NbExp=3; IntAct=EBI-747754, EBI-2602314; CC P28799; Q15973: ZNF124; NbExp=3; IntAct=EBI-747754, EBI-2555767; CC P28799; P52744: ZNF138; NbExp=3; IntAct=EBI-747754, EBI-10746567; CC P28799; Q9UJW8-4: ZNF180; NbExp=3; IntAct=EBI-747754, EBI-12055755; CC P28799; Q16600: ZNF239; NbExp=3; IntAct=EBI-747754, EBI-8787052; CC P28799; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-747754, EBI-8834821; CC P28799; Q8N895: ZNF366; NbExp=3; IntAct=EBI-747754, EBI-2813661; CC P28799; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-747754, EBI-12010736; CC P28799; Q96MN9-2: ZNF488; NbExp=3; IntAct=EBI-747754, EBI-25831733; CC P28799; Q6ZNH5: ZNF497; NbExp=3; IntAct=EBI-747754, EBI-10486136; CC P28799; Q96C55: ZNF524; NbExp=3; IntAct=EBI-747754, EBI-10283126; CC P28799; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-747754, EBI-8490788; CC P28799; Q7Z3I7: ZNF572; NbExp=3; IntAct=EBI-747754, EBI-10172590; CC P28799; Q96I27-2: ZNF625; NbExp=3; IntAct=EBI-747754, EBI-12038525; CC P28799; Q96N77-2: ZNF641; NbExp=3; IntAct=EBI-747754, EBI-12939666; CC P28799; Q9BS34: ZNF670; NbExp=3; IntAct=EBI-747754, EBI-745276; CC P28799; Q9H7X3: ZNF696; NbExp=3; IntAct=EBI-747754, EBI-11090299; CC P28799; Q5TEC3: ZNF697; NbExp=3; IntAct=EBI-747754, EBI-25845217; CC P28799; Q6NX45: ZNF774; NbExp=3; IntAct=EBI-747754, EBI-10251462; CC P28799; Q3KP31: ZNF791; NbExp=3; IntAct=EBI-747754, EBI-2849119; CC P28799; Q16670: ZSCAN26; NbExp=3; IntAct=EBI-747754, EBI-3920053; CC P28799; O15535: ZSCAN9; NbExp=3; IntAct=EBI-747754, EBI-751531; CC P28799; A0A384ME25; NbExp=3; IntAct=EBI-747754, EBI-10211777; CC P28799; Q7L8T7; NbExp=3; IntAct=EBI-747754, EBI-25831943; CC P28799; Q7Z783; NbExp=3; IntAct=EBI-747754, EBI-9088990; CC P28799; P09022: Hoxa1; Xeno; NbExp=2; IntAct=EBI-747754, EBI-3957603; CC P28799-2; Q9UII2: ATP5IF1; NbExp=3; IntAct=EBI-25860013, EBI-718459; CC P28799-2; P50750-2: CDK9; NbExp=3; IntAct=EBI-25860013, EBI-12029902; CC P28799-2; Q02930-3: CREB5; NbExp=3; IntAct=EBI-25860013, EBI-10192698; CC P28799-2; P80370: DLK1; NbExp=3; IntAct=EBI-25860013, EBI-21555397; CC P28799-2; O14531: DPYSL4; NbExp=3; IntAct=EBI-25860013, EBI-719542; CC P28799-2; Q92997: DVL3; NbExp=3; IntAct=EBI-25860013, EBI-739789; CC P28799-2; O15540: FABP7; NbExp=3; IntAct=EBI-25860013, EBI-10697159; CC P28799-2; Q96AQ9: FAM131C; NbExp=3; IntAct=EBI-25860013, EBI-741921; CC P28799-2; Q5HYJ3-3: FAM76B; NbExp=3; IntAct=EBI-25860013, EBI-11956087; CC P28799-2; Q8N7T0: hCG_1820408; NbExp=3; IntAct=EBI-25860013, EBI-25858908; CC P28799-2; P49639: HOXA1; NbExp=3; IntAct=EBI-25860013, EBI-740785; CC P28799-2; Q5TA79: LCE2A; NbExp=3; IntAct=EBI-25860013, EBI-10246607; CC P28799-2; Q8IXL7-2: MSRB3; NbExp=3; IntAct=EBI-25860013, EBI-10699187; CC P28799-2; Q14995: NR1D2; NbExp=3; IntAct=EBI-25860013, EBI-6144053; CC P28799-2; P09565: PP9974; NbExp=3; IntAct=EBI-25860013, EBI-10196507; CC P28799-2; Q14671: PUM1; NbExp=3; IntAct=EBI-25860013, EBI-948453; CC P28799-2; Q7Z7K5: PXN; NbExp=3; IntAct=EBI-25860013, EBI-25841978; CC P28799-2; Q969E2: SCAMP4; NbExp=3; IntAct=EBI-25860013, EBI-4403649; CC P28799-2; P34741: SDC2; NbExp=3; IntAct=EBI-25860013, EBI-1172957; CC P28799-2; Q9NTG7: SIRT3; NbExp=3; IntAct=EBI-25860013, EBI-724621; CC P28799-2; O95416: SOX14; NbExp=3; IntAct=EBI-25860013, EBI-9087806; CC P28799-2; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-25860013, EBI-5235340; CC P28799-2; P17735: TAT; NbExp=3; IntAct=EBI-25860013, EBI-12046643; CC P28799-2; Q8TDR4: TCP10L; NbExp=3; IntAct=EBI-25860013, EBI-3923210; CC P28799-2; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-25860013, EBI-25831574; CC P28799-2; Q9Y2B4: TP53TG5; NbExp=3; IntAct=EBI-25860013, EBI-21870909; CC P28799-2; P25490: YY1; NbExp=3; IntAct=EBI-25860013, EBI-765538; CC P28799-2; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-25860013, EBI-25850811; CC P28799-2; Q9UJW8-4: ZNF180; NbExp=3; IntAct=EBI-25860013, EBI-12055755; CC P28799-2; Q8N895: ZNF366; NbExp=3; IntAct=EBI-25860013, EBI-2813661; CC P28799-2; A0A087WZY1; NbExp=3; IntAct=EBI-25860013, EBI-13387614; CC P28799-2; Q7L8T7; NbExp=3; IntAct=EBI-25860013, EBI-25831943; CC PRO_0000012695; P07339: CTSD; NbExp=2; IntAct=EBI-21335602, EBI-2115097; CC PRO_0000012696; P07339: CTSD; NbExp=2; IntAct=EBI-21335615, EBI-2115097; CC PRO_0000012697; P07339: CTSD; NbExp=2; IntAct=EBI-21335629, EBI-2115097; CC PRO_0000012698; P07339: CTSD; NbExp=2; IntAct=EBI-21335642, EBI-2115097; CC PRO_0000012699; P07339: CTSD; NbExp=2; IntAct=EBI-21335656, EBI-2115097; CC PRO_0000012700; P07339: CTSD; NbExp=2; IntAct=EBI-21335669, EBI-2115097; CC PRO_0000012701; P07339: CTSD; NbExp=2; IntAct=EBI-21335682, EBI-2115097; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502}. Lysosome {ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:28073925, CC ECO:0000269|PubMed:28541286, ECO:0000269|PubMed:28743268}. CC Note=Endocytosed by SORT1 and delivred to lysosomes (PubMed:21092856, CC PubMed:28073925). Targeted to lysosome by PSAP via M6PR and LRP1, in CC both biosynthetic and endocytic pathways (PubMed:26370502, CC PubMed:28073925). Co-localized with GBA1 in the intracellular CC trafficking compartments until to lysosome (By similarity). CC {ECO:0000250|UniProtKB:P28798, ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:28073925}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P28799-1; Sequence=Displayed; CC Name=2; CC IsoId=P28799-2; Sequence=VSP_001837; CC Name=3; CC IsoId=P28799-3; Sequence=VSP_053472, VSP_053473; CC -!- TISSUE SPECIFICITY: In myelogenous leukemic cell lines of promonocytic, CC promyelocytic, and proerythroid lineage, in fibroblasts, and very CC strongly in epithelial cell lines. Present in inflammatory cells and CC bone marrow. Highest levels in kidney. CC -!- INDUCTION: Increased in response to lysosome alkalization. CC {ECO:0000269|PubMed:28073925}. CC -!- PTM: Cleaved by ELANE; proteolysis is blocked by SLPI and is CC concentration- and time-dependent and induces CXCL8/IL-8 production; CC granulin-3 and granulin-4 are resistant to ELANE (PubMed:12526812, CC PubMed:28743268). Cleaved by CTSL in lysosome thus regulating the CC maturation and turnover of progranulin within the lysosome CC (PubMed:28743268). {ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:28743268}. CC -!- DISEASE: Frontotemporal dementia 2 (FTD2) [MIM:607485]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. Gestural apraxia, CC parkinsonism, visual loss, and visual hallucinations are present in 25 CC to 40% of patients. {ECO:0000269|PubMed:16862116, CC ECO:0000269|PubMed:16983685, ECO:0000269|PubMed:18183624}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 11 (CLN11) [MIM:614706]: A CC form of neuronal ceroid lipofuscinosis characterized by rapidly CC progressive visual loss due to retinal dystrophy, seizures, cerebellar CC ataxia, and cerebellar atrophy. Cognitive decline may also occur. CC Neuronal ceroid lipofuscinoses are progressive neurodegenerative, CC lysosomal storage diseases characterized by intracellular accumulation CC of autofluorescent liposomal material. {ECO:0000269|PubMed:22608501}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the granulin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40757/GRN"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X62320; CAA44196.1; -; mRNA. DR EMBL; AF055008; AAC09359.1; -; mRNA. DR EMBL; M75161; AAA58617.1; -; mRNA. DR EMBL; AY124489; AAM94026.1; -; mRNA. DR EMBL; BT006844; AAP35490.1; -; mRNA. DR EMBL; AK023348; BAB14535.1; -; mRNA. DR EMBL; AK222522; BAD96242.1; -; mRNA. DR EMBL; CH471178; EAW51599.1; -; Genomic_DNA. DR EMBL; CH471178; EAW51600.1; -; Genomic_DNA. DR EMBL; BC000324; AAH00324.1; -; mRNA. DR EMBL; BC010577; AAH10577.1; -; mRNA. DR CCDS; CCDS11483.1; -. [P28799-1] DR PIR; JC1284; GYHU. DR RefSeq; NP_002078.1; NM_002087.4. [P28799-1] DR PDB; 1G26; NMR; -; A=281-311. DR PDB; 2JYE; NMR; -; A=281-337. DR PDB; 2JYT; NMR; -; A=364-417. DR PDB; 2JYU; NMR; -; A=364-417. DR PDB; 2JYV; NMR; -; A=123-179. DR PDB; 6NUG; NMR; -; A=284-307. DR PDB; 8T8R; X-ray; 2.87 A; B=578-593. DR PDB; 8T8S; X-ray; 2.99 A; C/D=578-593. DR PDBsum; 1G26; -. DR PDBsum; 2JYE; -. DR PDBsum; 2JYT; -. DR PDBsum; 2JYU; -. DR PDBsum; 2JYV; -. DR PDBsum; 6NUG; -. DR PDBsum; 8T8R; -. DR PDBsum; 8T8S; -. DR AlphaFoldDB; P28799; -. DR SMR; P28799; -. DR BioGRID; 109153; 249. DR CORUM; P28799; -. DR DIP; DIP-41742N; -. DR FunCoup; P28799; 1096. DR IntAct; P28799; 468. DR MINT; P28799; -. DR STRING; 9606.ENSP00000053867; -. DR GlyConnect; 1290; 5 N-Linked glycans (1 site), 3 O-Linked glycans (1 site). DR GlyCosmos; P28799; 6 sites, 5 glycans. DR GlyGen; P28799; 10 sites, 29 N-linked glycans (3 sites), 5 O-linked glycans (4 sites). DR iPTMnet; P28799; -. DR MetOSite; P28799; -. DR PhosphoSitePlus; P28799; -. DR SwissPalm; P28799; -. DR BioMuta; GRN; -. DR DMDM; 77416865; -. DR jPOST; P28799; -. DR MassIVE; P28799; -. DR PaxDb; 9606-ENSP00000053867; -. DR PeptideAtlas; P28799; -. DR ProteomicsDB; 54499; -. [P28799-1] DR ProteomicsDB; 54500; -. [P28799-2] DR ProteomicsDB; 81234; -. DR Pumba; P28799; -. DR TopDownProteomics; P28799-2; -. [P28799-2] DR TopDownProteomics; P28799-3; -. [P28799-3] DR Antibodypedia; 1406; 664 antibodies from 38 providers. DR DNASU; 2896; -. DR Ensembl; ENST00000053867.8; ENSP00000053867.2; ENSG00000030582.20. [P28799-1] DR GeneID; 2896; -. DR KEGG; hsa:2896; -. DR MANE-Select; ENST00000053867.8; ENSP00000053867.2; NM_002087.4; NP_002078.1. DR UCSC; uc002igp.2; human. [P28799-1] DR AGR; HGNC:4601; -. DR ClinPGx; PA28998; -. DR CTD; 2896; -. DR DisGeNET; 2896; -. DR GeneCards; GRN; -. DR GeneReviews; GRN; -. DR HGNC; HGNC:4601; GRN. DR HPA; ENSG00000030582; Low tissue specificity. DR MalaCards; GRN; -. DR MIM; 138945; gene. DR MIM; 607485; phenotype. DR MIM; 614706; phenotype. DR NIAGADS; ENSG00000030582; -. DR OpenTargets; ENSG00000030582; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 314629; CLN11 disease. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000030582; -. DR eggNOG; KOG4296; Eukaryota. DR GeneTree; ENSGT00470000042293; -. DR HOGENOM; CLU_026274_0_0_1; -. DR InParanoid; P28799; -. DR OMA; CCPYSSA; -. DR OrthoDB; 5854875at2759; -. DR PAN-GO; P28799; 2 GO annotations based on evolutionary models. DR PhylomeDB; P28799; -. DR PathwayCommons; P28799; -. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; P28799; -. DR SIGNOR; P28799; -. DR Agora; ENSG00000030582; -. DR BioGRID-ORCS; 2896; 18 hits in 1158 CRISPR screens. DR ChiTaRS; GRN; human. DR EvolutionaryTrace; P28799; -. DR GeneWiki; Granulin; -. DR GenomeRNAi; 2896; -. DR Pharos; P28799; Tbio. DR PRO; PR:P28799; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P28799; protein. DR Bgee; ENSG00000030582; Expressed in monocyte and 210 other cell types or tissues. DR ExpressionAtlas; P28799; baseline and differential. DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome. DR GO; GO:0150053; C:cerebellar climbing fiber to Purkinje cell synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005768; C:endosome; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:ARUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:HPA. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW. DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc. DR GO; GO:0051087; F:protein-folding chaperone binding; IDA:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISS:UniProtKB. DR GO; GO:0001835; P:blastocyst hatching; IEA:Ensembl. DR GO; GO:0007566; P:embryo implantation; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0007042; P:lysosomal lumen acidification; IMP:UniProtKB. DR GO; GO:1905146; P:lysosomal protein catabolic process; IEA:Ensembl. DR GO; GO:0007041; P:lysosomal transport; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB. DR GO; GO:0099558; P:maintenance of synapse structure; IEA:Ensembl. DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB. DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB. DR GO; GO:1902564; P:negative regulation of neutrophil activation; IDA:UniProtKB. DR GO; GO:0060266; P:negative regulation of respiratory burst involved in inflammatory response; IDA:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB. DR GO; GO:1905247; P:positive regulation of aspartic-type peptidase activity; IMP:UniProtKB. DR GO; GO:0048680; P:positive regulation of axon regeneration; ISS:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ARUK-UCL. DR GO; GO:1900426; P:positive regulation of defense response to bacterium; ISS:UniProtKB. DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IDA:UniProtKB. DR GO; GO:0106016; P:positive regulation of inflammatory response to wounding; ISS:UniProtKB. DR GO; GO:1905673; P:positive regulation of lysosome organization; IDA:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB. DR GO; GO:1903334; P:positive regulation of protein folding; ISS:UniProtKB. DR GO; GO:1904075; P:positive regulation of trophectodermal cell proliferation; IEA:Ensembl. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0050727; P:regulation of inflammatory response; IBA:GO_Central. DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; NAS:ProtInc. DR GO; GO:0001834; P:trophectodermal cell proliferation; IEA:Ensembl. DR FunFam; 2.10.25.160:FF:000001; Granulin precursor; 5. DR FunFam; 2.10.25.160:FF:000004; Granulin precursor; 1. DR FunFam; 2.10.25.160:FF:000003; Progranulin; 1. DR Gene3D; 2.10.25.160; Granulin; 7. DR InterPro; IPR000118; Granulin. DR InterPro; IPR039036; Granulin_fam. DR InterPro; IPR037277; Granulin_sf. DR PANTHER; PTHR12274; GRANULIN; 1. DR PANTHER; PTHR12274:SF3; PROGRANULIN; 1. DR Pfam; PF00396; Granulin; 7. DR SMART; SM00277; GRAN; 7. DR SUPFAM; SSF57277; Granulin repeat; 6. DR PROSITE; PS00799; GRANULINS; 7. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytokine; Direct protein sequencing; KW Disulfide bond; Glycoprotein; Lysosome; Neurodegeneration; KW Neuronal ceroid lipofuscinosis; Proteomics identification; KW Reference proteome; Repeat; Secreted; Signal. FT SIGNAL 1..17 FT /evidence="ECO:0000255" FT CHAIN 18..593 FT /note="Progranulin" FT /id="PRO_0000012693" FT PEPTIDE 18..?47 FT /note="Paragranulin" FT /id="PRO_0000012694" FT PEPTIDE ?58..?113 FT /note="Granulin-1" FT /id="PRO_0000012695" FT PEPTIDE 123..179 FT /note="Granulin-2" FT /id="PRO_0000012696" FT PEPTIDE 206..261 FT /note="Granulin-3" FT /id="PRO_0000012697" FT PEPTIDE 281..336 FT /note="Granulin-4" FT /id="PRO_0000012698" FT PEPTIDE 364..417 FT /note="Granulin-5" FT /id="PRO_0000012699" FT PEPTIDE 442..?496 FT /note="Granulin-6" FT /id="PRO_0000012700" FT PEPTIDE ?518..?573 FT /note="Granulin-7" FT /id="PRO_0000012701" FT CARBOHYD 118 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 265 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:20188224" FT CARBOHYD 368 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT CARBOHYD 530 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT DISULFID 126..139 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 133..149 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 284..296 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 290..306 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 297..314 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 307..321 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 315..328 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 322..335 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 366..378 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 372..388 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 397..410 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 404..416 FT /evidence="ECO:0000269|PubMed:18359860" FT VAR_SEQ 1..71 FT /note="MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTT FT LSRHLGGPCQVDAHCSAGH -> MAITAAHGASTAVQTGDPASKDQVTTPWVPSSALIV FT SSNARTSPRAVLWSMAPGGAAPCPRLPAVKTGCTA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053472" FT VAR_SEQ 72..251 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053473" FT VAR_SEQ 377..531 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.6" FT /id="VSP_001837" FT VARIANT 9 FT /note="A -> D (in FTD2; no significant difference in the FT total mRNA between cases and controls; although the mutant FT protein is expressed it is not secreted and appears to be FT trapped within an intracellular compartment; FT dbSNP:rs63751243)" FT /evidence="ECO:0000269|PubMed:16983685, FT ECO:0000269|PubMed:18183624" FT /id="VAR_044451" FT VARIANT 19 FT /note="R -> W (in dbSNP:rs63750723)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064625" FT VARIANT 55 FT /note="R -> W (in dbSNP:rs1555610922)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064626" FT VARIANT 69 FT /note="A -> T (in dbSNP:rs199944486)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064627" FT VARIANT 119 FT /note="Missing (in dbSNP:rs758168578)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064628" FT VARIANT 120 FT /note="S -> Y (in dbSNP:rs63750043)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064629" FT VARIANT 182 FT /note="T -> M (in dbSNP:rs63750479)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064630" FT VARIANT 221 FT /note="C -> S (in dbSNP:rs758322775)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064631" FT VARIANT 275 FT /note="P -> L (in dbSNP:rs529849967)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064632" FT VARIANT 376 FT /note="D -> N (in dbSNP:rs143030899)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064633" FT VARIANT 398 FT /note="S -> L (in dbSNP:rs148213321)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064634" FT VARIANT 433 FT /note="R -> Q (in dbSNP:rs114248177)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064635" FT VARIANT 515 FT /note="G -> A (in dbSNP:rs25647)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_014830" FT VARIANT 564 FT /note="R -> H (in dbSNP:rs971443926)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064636" FT CONFLICT 219 FT /note="S -> H (in Ref. 12; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 290 FT /note="C -> S (in Ref. 13; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 386 FT /note="W -> H (in Ref. 12; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 407 FT /note="G -> R (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 428 FT /note="K -> E (in Ref. 8; BAD96242)" FT /evidence="ECO:0000305" FT CONFLICT 434 FT /note="A -> G (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 454 FT /note="Q -> G (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 460 FT /note="L -> Q (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 547 FT /note="R -> A (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 567 FT /note="A -> R (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT STRAND 137..141 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 143..145 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 147..151 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 282..285 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 288..290 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 294..298 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 304..308 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 315..319 FT /evidence="ECO:0007829|PDB:2JYE" FT TURN 330..333 FT /evidence="ECO:0007829|PDB:2JYE" FT TURN 367..369 FT /evidence="ECO:0007829|PDB:2JYU" FT STRAND 377..380 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 386..389 FT /evidence="ECO:0007829|PDB:2JYT" FT TURN 399..402 FT /evidence="ECO:0007829|PDB:2JYU" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JYT" FT TURN 412..414 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 415..417 FT /evidence="ECO:0007829|PDB:2JYT" SQ SEQUENCE 593 AA; 63544 MW; 4E5947F1B4EDE619 CRC64; MWTLVSWVAL TAGLVAGTRC PDGQFCPVAC CLDPGGASYS CCRPLLDKWP TTLSRHLGGP CQVDAHCSAG HSCIFTVSGT SSCCPFPEAV ACGDGHHCCP RGFHCSADGR SCFQRSGNNS VGAIQCPDSQ FECPDFSTCC VMVDGSWGCC PMPQASCCED RVHCCPHGAF CDLVHTRCIT PTGTHPLAKK LPAQRTNRAV ALSSSVMCPD ARSRCPDGST CCELPSGKYG CCPMPNATCC SDHLHCCPQD TVCDLIQSKC LSKENATTDL LTKLPAHTVG DVKCDMEVSC PDGYTCCRLQ SGAWGCCPFT QAVCCEDHIH CCPAGFTCDT QKGTCEQGPH QVPWMEKAPA HLSLPDPQAL KRDVPCDNVS SCPSSDTCCQ LTSGEWGCCP IPEAVCCSDH QHCCPQGYTC VAEGQCQRGS EIVAGLEKMP ARRASLSHPR DIGCDQHTSC PVGQTCCPSL GGSWACCQLP HAVCCEDRQH CCPAGYTCNV KARSCEKEVV SAQPATFLAR SPHVGVKDVE CGEGHFCHDN QTCCRDNRQG WACCPYRQGV CCADRRHCCP AGFRCAARGT KCLRREAPRW DAPLRDPALR QLL // ID JAM2_HUMAN Reviewed; 298 AA. AC P57087; B2R6T9; B4DGT9; Q6UXG6; Q6YNC1; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2000, sequence version 1. DT 28-JAN-2026, entry version 210. DE RecName: Full=Junctional adhesion molecule B; DE Short=JAM-B; DE AltName: Full=Junctional adhesion molecule 2 {ECO:0000303|PubMed:10945976}; DE Short=JAM-2 {ECO:0000303|PubMed:10945976}; DE AltName: Full=Vascular endothelial junction-associated molecule {ECO:0000303|PubMed:10779521}; DE Short=VE-JAM {ECO:0000303|PubMed:10779521}; DE AltName: CD_antigen=CD322; DE Flags: Precursor; GN Name=JAM2 {ECO:0000312|HGNC:HGNC:14686}; GN Synonyms=C21orf43 {ECO:0000312|HGNC:HGNC:14686}, GN VEJAM {ECO:0000303|PubMed:10779521}; ORFNames=UNQ219/PRO245; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 29-33, RP SUBCELLULAR LOCATION, TOPOLOGY, AND TISSUE SPECIFICITY. RC TISSUE=Vascular endothelial cell; RX PubMed=10779521; DOI=10.1074/jbc.m003189200; RA Palmeri D., van Zante A., Huang C.-C., Hemmerich S., Rosen S.D.; RT "Vascular endothelial junction-associated molecule, a novel member of the RT immunoglobulin superfamily, is localized to intercellular boundaries of RT endothelial cells."; RL J. Biol. Chem. 275:19139-19145(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Placenta; RX PubMed=10945976; DOI=10.1074/jbc.m002718200; RA Cunningham S.A., Arrate M.P., Rodriguez J.M., Bjercke R.J., Vanderslice P., RA Morris A.P., Brock T.A.; RT "A novel protein with homology to the junctional adhesion molecule: RT Characterization of leukocyte interactions."; RL J. Biol. Chem. 275:34750-34756(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=12036298; DOI=10.1006/geno.2002.6782; RA Gardiner K., Slavov D., Bechtel L., Davisson M.; RT "Annotation of human chromosome 21 for relevance to Down syndrome: gene RT structure and expression analysis."; RL Genomics 79:833-843(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 29-43. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [9] RP FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=11590146; DOI=10.1074/jbc.m105972200; RA Arrate M.P., Rodriguez J.M., Tran T.M., Brock T.A., Cunningham S.A.; RT "Cloning of human junctional adhesion molecule 3 (JAM3) and its RT identification as the JAM2 counter-receptor."; RL J. Biol. Chem. 276:45826-45832(2001). RN [10] RP FUNCTION. RX PubMed=12239159; DOI=10.1182/blood-2001-11-0098; RA Johnson-Leger C.A., Aurrand-Lions M., Beltraminelli N., Fasel N., RA Imhof B.A.; RT "Junctional adhesion molecule-2 (JAM-2) promotes lymphocyte RT transendothelial migration."; RL Blood 100:2479-2486(2002). RN [11] RP FUNCTION, DOMAIN, AND MUTAGENESIS OF ASP-82. RX PubMed=12070135; DOI=10.1074/jbc.c200331200; RA Cunningham S.A., Rodriguez J.M., Arrate M.P., Tran T.M., Brock T.A.; RT "JAM2 interacts with alpha4beta1. Facilitation by JAM3."; RL J. Biol. Chem. 277:27589-27592(2002). RN [12] RP FUNCTION. RX PubMed=11823489; DOI=10.4049/jimmunol.168.4.1618; RA Liang T.W., Chiu H.H., Gurney A., Sidle A., Tumas D.B., Schow P., RA Foster J., Klassen T., Dennis K., DeMarco R.A., Pham T., Frantz G., RA Fong S.; RT "Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts RT with T, NK, and dendritic cells through JAM 3."; RL J. Immunol. 168:1618-1626(2002). RN [13] RP REVIEW, AND NOMENCLATURE. RX PubMed=12810109; DOI=10.1016/s1471-4906(03)00117-0; RA Muller W.A.; RT "Leukocyte-endothelial-cell interactions in leukocyte transmigration and RT the inflammatory response."; RL Trends Immunol. 24:327-334(2003). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-98. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [15] RP FUNCTION. RX PubMed=24357068; DOI=10.1002/stem.1624; RA Arcangeli M.L., Bardin F., Frontera V., Bidaut G., Obrados E., Adams R.H., RA Chabannon C., Aurrand-Lions M.; RT "Function of Jam-B/Jam-C interaction in homing and mobilization of human RT and mouse hematopoietic stem and progenitor cells."; RL Stem Cells 32:1043-1054(2014). RN [16] RP INVOLVEMENT IN IBGC8, VARIANTS IBGC8 60-ARG--ILE-298 DEL; HIS-108 AND RP 229-ARG--ILE-298 DEL, AND CHARACTERIZATION OF VARIANT IBGC8 RP 229-ARG--ILE-298 DEL. RX PubMed=32142645; DOI=10.1016/j.ajhg.2020.02.007; RG SYNAPS Study Group; RA Schottlaender L.V., Abeti R., Jaunmuktane Z., Macmillan C., Chelban V., RA O'Callaghan B., McKinley J., Maroofian R., Efthymiou S., RA Athanasiou-Fragkouli A., Forbes R., Soutar M.P.M., Livingston J.H., RA Kalmar B., Swayne O., Hotton G., Pittman A., Mendes de Oliveira J.R., RA de Grandis M., Richard-Loendt A., Launchbury F., Althonayan J., RA McDonnell G., Carr A., Khan S., Beetz C., Bisgin A., Tug Bozdogan S., RA Begtrup A., Torti E., Greensmith L., Giunti P., Morrison P.J., Brandner S., RA Aurrand-Lions M., Houlden H.; RT "Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial RT Brain Calcification."; RL Am. J. Hum. Genet. 106:412-421(2020). RN [17] RP VARIANT IBGC8 CYS-168, CHARACTERIZATION OF VARIANT IBGC8 CYS-168, RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=31851307; DOI=10.1093/brain/awz392; RA Cen Z., Chen Y., Chen S., Wang H., Yang D., Zhang H., Wu H., Wang L., RA Tang S., Ye J., Shen J., Wang H., Fu F., Chen X., Xie F., Liu P., Xu X., RA Cao J., Cai P., Pan Q., Li J., Yang W., Shan P.F., Li Y., Liu J.Y., RA Zhang B., Luo W.; RT "Biallelic loss-of-function mutations in JAM2 cause primary familial brain RT calcification."; RL Brain 143:491-502(2020). CC -!- FUNCTION: Junctional adhesion protein that mediates heterotypic cell- CC cell interactions with its cognate receptor JAM3 to regulate different CC cellular processes (PubMed:11590146, PubMed:11823489, PubMed:24357068). CC Plays a role in homing and mobilization of hematopoietic stem and CC progenitor cells within the bone marrow (PubMed:24357068). At the CC surface of bone marrow stromal cells, it contributes to the retention CC of the hematopoietic stem and progenitor cells expressing JAM3 CC (PubMed:11590146, PubMed:24357068). Plays a central role in leukocytes CC extravasation by facilitating not only transmigration but also CC tethering and rolling of leukocytes along the endothelium CC (PubMed:12239159). Tethering and rolling of leukocytes are dependent on CC the binding by JAM2 of the integrin alpha-4/beta-1 (PubMed:12070135). CC Plays a role in spermatogenesis where JAM2 and JAM3, which are CC respectively expressed by Sertoli and germ cells, mediate an CC interaction between both cell types and play an essential role in the CC anchorage of germ cells onto Sertoli cells and the assembly of cell CC polarity complexes during spermatid differentiation (By similarity). CC Also functions as an inhibitory somatodendritic cue that prevents the CC myelination of non-axonal parts of neurons (By similarity). During CC myogenesis, it is involved in myocyte fusion (By similarity). May also CC play a role in angiogenesis (By similarity). CC {ECO:0000250|UniProtKB:A0A0R4IGV4, ECO:0000250|UniProtKB:Q9JI59, CC ECO:0000269|PubMed:11590146, ECO:0000269|PubMed:11823489, CC ECO:0000269|PubMed:12070135, ECO:0000269|PubMed:12239159, CC ECO:0000269|PubMed:24357068}. CC -!- INTERACTION: CC P57087; Q9BX67: JAM3; NbExp=4; IntAct=EBI-3918416, EBI-4314733; CC P57087; Q8TEW0: PARD3; NbExp=2; IntAct=EBI-3918416, EBI-81968; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10779521, CC ECO:0000269|PubMed:11590146, ECO:0000269|PubMed:31851307}; Single-pass CC type I membrane protein {ECO:0000269|PubMed:10779521, CC ECO:0000269|PubMed:11590146}. Cell junction CC {ECO:0000269|PubMed:10779521, ECO:0000269|PubMed:10945976}. Cell CC junction, tight junction {ECO:0000250|UniProtKB:Q9JI59}. Note=Localized CC at tight junctions of both epithelial and endothelial cells (By CC similarity). Specifically localized within the somatodendritic CC compartment of neurons and excluded from the axon (By similarity). CC {ECO:0000250|UniProtKB:Q9JI59}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P57087-1; Sequence=Displayed; CC Name=2; CC IsoId=P57087-2; Sequence=VSP_045153; CC Name=3; CC IsoId=P57087-3; Sequence=VSP_047352; CC -!- TISSUE SPECIFICITY: Highly expressed in heart, placenta, lung, foreskin CC and lymph node (PubMed:10779521, PubMed:10945976). Prominently CC expressed on high endothelial venules and also present on the CC endothelia of other vessels (at protein level) (PubMed:10779521, CC PubMed:10945976). Also expressed in the brain in the caudate nuclei CC (PubMed:31851307). {ECO:0000269|PubMed:10779521, CC ECO:0000269|PubMed:10945976, ECO:0000269|PubMed:31851307}. CC -!- DOMAIN: The Ig-like V-type domain is necessary and sufficient to CC mediate interaction with JAM3 and integrin alpha-4/beta-1. CC {ECO:0000269|PubMed:12070135}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 8, autosomal CC recessive (IBGC8) [MIM:618824]: A form of basal ganglia calcification, CC a genetically heterogeneous condition characterized by symmetric CC calcification in the basal ganglia and other brain regions. Affected CC individuals can either be asymptomatic or show a wide spectrum of CC neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, CC ataxia, dementia, psychosis, seizures, and chronic headache. Serum CC levels of calcium, phosphate, alkaline phosphatase and parathyroid CC hormone are normal. The neuropathological hallmark of the disease is CC vascular and pericapillary calcification, mainly of calcium phosphate, CC in the affected brain areas. {ECO:0000269|PubMed:31851307, CC ECO:0000269|PubMed:32142645}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF255910; AAF81223.1; -; mRNA. DR EMBL; AY016009; AAG49022.1; -; mRNA. DR EMBL; AY077698; AAL82538.1; -; mRNA. DR EMBL; AY358361; AAQ88727.1; -; mRNA. DR EMBL; AK294769; BAG57900.1; -; mRNA. DR EMBL; AK312708; BAG35586.1; -; mRNA. DR EMBL; AP000223; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000224; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000225; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000226; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC017779; AAH17779.1; -; mRNA. DR CCDS; CCDS42911.1; -. [P57087-1] DR CCDS; CCDS58787.1; -. [P57087-3] DR CCDS; CCDS58788.1; -. [P57087-2] DR RefSeq; NP_001257336.1; NM_001270407.2. [P57087-2] DR RefSeq; NP_001257337.1; NM_001270408.2. [P57087-3] DR RefSeq; NP_067042.1; NM_021219.4. [P57087-1] DR AlphaFoldDB; P57087; -. DR SMR; P57087; -. DR BioGRID; 121824; 12. DR CORUM; P57087; -. DR FunCoup; P57087; 431. DR IntAct; P57087; 21. DR MINT; P57087; -. DR STRING; 9606.ENSP00000383376; -. DR ChEMBL; CHEMBL5483010; -. DR GlyCosmos; P57087; 3 sites, No reported glycans. DR GlyGen; P57087; 3 sites, 4 N-linked glycans (1 site). DR iPTMnet; P57087; -. DR PhosphoSitePlus; P57087; -. DR SwissPalm; P57087; -. DR BioMuta; JAM2; -. DR DMDM; 10720348; -. DR jPOST; P57087; -. DR MassIVE; P57087; -. DR PaxDb; 9606-ENSP00000383376; -. DR PeptideAtlas; P57087; -. DR ProteomicsDB; 4159; -. DR ProteomicsDB; 56996; -. [P57087-1] DR Antibodypedia; 4909; 470 antibodies from 37 providers. DR DNASU; 58494; -. DR Ensembl; ENST00000312957.9; ENSP00000318416.6; ENSG00000154721.16. [P57087-2] DR Ensembl; ENST00000400532.5; ENSP00000383376.1; ENSG00000154721.16. [P57087-3] DR Ensembl; ENST00000480456.6; ENSP00000420419.1; ENSG00000154721.16. [P57087-1] DR GeneID; 58494; -. DR KEGG; hsa:58494; -. DR MANE-Select; ENST00000480456.6; ENSP00000420419.1; NM_021219.4; NP_067042.1. DR UCSC; uc002ylp.3; human. [P57087-1] DR AGR; HGNC:14686; -. DR ClinPGx; PA29992; -. DR CTD; 58494; -. DR DisGeNET; 58494; -. DR GeneCards; JAM2; -. DR HGNC; HGNC:14686; JAM2. DR HPA; ENSG00000154721; Tissue enhanced (placenta). DR MalaCards; JAM2; -. DR MIM; 606870; gene. DR MIM; 618824; phenotype. DR OpenTargets; ENSG00000154721; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000154721; -. DR eggNOG; ENOG502QZ6E; Eukaryota. DR GeneTree; ENSGT00940000160634; -. DR HOGENOM; CLU_067351_1_0_1; -. DR InParanoid; P57087; -. DR OMA; ASEYRWY; -. DR OrthoDB; 10015491at2759; -. DR PAN-GO; P57087; 5 GO annotations based on evolutionary models. DR PhylomeDB; P57087; -. DR PathwayCommons; P57087; -. DR Reactome; R-HSA-202733; Cell surface interactions at the vascular wall. DR Reactome; R-HSA-216083; Integrin cell surface interactions. DR SignaLink; P57087; -. DR Agora; ENSG00000154721; -. DR BioGRID-ORCS; 58494; 14 hits in 1149 CRISPR screens. DR ChiTaRS; JAM2; human. DR GeneWiki; JAM2; -. DR GenomeRNAi; 58494; -. DR Pharos; P57087; Tbio. DR PRO; PR:P57087; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; P57087; protein. DR Bgee; ENSG00000154721; Expressed in ventricular zone and 198 other cell types or tissues. DR ExpressionAtlas; P57087; baseline and differential. DR GO; GO:0005923; C:bicellular tight junction; IEA:UniProtKB-SubCell. DR GO; GO:0009986; C:cell surface; IDA:ARUK-UCL. DR GO; GO:0044291; C:cell-cell contact zone; IDA:ARUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098636; C:protein complex involved in cell adhesion; IDA:UniProtKB. DR GO; GO:0036477; C:somatodendritic compartment; ISS:UniProtKB. DR GO; GO:0070160; C:tight junction; ISS:UniProtKB. DR GO; GO:0005178; F:integrin binding; IDA:UniProtKB. DR GO; GO:0098609; P:cell-cell adhesion; IMP:UniProtKB. DR GO; GO:0045123; P:cellular extravasation; IDA:UniProtKB. DR GO; GO:0097241; P:hematopoietic stem cell migration to bone marrow; IMP:UniProtKB. DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IBA:GO_Central. DR GO; GO:0050901; P:leukocyte tethering or rolling; IDA:ARUK-UCL. DR GO; GO:0071593; P:lymphocyte aggregation; IDA:ARUK-UCL. DR GO; GO:0035633; P:maintenance of blood-brain barrier; NAS:ARUK-UCL. DR GO; GO:0031642; P:negative regulation of myelination; ISS:UniProtKB. DR GO; GO:2000403; P:positive regulation of lymphocyte migration; IDA:ARUK-UCL. DR GO; GO:0007286; P:spermatid development; ISS:UniProtKB. DR CDD; cd20946; IgV_1_JAM1-like; 1. DR FunFam; 2.60.40.10:FF:001393; Junctional adhesion molecule 2; 1. DR FunFam; 2.60.40.10:FF:000342; Junctional adhesion molecule A; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 2. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR003599; Ig_sub. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR013106; Ig_V-set. DR InterPro; IPR042625; JAM2. DR PANTHER; PTHR44663; JUNCTIONAL ADHESION MOLECULE B; 1. DR PANTHER; PTHR44663:SF2; JUNCTIONAL ADHESION MOLECULE B; 1. DR Pfam; PF13927; Ig_3; 1. DR Pfam; PF07686; V-set; 1. DR SMART; SM00409; IG; 2. DR SMART; SM00408; IGc2; 2. DR SUPFAM; SSF48726; Immunoglobulin; 2. DR PROSITE; PS50835; IG_LIKE; 2. PE 1: Evidence at protein level; KW Alternative splicing; Cell junction; Cell membrane; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Immunoglobulin domain; Membrane; Proteomics identification; KW Reference proteome; Signal; Tight junction; Transmembrane; KW Transmembrane helix. FT SIGNAL 1..28 FT /evidence="ECO:0000269|PubMed:10779521, FT ECO:0000269|PubMed:15340161" FT CHAIN 29..298 FT /note="Junctional adhesion molecule B" FT /id="PRO_0000015069" FT TOPO_DOM 29..238 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 239..259 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 260..298 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 32..127 FT /note="Ig-like V-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT DOMAIN 134..238 FT /note="Ig-like C2-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT CARBOHYD 98 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952" FT CARBOHYD 187 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 50..109 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT DISULFID 155..214 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT VAR_SEQ 44..79 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045153" FT VAR_SEQ 289..298 FT /note="DFKHTKSFII -> VQWLTPVIPALWKAAAGGSRGQEF (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:12975309" FT /id="VSP_047352" FT VARIANT 60..298 FT /note="Missing (in IBGC8)" FT /evidence="ECO:0000269|PubMed:32142645" FT /id="VAR_083943" FT VARIANT 108 FT /note="R -> H (in IBGC8; dbSNP:rs1383641309)" FT /evidence="ECO:0000269|PubMed:32142645" FT /id="VAR_083944" FT VARIANT 168 FT /note="W -> C (in IBGC8; loss of localization to the plasma FT membrane; mainly retained in the cytoplasm; FT dbSNP:rs1230941179)" FT /evidence="ECO:0000269|PubMed:31851307" FT /id="VAR_083945" FT VARIANT 229..298 FT /note="Missing (in IBGC8; loss of protein expression)" FT /evidence="ECO:0000269|PubMed:32142645" FT /id="VAR_083946" FT VARIANT 286 FT /note="S -> R (in dbSNP:rs9976382)" FT /id="VAR_049973" FT MUTAGEN 82 FT /note="D->A: No effect on binding of JAM3 or integrin." FT /evidence="ECO:0000269|PubMed:12070135" FT CONFLICT 270 FT /note="E -> G (in Ref. 3; AAL82538)" FT /evidence="ECO:0000305" SQ SEQUENCE 298 AA; 33207 MW; CA78E518E22DCAEE CRC64; MARRSRHRLL LLLLRYLVVA LGYHKAYGFS APKDQQVVTA VEYQEAILAC KTPKKTVSSR LEWKKLGRSV SFVYYQQTLQ GDFKNRAEMI DFNIRIKNVT RSDAGKYRCE VSAPSEQGQN LEEDTVTLEV LVAPAVPSCE VPSSALSGTV VELRCQDKEG NPAPEYTWFK DGIRLLENPR LGSQSTNSSY TMNTKTGTLQ FNTVSKLDTG EYSCEARNSV GYRRCPGKRM QVDDLNISGI IAAVVVVALV ISVCGLGVCY AQRKGYFSKE TSFQKSNSSS KATTMSENDF KHTKSFII // ID MYORG_HUMAN Reviewed; 714 AA. AC Q6NSJ0; Q5T587; Q5T588; Q9ULQ9; DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot. DT 24-JUL-2007, sequence version 2. DT 28-JAN-2026, entry version 153. DE RecName: Full=Alpha-galactosidase MYORG {ECO:0000305|PubMed:36129849}; DE EC=3.2.1.22 {ECO:0000305|PubMed:36129849}; DE AltName: Full=Myogenesis regulating glycosidase {ECO:0000312|HGNC:HGNC:19918}; DE AltName: Full=Nuclear envelope transmembrane protein 37 {ECO:0000303|PubMed:19706595}; GN Name=MYORG {ECO:0000312|HGNC:HGNC:19918}; GN Synonyms=KIAA1161 {ECO:0000312|EMBL:BAA86475.2}, GN NET37 {ECO:0000303|PubMed:19706595}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ILE-4 AND GLU-53. RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 35-714, AND VARIANT GLU-53. RC TISSUE=Brain; RX PubMed=10574461; DOI=10.1093/dnares/6.5.329; RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.; RT "Characterization of cDNA clones selected by the GeneMark analysis from RT size-fractionated cDNA libraries from human brain."; RL DNA Res. 6:329-336(1999). RN [4] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-250. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [5] RP SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF ASP-463. RX PubMed=19706595; DOI=10.1074/jbc.m109.034041; RA Datta K., Guan T., Gerace L.; RT "NET37, a nuclear envelope transmembrane protein with glycosidase homology, RT is involved in myoblast differentiation."; RL J. Biol. Chem. 284:29666-29676(2009). RN [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [7] {ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, ECO:0007744|PDB:7QQH} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 80-714 IN COMPLEX WITH RP GAL-ALPHA1,4-GLC, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL RP PROPERTIES, SUBUNIT, SUBCELLULAR LOCATION, ACTIVE SITE, GLYCOSYLATION AT RP ASN-240; ASN-250; ASN-346; ASN-372; ASN-398 AND ASN-511, AND DISULFIDE RP BONDS. RX PubMed=36129849; DOI=10.1371/journal.pbio.3001764; RA Meek R.W., Brockerman J., Fordwour O.B., Zandberg W.F., Davies G.J., RA Vocadlo D.J.; RT "The primary familial brain calcification-associated protein MYORG is an RT alpha-galactosidase with restricted substrate specificity."; RL PLoS Biol. 20:e3001764-e3001764(2022). RN [8] RP SUBCELLULAR LOCATION, INVOLVEMENT IN IBGC7, AND VARIANTS IBGC7 VAL-35; RP 75-TRP--SER-714 DEL; LEU-ALA-PHE-ARG-116 INS; 203-GLN--SER-714 DEL; RP LEU-232; LEU-261; 365-PHE-ASP-366 DEL; GLY-441 AND 443-TRP--SER-714 DEL. RX PubMed=29910000; DOI=10.1016/j.neuron.2018.05.037; RA Yao X.P., Cheng X., Wang C., Zhao M., Guo X.X., Su H.Z., Lai L.L., RA Zou X.H., Chen X.J., Zhao Y., Dong E.L., Lu Y.Q., Wu S., Li X., Fan G., RA Yu H., Xu J., Wang N., Xiong Z.Q., Chen W.J.; RT "Biallelic mutations in MYORG cause autosomal recessive primary familial RT brain calcification."; RL Neuron 98:1116-1123(2018). RN [9] RP INVOLVEMENT IN IBGC7, AND VARIANT IBGC7 ASP-354 DEL. RX PubMed=30656188; DOI=10.1002/acn3.684; RA Arkadir D., Lossos A., Rahat D., Abu Snineh M., Schueler-Furman O., RA Nitschke S., Minassian B.A., Sadaka Y., Lerer I., Tabach Y., Meiner V.; RT "MYORG is associated with recessive primary familial brain calcification."; RL Ann. Clin. Transl. Neurol. 6:106-113(2019). RN [10] RP INVOLVEMENT IN IBGC7, AND VARIANTS IBGC7 GLU-64; ARG-113; RP LEU-ALA-PHE-ARG-116 INS; ALA-236 INS; CYS-249; ASP-373; HIS-434; RP 445-GLN--SER-714 DEL; ASN-476; SER-513 DEL; TRP-611; PRO-622; THR-656 AND RP GLN-660. RX PubMed=31009047; DOI=10.1093/brain/awz095; RG French PFBC study group; RA Grangeon L., Wallon D., Charbonnier C., Quenez O., Richard A.C., RA Rousseau S., Budowski C., Lebouvier T., Corbille A.G., Vidailhet M., RA Meneret A., Roze E., Anheim M., Tranchant C., Favrole P., Antoine J.C., RA Defebvre L., Ayrignac X., Labauge P., Pariente J., Clanet M., Maltete D., RA Rovelet-Lecrux A., Boland A., Deleuze J.F., Frebourg T., Hannequin D., RA Campion D., Nicolas G.; RT "Biallelic MYORG mutation carriers exhibit primary brain calcification with RT a distinct phenotype."; RL Brain 142:1573-1586(2019). RN [11] RP INVOLVEMENT IN IBGC7, AND VARIANT IBGC7 445-GLN--SER-714 DEL. RX PubMed=30460687; DOI=10.1111/cge.13467; RA Peng Y., Wang P., Chen Z., Jiang H.; RT "A novel mutation in MYORG causes primary familial brain calcification with RT central neuropathic pain."; RL Clin. Genet. 95:433-435(2019). RN [12] RP INVOLVEMENT IN IBGC7, AND VARIANTS IBGC7 LEU-ALA-PHE-ARG-116 INS; RP 143-LEU--ILE-147 DEL; CYS-229 AND 477-TYR--SER-714 DEL. RX PubMed=30589467; DOI=10.1002/mds.27582; RA Chen Y., Fu F., Chen S., Cen Z., Tang H., Huang J., Xie F., Zheng X., RA Yang D., Wang H., Huang X., Zhang Y., Zhou Y., Liu J.Y., Luo W.; RT "Evaluation of MYORG mutations as a novel cause of primary familial brain RT calcification."; RL Mov. Disord. 34:291-297(2019). RN [13] RP INVOLVEMENT IN IBGC7. RX PubMed=30895394; DOI=10.1007/s10048-019-00571-8; RA Ramos E.M., Roca A., Chumchim N., Dokuru D.R., Van Berlo V., De Michele G., RA Lieto M., Tedeschi E., De Michele G., Coppola G.; RT "Primary familial brain calcification caused by a novel homozygous MYORG RT mutation in a consanguineous Italian family."; RL Neurogenetics 20:99-102(2019). CC -!- FUNCTION: Alpha-galactosidase with unusual specificity for the Gal- CC alpha1,4-Glc structure, whose in vivo substrate is still unknown CC (PubMed:36129849). Promotes myogenesis by activating AKT signaling CC through the maturation and secretion of IGF2 (By similarity). CC {ECO:0000250|UniProtKB:Q69ZQ1, ECO:0000269|PubMed:36129849}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Hydrolysis of terminal, non-reducing alpha-D-galactose CC residues in alpha-D-galactosides, including galactose CC oligosaccharides, galactomannans and galactolipids.; EC=3.2.1.22; CC Evidence={ECO:0000305|PubMed:36129849}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=980 uM for Gal-alpha1,4-Glc {ECO:0000269|PubMed:36129849}; CC Note=kcat is 0.047 min-1 with the disaccharide Gal-alpha1,4-Glc as CC substrate. {ECO:0000269|PubMed:36129849}; CC pH dependence: CC Optimum pH is 6.0. {ECO:0000269|PubMed:36129849}; CC -!- SUBUNIT: Homodimer (PubMed:36129849). Interacts with IGF2; this CC interaction is required for IGF2 secretion. CC {ECO:0000250|UniProtKB:Q69ZQ1, ECO:0000269|PubMed:36129849}. CC -!- SUBCELLULAR LOCATION: Nucleus membrane {ECO:0000250|UniProtKB:Q69ZQ1}; CC Single-pass type II membrane protein {ECO:0000250|UniProtKB:Q69ZQ1}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:29910000, CC ECO:0000269|PubMed:36129849}; Single-pass type II membrane protein CC {ECO:0000250|UniProtKB:Q69ZQ1}. Note=Only a minor fraction is present CC in the peripheral endoplasmic reticulum. CC {ECO:0000250|UniProtKB:Q69ZQ1}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:36129849}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 7, autosomal CC recessive (IBGC7) [MIM:618317]: A form of basal ganglia calcification, CC a genetically heterogeneous condition characterized by symmetric CC calcification in the basal ganglia and other brain regions. Affected CC individuals can either be asymptomatic or show a wide spectrum of CC neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, CC ataxia, dementia, psychosis, seizures, and chronic headache. Serum CC levels of calcium, phosphate, alkaline phosphatase and parathyroid CC hormone are normal. The neuropathological hallmark of the disease is CC vascular and pericapillary calcification, mainly of calcium phosphate, CC in the affected brain areas. {ECO:0000269|PubMed:29910000, CC ECO:0000269|PubMed:30460687, ECO:0000269|PubMed:30589467, CC ECO:0000269|PubMed:30656188, ECO:0000269|PubMed:30895394, CC ECO:0000269|PubMed:31009047}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 31 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL356494; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC070098; AAH70098.1; -; mRNA. DR EMBL; BC110493; AAI10494.1; -; mRNA. DR EMBL; AB032987; BAA86475.2; -; mRNA. DR CCDS; CCDS78391.1; -. DR RefSeq; NP_065753.2; NM_020702.5. DR RefSeq; XP_011516268.1; XM_011517966.4. DR RefSeq; XP_016870419.1; XM_017014930.3. DR PDB; 7QQF; X-ray; 2.43 A; A/B/C/D=80-714. DR PDB; 7QQG; X-ray; 2.43 A; A/B/C/D=80-714. DR PDB; 7QQH; X-ray; 2.25 A; A/B/C/D=80-714. DR PDBsum; 7QQF; -. DR PDBsum; 7QQG; -. DR PDBsum; 7QQH; -. DR AlphaFoldDB; Q6NSJ0; -. DR SMR; Q6NSJ0; -. DR BioGRID; 121532; 64. DR FunCoup; Q6NSJ0; 461. DR IntAct; Q6NSJ0; 55. DR STRING; 9606.ENSP00000297625; -. DR CAZy; GH31; Glycoside Hydrolase Family 31. DR GlyConnect; 1882; 2 N-Linked glycans (1 site). DR GlyCosmos; Q6NSJ0; 3 sites, 2 glycans. DR GlyGen; Q6NSJ0; 6 sites, 13 N-linked glycans (5 sites). DR iPTMnet; Q6NSJ0; -. DR PhosphoSitePlus; Q6NSJ0; -. DR SwissPalm; Q6NSJ0; -. DR BioMuta; MYORG; -. DR DMDM; 158563982; -. DR jPOST; Q6NSJ0; -. DR MassIVE; Q6NSJ0; -. DR PaxDb; 9606-ENSP00000297625; -. DR PeptideAtlas; Q6NSJ0; -. DR ProteomicsDB; 66636; -. DR Pumba; Q6NSJ0; -. DR Antibodypedia; 55615; 40 antibodies from 12 providers. DR DNASU; 57462; -. DR Ensembl; ENST00000297625.8; ENSP00000297625.8; ENSG00000164976.10. DR GeneID; 57462; -. DR KEGG; hsa:57462; -. DR MANE-Select; ENST00000297625.8; ENSP00000297625.8; NM_020702.5; NP_065753.2. DR UCSC; uc033cpb.2; human. DR AGR; HGNC:19918; -. DR ClinPGx; PA134929853; -. DR CTD; 57462; -. DR DisGeNET; 57462; -. DR GeneCards; MYORG; -. DR HGNC; HGNC:19918; MYORG. DR HPA; ENSG00000164976; Tissue enhanced (skeletal). DR MalaCards; MYORG; -. DR MIM; 618255; gene. DR MIM; 618317; phenotype. DR OpenTargets; ENSG00000164976; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000164976; -. DR eggNOG; KOG1065; Eukaryota. DR GeneTree; ENSGT00940000161008; -. DR HOGENOM; CLU_008294_0_0_1; -. DR InParanoid; Q6NSJ0; -. DR OMA; AFFTWVH; -. DR OrthoDB; 10070917at2759; -. DR PAN-GO; Q6NSJ0; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q6NSJ0; -. DR PathwayCommons; Q6NSJ0; -. DR SignaLink; Q6NSJ0; -. DR Agora; ENSG00000164976; -. DR BioGRID-ORCS; 57462; 9 hits in 392 CRISPR screens. DR ChiTaRS; MYORG; human. DR GenomeRNAi; 57462; -. DR Pharos; Q6NSJ0; Tbio. DR PRO; PR:Q6NSJ0; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; Q6NSJ0; protein. DR Bgee; ENSG00000164976; Expressed in ventricular zone and 122 other cell types or tissues. DR ExpressionAtlas; Q6NSJ0; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; ISS:UniProtKB. DR GO; GO:0004557; F:alpha-galactosidase activity; IDA:UniProtKB. DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro. DR GO; GO:0043568; P:positive regulation of insulin-like growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB. DR GO; GO:0048741; P:skeletal muscle fiber development; IMP:UniProtKB. DR CDD; cd06592; GH31_NET37; 1. DR FunFam; 2.60.40.1180:FF:000006; Putative family 31 glucosidase KIAA1161; 1. DR FunFam; 3.20.20.80:FF:000037; Putative family 31 glucosidase KIAA1161; 1. DR Gene3D; 3.20.20.80; Glycosidases; 1. DR Gene3D; 2.60.40.1180; Golgi alpha-mannosidase II; 1. DR InterPro; IPR050985; Alpha-glycosidase_related. DR InterPro; IPR017853; GH. DR InterPro; IPR048395; Glyco_hydro_31_C. DR InterPro; IPR000322; Glyco_hydro_31_TIM. DR InterPro; IPR013780; Glyco_hydro_b. DR PANTHER; PTHR43053; GLYCOSIDASE FAMILY 31; 1. DR PANTHER; PTHR43053:SF4; MYOGENESIS-REGULATING GLYCOSIDASE; 1. DR Pfam; PF01055; Glyco_hydro_31_2nd; 2. DR Pfam; PF21365; Glyco_hydro_31_3rd; 1. DR SUPFAM; SSF51445; (Trans)glycosidases; 1. DR SUPFAM; SSF51011; Glycosyl hydrolase domain; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; Disulfide bond; Endoplasmic reticulum; KW Glycoprotein; Glycosidase; Hydrolase; Membrane; Nucleus; KW Proteomics identification; Reference proteome; Signal-anchor; KW Transmembrane; Transmembrane helix. FT CHAIN 1..714 FT /note="Alpha-galactosidase MYORG" FT /id="PRO_0000295752" FT TOPO_DOM 1..56 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q69ZQ1" FT TRANSMEM 57..77 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 78..714 FT /note="Lumenal" FT /evidence="ECO:0000250|UniProtKB:Q69ZQ1" FT ACT_SITE 463 FT /note="Nucleophile" FT /evidence="ECO:0000305|PubMed:36129849" FT ACT_SITE 520 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000305|PubMed:36129849" FT BINDING 213 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 353 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 354 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 426 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 461 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 504 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 517 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT BINDING 520 FT /ligand="an alpha-D-galactoside" FT /ligand_id="ChEBI:CHEBI:46953" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT CARBOHYD 240 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, FT ECO:0007744|PDB:7QQH" FT CARBOHYD 250 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQH" FT CARBOHYD 346 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, FT ECO:0007744|PDB:7QQH" FT CARBOHYD 372 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG" FT CARBOHYD 398 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG" FT CARBOHYD 511 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, FT ECO:0007744|PDB:7QQH" FT DISULFID 125..134 FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, FT ECO:0007744|PDB:7QQH" FT DISULFID 158..284 FT /evidence="ECO:0000269|PubMed:36129849, FT ECO:0007744|PDB:7QQF, ECO:0007744|PDB:7QQG, FT ECO:0007744|PDB:7QQH" FT VARIANT 4 FT /note="N -> I (in dbSNP:rs2297776)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_033359" FT VARIANT 35 FT /note="M -> V (in IBGC7; dbSNP:rs765483979)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081940" FT VARIANT 53 FT /note="D -> E (in dbSNP:rs4879781)" FT /evidence="ECO:0000269|PubMed:10574461, FT ECO:0000269|PubMed:15489334" FT /id="VAR_033360" FT VARIANT 64 FT /note="G -> E (in IBGC7; uncertain significance; FT dbSNP:rs756514041)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081941" FT VARIANT 75..714 FT /note="Missing (in IBGC7)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081942" FT VARIANT 113 FT /note="L -> R (in IBGC7; uncertain significance; FT dbSNP:rs753277260)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081943" FT VARIANT 116 FT /note="R -> RLAFR (in IBGC7)" FT /evidence="ECO:0000269|PubMed:29910000, FT ECO:0000269|PubMed:30589467, ECO:0000269|PubMed:31009047" FT /id="VAR_081944" FT VARIANT 143..147 FT /note="Missing (in IBGC7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30589467" FT /id="VAR_081945" FT VARIANT 199 FT /note="R -> S (in dbSNP:rs12377)" FT /id="VAR_033361" FT VARIANT 203..714 FT /note="Missing (in IBGC7)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081946" FT VARIANT 229 FT /note="W -> C (in IBGC7; uncertain significance; FT dbSNP:rs1588004637)" FT /evidence="ECO:0000269|PubMed:30589467" FT /id="VAR_081947" FT VARIANT 232 FT /note="S -> L (in IBGC7; uncertain significance; FT dbSNP:rs757434146)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081948" FT VARIANT 236 FT /note="A -> AA (in IBGC7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081949" FT VARIANT 249 FT /note="W -> C (in IBGC7; uncertain significance; FT dbSNP:rs1356560096)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081950" FT VARIANT 261 FT /note="R -> L (in IBGC7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081951" FT VARIANT 354 FT /note="Missing (in IBGC7; uncertain significance; FT dbSNP:rs1180204613)" FT /evidence="ECO:0000269|PubMed:30656188" FT /id="VAR_081952" FT VARIANT 365..366 FT /note="Missing (in IBGC7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081953" FT VARIANT 373 FT /note="A -> D (in IBGC7; uncertain significance; FT dbSNP:rs1588004082)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081954" FT VARIANT 385 FT /note="F -> Y (in dbSNP:rs7852399)" FT /id="VAR_033362" FT VARIANT 434 FT /note="D -> H (in IBGC7; uncertain significance; FT dbSNP:rs916933188)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081955" FT VARIANT 441 FT /note="R -> G (in IBGC7; dbSNP:rs749427106)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081956" FT VARIANT 443..714 FT /note="Missing (in IBGC7)" FT /evidence="ECO:0000269|PubMed:29910000" FT /id="VAR_081957" FT VARIANT 445..714 FT /note="Missing (in IBGC7)" FT /evidence="ECO:0000269|PubMed:30460687, FT ECO:0000269|PubMed:31009047" FT /id="VAR_081958" FT VARIANT 476 FT /note="T -> N (in IBGC7; uncertain significance; FT dbSNP:rs769099047)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081959" FT VARIANT 477..714 FT /note="Missing (in IBGC7)" FT /evidence="ECO:0000269|PubMed:30589467" FT /id="VAR_081960" FT VARIANT 513 FT /note="Missing (in IBGC7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081961" FT VARIANT 611 FT /note="R -> W (in IBGC7; uncertain significance; FT dbSNP:rs536187898)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081962" FT VARIANT 622 FT /note="L -> P (in IBGC7; uncertain significance; FT dbSNP:rs1239594469)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081963" FT VARIANT 656 FT /note="I -> T (in IBGC7; uncertain significance; FT dbSNP:rs370944350)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081964" FT VARIANT 660 FT /note="L -> Q (in IBGC7; uncertain significance; FT dbSNP:rs1588002920)" FT /evidence="ECO:0000269|PubMed:31009047" FT /id="VAR_081965" FT MUTAGEN 463 FT /note="D->A: Does not change nuclear membrane localization. FT Does not rescue the myogenetic defect induced by depletion FT of endogenous MYORG." FT /evidence="ECO:0000269|PubMed:19706595" FT STRAND 93..96 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 99..103 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 109..117 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 122..124 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 125..128 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 131..137 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 142..153 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 156..164 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 166..168 FT /evidence="ECO:0007829|PDB:7QQF" FT STRAND 172..177 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 185..189 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 202..208 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 214..216 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 218..220 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 223..231 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 234..239 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 245..250 FT /evidence="ECO:0007829|PDB:7QQH" FT TURN 251..254 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 255..260 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 278..285 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 289..300 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 310..313 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 317..320 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 321..324 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 325..327 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 330..342 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 350..352 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 357..359 FT /evidence="ECO:0007829|PDB:7QQH" FT TURN 367..369 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 373..382 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 387..391 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 393..396 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 402..408 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 417..420 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 423..425 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 428..433 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 438..455 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 459..462 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 467..469 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 485..491 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 492..500 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 502..504 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 506..508 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 514..517 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 523..526 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 531..533 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 534..543 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 548..550 FT /evidence="ECO:0007829|PDB:7QQH" FT TURN 564..567 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 571..581 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 584..586 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 588..591 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 593..595 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 598..613 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 615..629 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 633..635 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 637..639 FT /evidence="ECO:0007829|PDB:7QQH" FT HELIX 645..649 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 654..656 FT /evidence="ECO:0007829|PDB:7QQH" FT TURN 657..659 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 660..663 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 671..677 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 679..684 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 694..701 FT /evidence="ECO:0007829|PDB:7QQH" FT STRAND 708..713 FT /evidence="ECO:0007829|PDB:7QQH" SQ SEQUENCE 714 AA; 81087 MW; D17E4A75A81DBB46 CRC64; MLQNPQEKSQ AYPRRRRPGC YAYRQNPEAI AAAAMYTFLP DNFSPAKPKP SKDLKPLLGS AVLGLLLVLA AVVAWCYYSV SLRKAERLRA ELLDLKAGGF SIRNQKGEQV FRLAFRSGAL DLDSCSRDGA LLGCSLTADG LPLHFFIQTV RPKDTVMCYR VRWEEAAPGR AVEHAMFLGD AAAHWYGGAE MRTQHWPIRL DGQQEPQPFV TSDVYSSDAA FGGILERYWL SSRAAAIKVN DSVPFHLGWN STERSLRLQA RYHDTPYKPP AGRAAAPELS YRVCVGSDVT SIHKYMVRRY FNKPSRVPAP EAFRDPIWST WALYGRAVDQ DKVLRFAQQI RLHHFNSSHL EIDDMYTPAY GDFDFDEVKF PNASDMFRRL RDAGFRVTLW VHPFVNYNSS RFGEGVEREL FVREPTGRLP ALVRWWNGIG AVLDFTHPKA RDWFQGHLRR LRSRYSVASF KFDAGEVSYL PRDFSTYRPL PDPSVWSRRY TEMALPFFSL AEVRVGYQSQ NISCFFRLVD RDSVWGYDLG LRSLIPAVLT VSMLGYPFIL PDMVGGNAVP QRTAGGDVPE RELYIRWLEV AAFMPAMQFS IPPWRYDAEV VAIAQKFAAL RASLVAPLLL ELAGEVTDTG DPIVRPLWWI APGDETAHRI DSQFLIGDTL LVAPVLEPGK QERDVYLPAG KWRSYKGELF DKTPVLLTDY PVDLDEIAYF TWAS // ID NAA60_HUMAN Reviewed; 242 AA. AC Q9H7X0; B3KRQ0; B4DLZ0; B4DPZ8; B4DYC4; D3DUC2; E7EQ65; Q6IA31; Q6UX26; DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2001, sequence version 1. DT 28-JAN-2026, entry version 163. DE RecName: Full=N-alpha-acetyltransferase 60 {ECO:0000303|PubMed:25732826, ECO:0000312|HGNC:HGNC:25875}; DE Short=hNaa60 {ECO:0000303|PubMed:27320834, ECO:0000303|PubMed:27550639}; DE EC=2.3.1.259 {ECO:0000269|PubMed:25732826}; DE AltName: Full=Histone acetyltransferase type B protein 4 {ECO:0000303|PubMed:21981917}; DE Short=HAT4 {ECO:0000303|PubMed:21981917}; DE EC=2.3.1.48 {ECO:0000305|PubMed:21981917}; DE AltName: Full=N-acetyltransferase 15; DE AltName: Full=N-alpha-acetyltransferase F; DE Short=NatF; GN Name=NAA60 {ECO:0000303|PubMed:25732826, ECO:0000312|HGNC:HGNC:25875}; GN Synonyms=HAT4 {ECO:0000303|PubMed:21981917}, NAT15; GN ORFNames=UNQ2771/PRO7155; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). RC TISSUE=Fetal brain, Mesangial cell, Teratocarcinoma, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP IMPRINTING, AND INDUCTION. RX PubMed=21593219; DOI=10.1093/hmg/ddr224; RA Nakabayashi K., Trujillo A.M., Tayama C., Camprubi C., Yoshida W., RA Lapunzina P., Sanchez A., Soejima H., Aburatani H., Nagae G., Ogata T., RA Hata K., Monk D.; RT "Methylation screening of reciprocal genome-wide UPDs identifies novel RT human-specific imprinted genes."; RL Hum. Mol. Genet. 20:3188-3197(2011). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACETYLATION AT LYS-79; RP LYS-105; LYS-109; LYS-121 AND LYS-156, AND MUTAGENESIS OF LYS-79; LYS-105; RP LYS-109; GLY-111; LYS-121 AND LYS-156. RX PubMed=21981917; DOI=10.1016/j.molcel.2011.07.032; RA Yang X., Yu W., Shi L., Sun L., Liang J., Yi X., Li Q., Zhang Y., Yang F., RA Han X., Zhang D., Yang J., Yao Z., Shang Y.; RT "HAT4, a Golgi apparatus-anchored B-type histone acetyltransferase, RT acetylates free histone H4 and facilitates chromatin assembly."; RL Mol. Cell 44:39-50(2011). RN [9] RP FUNCTION. RX PubMed=21750686; DOI=10.1371/journal.pgen.1002169; RA Van Damme P., Hole K., Pimenta-Marques A., Helsens K., Vandekerckhove J., RA Martinho R.G., Gevaert K., Arnesen T.; RT "NatF contributes to an evolutionary shift in protein N-terminal RT acetylation and is important for normal chromosome segregation."; RL PLoS Genet. 7:E1002169-E1002169(2011). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TOPOLOGY, AND RP MUTAGENESIS OF CYS-19; CYS-30; CYS-132; CYS-207; 221-LEU-LEU-222 AND RP CYS-222. RX PubMed=25732826; DOI=10.1016/j.celrep.2015.01.053; RA Aksnes H., Van Damme P., Goris M., Starheim K.K., Marie M., Stoeve S.I., RA Hoel C., Kalvik T.V., Hole K., Glomnes N., Furnes C., Ljostveit S., RA Ziegler M., Niere M., Gevaert K., Arnesen T.; RT "An organellar nalpha-acetyltransferase, naa60, acetylates cytosolic N RT termini of transmembrane proteins and maintains Golgi integrity."; RL Cell Rep. 10:1362-1374(2015). RN [11] RP INVOLVEMENT IN IBGC9, VARIANTS IBGC9 ARG-17; CYS-44; TYR-131 AND THR-143, RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS IBGC9 RP ARG-17; CYS-44; TYR-131 AND THR-143. RX PubMed=38480682; DOI=10.1038/s41467-024-46354-0; RA Chelban V., Aksnes H., Maroofian R., LaMonica L.C., Seabra L., RA Siggervaag A., Devic P., Shamseldin H.E., Vandrovcova J., Murphy D., RA Richard A.C., Quenez O., Bonnevalle A., Zanetti M.N., Kaiyrzhanov R., RA Salpietro V., Efthymiou S., Schottlaender L.V., Morsy H., Scardamaglia A., RA Tariq A., Pagnamenta A.T., Pennavaria A., Krogstad L.S., Bekkelund A.K., RA Caiella A., Glomnes N., Broenstad K.M., Tury S., Moreno De Luca A., RA Boland-Auge A., Olaso R., Deleuze J.F., Anheim M., Cretin B., Vona B., RA Alajlan F., Abdulwahab F., Battini J.L., Ipek R., Bauer P., Zifarelli G., RA Gungor S., Kurul S.H., Lochmuller H., Da'as S.I., Fakhro K.A., RA Gomez-Pascual A., Botia J.A., Wood N.W., Horvath R., Ernst A.M., RA Rothman J.E., McEntagart M., Crow Y.J., Alkuraya F.S., Nicolas G., RA Arnesen T., Houlden H.; RT "Biallelic NAA60 variants with impaired n-terminal acetylation capacity RT cause autosomal recessive primary familial brain calcifications."; RL Nat. Commun. 15:2269-2269(2024). RN [12] {ECO:0000312|PDB:5HGZ, ECO:0000312|PDB:5HH0, ECO:0000312|PDB:5HH1} RP X-RAY CRYSTALLOGRAPHY (1.38 ANGSTROMS) OF 4-242 IN COMPLEX WITH ACETYL-COA, RP FUNCTION, ACTIVE SITES, AND MUTAGENESIS OF PHE-34; GLU-37; TYR-38; LYS-79; RP GLU-80; ASP-81; ASP-83; TYR-97; HIS-138; ASN-143 AND TYR-165. RX PubMed=27550639; DOI=10.1038/srep31425; RA Chen J.Y., Liu L., Cao C.L., Li M.J., Tan K., Yang X., Yun C.H.; RT "Structure and function of human Naa60 (NatF), a Golgi-localized bi- RT functional acetyltransferase."; RL Sci. Rep. 6:31425-31425(2016). RN [13] {ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW} RP X-RAY CRYSTALLOGRAPHY (1.53 ANGSTROMS) OF 3-184 IN COMPLEX WITH ACETYL-COA RP AND SUBSTRATE, FUNCTION, ACTIVE SITES, SUBUNIT, AND MUTAGENESIS OF PRO-35; RP ILE-36; TYR-38; ASP-81; ILE-84; TYR-97; HIS-138; LEU-140; TYR-164; TYR-165 RP AND ILE-167. RX PubMed=27320834; DOI=10.1016/j.str.2016.04.020; RA Stoeve S.I., Magin R.S., Foyn H., Haug B.E., Marmorstein R., Arnesen T.; RT "Crystal structure of the Golgi-associated human Nalpha-Acetyltransferase RT 60 Reveals the molecular determinants for substrate-specific acetylation."; RL Structure 24:1044-1056(2016). CC -!- FUNCTION: N-alpha-acetyltransferase that specifically mediates the CC acetylation of N-terminal residues of the transmembrane proteins, with CC a strong preference for N-termini facing the cytosol (PubMed:25732826, CC PubMed:38480682). Displays N-terminal acetyltransferase activity CC towards a range of N-terminal sequences including those starting with CC Met-Lys, Met-Val, Met-Ala and Met-Met (PubMed:21750686, CC PubMed:25732826, PubMed:27320834, PubMed:27550639). Required for normal CC chromosomal segregation during anaphase (PubMed:21750686). May also CC show histone acetyltransferase activity; such results are however CC unclear in vivo and would require additional experimental evidences CC (PubMed:21981917). {ECO:0000269|PubMed:21750686, CC ECO:0000269|PubMed:25732826, ECO:0000269|PubMed:27320834, CC ECO:0000269|PubMed:27550639, ECO:0000269|PubMed:38480682, CC ECO:0000305|PubMed:21981917}. CC -!- CATALYTIC ACTIVITY: CC Reaction=N-terminal L-methionyl-[transmembrane protein] + acetyl-CoA = CC N-terminal N(alpha)-acetyl-L-methionyl-[transmembrane protein] + CoA CC + H(+); Xref=Rhea:RHEA:50604, Rhea:RHEA-COMP:12745, Rhea:RHEA- CC COMP:12746, ChEBI:CHEBI:15378, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, CC ChEBI:CHEBI:64731, ChEBI:CHEBI:133414; EC=2.3.1.259; CC Evidence={ECO:0000269|PubMed:25732826}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] CC + CoA + H(+); Xref=Rhea:RHEA:45948, Rhea:RHEA-COMP:9752, Rhea:RHEA- CC COMP:10731, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57288, ChEBI:CHEBI:61930; EC=2.3.1.48; CC Evidence={ECO:0000305|PubMed:21981917}; CC -!- SUBUNIT: Monomer and homodimer; monomer in presence of substrate and CC homodimer in its absence (PubMed:27320834). CC {ECO:0000269|PubMed:27320834}. CC -!- INTERACTION: CC Q9H7X0; P55212: CASP6; NbExp=3; IntAct=EBI-12260336, EBI-718729; CC Q9H7X0; P13473-2: LAMP2; NbExp=3; IntAct=EBI-12260336, EBI-21591415; CC Q9H7X0; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-12260336, EBI-16439278; CC Q9H7X0; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-12260336, EBI-5280197; CC Q9H7X0; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-12260336, EBI-2623095; CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:21981917, ECO:0000269|PubMed:25732826, CC ECO:0000269|PubMed:38480682}; Peripheral membrane protein CC {ECO:0000269|PubMed:25732826}; Cytoplasmic side CC {ECO:0000269|PubMed:25732826}. Note=Probably forms an intramembrane CC hairpin-like structure in the membrane. {ECO:0000305|PubMed:25732826}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=Q9H7X0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9H7X0-2; Sequence=VSP_044123; CC Name=3; CC IsoId=Q9H7X0-3; Sequence=VSP_044122; CC Name=4; CC IsoId=Q9H7X0-4; Sequence=VSP_044124; CC Name=5; CC IsoId=Q9H7X0-5; Sequence=VSP_044125; CC -!- INDUCTION: Isoform 2: Imprinted (PubMed:21593219). Promoter methylation CC of the paternal allele may restrict expression to the maternal allele CC in placenta and leukocytes (PubMed:21593219). Isoform 1: Biallelically CC expressed (PubMed:21593219). {ECO:0000269|PubMed:21593219}. CC -!- PTM: Acetylated: autoacetylation is required for optimal CC acetyltransferase activity. {ECO:0000269|PubMed:21981917}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 9, autosomal CC recessive (IBGC9) [MIM:620786]: A form of basal ganglia calcification, CC a genetically heterogeneous condition characterized by symmetric CC calcification in the basal ganglia and other brain regions. Affected CC individuals can either be asymptomatic or show a wide spectrum of CC neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, CC ataxia, dementia, psychosis, seizures, and chronic headache. Serum CC levels of calcium, phosphate, alkaline phosphatase and parathyroid CC hormone are normal. The neuropathological hallmark of the disease is CC vascular and pericapillary calcification, mainly of calcium phosphate, CC in the affected brain areas. {ECO:0000269|PubMed:38480682}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: [Isoform 2]: In placenta and leukocytes, expressed from CC the maternal allele, due to imprinting of the paternal allele. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 4]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the acetyltransferase family. NAA60 subfamily. CC {ECO:0000305}. CC -!- CAUTION: According to a report, displays histone acetyltransferase CC activity while localized in the Golgi apparatus (PubMed:21981917). May CC mediate acetylation of free histone H4 and promote nucleosome assembly CC (PubMed:21981917). Such results are however unclear in vivo and recent CC reports strongly suggest that it acts as a N-alpha-acetyltransferase CC that specifically targets N-terminal residues of transmembrane proteins CC (PubMed:21750686, PubMed:25732826). {ECO:0000269|PubMed:21750686, CC ECO:0000269|PubMed:21981917, ECO:0000269|PubMed:25732826}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY358543; AAQ88907.1; -; mRNA. DR EMBL; AK024216; BAB14853.1; -; mRNA. DR EMBL; AK092005; BAG52462.1; -; mRNA. DR EMBL; AK297219; BAG59702.1; -; mRNA. DR EMBL; AK298566; BAG60760.1; -; mRNA. DR EMBL; AK302361; BAG63686.1; -; mRNA. DR EMBL; CR457324; CAG33605.1; -; mRNA. DR EMBL; AC004224; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC025283; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471112; EAW85358.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85359.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85360.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85361.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85362.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85363.1; -; Genomic_DNA. DR EMBL; CH471112; EAW85364.1; -; Genomic_DNA. DR EMBL; BC011267; AAH11267.1; -; mRNA. DR CCDS; CCDS45396.1; -. [Q9H7X0-1] DR CCDS; CCDS81937.1; -. [Q9H7X0-2] DR CCDS; CCDS81938.1; -. [Q9H7X0-5] DR CCDS; CCDS81939.1; -. [Q9H7X0-4] DR CCDS; CCDS81941.1; -. [Q9H7X0-3] DR RefSeq; NP_001077069.1; NM_001083600.3. [Q9H7X0-1] DR RefSeq; NP_001077070.1; NM_001083601.3. [Q9H7X0-1] DR RefSeq; NP_001304022.1; NM_001317093.1. [Q9H7X0-2] DR RefSeq; NP_001304023.1; NM_001317094.1. DR RefSeq; NP_001304024.1; NM_001317095.2. [Q9H7X0-3] DR RefSeq; NP_001304025.1; NM_001317096.2. [Q9H7X0-5] DR RefSeq; NP_001304026.1; NM_001317097.2. [Q9H7X0-4] DR RefSeq; NP_001304027.1; NM_001317098.2. [Q9H7X0-4] DR RefSeq; NP_079121.1; NM_024845.4. [Q9H7X0-1] DR PDB; 5HGZ; X-ray; 1.38 A; A=4-242. DR PDB; 5HH0; X-ray; 1.60 A; A=4-199. DR PDB; 5HH1; X-ray; 1.80 A; A=4-199. DR PDB; 5ICV; X-ray; 1.53 A; A/B=5-184. DR PDB; 5ICW; X-ray; 1.95 A; A/B/C/D=3-184. DR PDBsum; 5HGZ; -. DR PDBsum; 5HH0; -. DR PDBsum; 5HH1; -. DR PDBsum; 5ICV; -. DR PDBsum; 5ICW; -. DR AlphaFoldDB; Q9H7X0; -. DR SMR; Q9H7X0; -. DR BioGRID; 122986; 47. DR DIP; DIP-62077N; -. DR FunCoup; Q9H7X0; 1077. DR IntAct; Q9H7X0; 6. DR MINT; Q9H7X0; -. DR STRING; 9606.ENSP00000401237; -. DR ChEMBL; CHEMBL4630856; -. DR iPTMnet; Q9H7X0; -. DR PhosphoSitePlus; Q9H7X0; -. DR SwissPalm; Q9H7X0; -. DR BioMuta; NAA60; -. DR DMDM; 74733721; -. DR jPOST; Q9H7X0; -. DR MassIVE; Q9H7X0; -. DR PaxDb; 9606-ENSP00000385903; -. DR PeptideAtlas; Q9H7X0; -. DR ProteomicsDB; 17514; -. DR ProteomicsDB; 5517; -. DR ProteomicsDB; 81152; -. [Q9H7X0-1] DR Pumba; Q9H7X0; -. DR Antibodypedia; 24137; 148 antibodies from 19 providers. DR DNASU; 79903; -. DR Ensembl; ENST00000360862.9; ENSP00000354108.5; ENSG00000122390.20. [Q9H7X0-3] DR Ensembl; ENST00000407558.9; ENSP00000385903.4; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000414063.6; ENSP00000393224.2; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000421765.7; ENSP00000405873.3; ENSG00000122390.20. [Q9H7X0-5] DR Ensembl; ENST00000424546.6; ENSP00000401237.2; ENSG00000122390.20. [Q9H7X0-2] DR Ensembl; ENST00000570819.5; ENSP00000460763.1; ENSG00000122390.20. [Q9H7X0-4] DR Ensembl; ENST00000572169.6; ENSP00000458928.2; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000572584.2; ENSP00000459057.1; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000572942.5; ENSP00000461730.1; ENSG00000122390.20. [Q9H7X0-4] DR Ensembl; ENST00000573580.5; ENSP00000459055.1; ENSG00000122390.20. [Q9H7X0-3] DR Ensembl; ENST00000575076.5; ENSP00000458667.1; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000577013.6; ENSP00000458575.2; ENSG00000122390.20. [Q9H7X0-3] DR Ensembl; ENST00000649205.1; ENSP00000497988.1; ENSG00000122390.20. [Q9H7X0-1] DR Ensembl; ENST00000649360.1; ENSP00000497411.1; ENSG00000122390.20. [Q9H7X0-1] DR GeneID; 79903; -. DR KEGG; hsa:79903; -. DR MANE-Select; ENST00000407558.9; ENSP00000385903.4; NM_001083601.3; NP_001077070.1. DR UCSC; uc002cvg.3; human. [Q9H7X0-1] DR AGR; HGNC:25875; -. DR ClinPGx; PA164723438; -. DR CTD; 79903; -. DR DisGeNET; 79903; -. DR GeneCards; NAA60; -. DR HGNC; HGNC:25875; NAA60. DR HPA; ENSG00000122390; Low tissue specificity. DR MalaCards; NAA60; -. DR MIM; 614246; gene. DR MIM; 620786; phenotype. DR OpenTargets; ENSG00000122390; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000122390; -. DR eggNOG; KOG3138; Eukaryota. DR GeneTree; ENSGT00390000008314; -. DR HOGENOM; CLU_1427523_0_0_1; -. DR InParanoid; Q9H7X0; -. DR OMA; IHFYKKM; -. DR OrthoDB; 47017at2759; -. DR PAN-GO; Q9H7X0; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q9H7X0; -. DR BioCyc; MetaCyc:ENSG00000122390-MONOMER; -. DR BRENDA; 2.3.1.259; 2681. DR PathwayCommons; Q9H7X0; -. DR SignaLink; Q9H7X0; -. DR Agora; ENSG00000122390; -. DR BioGRID-ORCS; 79903; 11 hits in 1166 CRISPR screens. DR ChiTaRS; NAA60; human. DR GenomeRNAi; 79903; -. DR Pharos; Q9H7X0; Tbio. DR PRO; PR:Q9H7X0; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q9H7X0; protein. DR Bgee; ENSG00000122390; Expressed in pancreatic ductal cell and 198 other cell types or tissues. DR ExpressionAtlas; Q9H7X0; baseline and differential. DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB. DR GO; GO:0004402; F:histone acetyltransferase activity; IBA:GO_Central. DR GO; GO:0010485; F:histone H4 acetyltransferase activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0120518; F:protein N-terminal-methionine acetyltransferase activity; IEA:UniProtKB-EC. DR GO; GO:0004596; F:protein-N-terminal amino-acid acetyltransferase activity; IDA:UniProtKB. DR GO; GO:0008283; P:cell population proliferation; IMP:UniProtKB. DR GO; GO:0007059; P:chromosome segregation; ISS:UniProtKB. DR GO; GO:0017196; P:N-terminal peptidyl-methionine acetylation; IDA:UniProtKB. DR GO; GO:0006474; P:N-terminal protein amino acid acetylation; IDA:UniProtKB. DR GO; GO:0006334; P:nucleosome assembly; IDA:UniProtKB. DR CDD; cd04301; NAT_SF; 1. DR FunFam; 3.40.630.30:FF:000028; N-alpha-acetyltransferase 60 isoform X1; 1. DR Gene3D; 3.40.630.30; -; 1. DR InterPro; IPR016181; Acyl_CoA_acyltransferase. DR InterPro; IPR000182; GNAT_dom. DR InterPro; IPR045141; NAA60-like. DR PANTHER; PTHR14744; N-ALPHA-ACETYLTRANSFERASE 60; 1. DR PANTHER; PTHR14744:SF15; N-ALPHA-ACETYLTRANSFERASE 60; 1. DR Pfam; PF00583; Acetyltransf_1; 1. DR SUPFAM; SSF55729; Acyl-CoA N-acyltransferases (Nat); 1. DR PROSITE; PS51186; GNAT; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Acyltransferase; Alternative promoter usage; KW Alternative splicing; Chromatin regulator; Chromosome partition; KW Golgi apparatus; Membrane; Proteomics identification; Reference proteome; KW Transferase. FT CHAIN 1..242 FT /note="N-alpha-acetyltransferase 60" FT /id="PRO_0000321566" FT TOPO_DOM 1..192 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25732826" FT INTRAMEM 193..236 FT /note="Helical" FT /evidence="ECO:0000305|PubMed:25732826" FT TOPO_DOM 237..242 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25732826" FT DOMAIN 13..182 FT /note="N-acetyltransferase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00532" FT REGION 162..173 FT /note="Required for homodimerization" FT /evidence="ECO:0000269|PubMed:27320834" FT ACT_SITE 97 FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT ACT_SITE 138 FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT BINDING 38 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 99 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 101..103 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639, ECO:0000312|PDB:5HGZ, FT ECO:0000312|PDB:5HH0, ECO:0000312|PDB:5HH1, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 109..114 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639, ECO:0000312|PDB:5HGZ, FT ECO:0000312|PDB:5HH0, ECO:0000312|PDB:5HH1, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 143 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639, ECO:0000312|PDB:5HGZ, FT ECO:0000312|PDB:5HH0, ECO:0000312|PDB:5HH1, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 150..153 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639, ECO:0000312|PDB:5HGZ, FT ECO:0000312|PDB:5HH0, ECO:0000312|PDB:5HH1, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT BINDING 165 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000312|PDB:5ICV, ECO:0000312|PDB:5ICW" FT SITE 34 FT /note="Required to position thioacetyl group" FT /evidence="ECO:0000269|PubMed:27550639" FT MOD_RES 79 FT /note="N6-acetyllysine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:21981917" FT MOD_RES 105 FT /note="N6-acetyllysine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:21981917" FT MOD_RES 109 FT /note="N6-acetyllysine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:21981917" FT MOD_RES 121 FT /note="N6-acetyllysine; by autocatalysis" FT /evidence="ECO:0000305|PubMed:21981917" FT MOD_RES 156 FT /note="N6-acetyllysine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:21981917" FT VAR_SEQ 1..65 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044122" FT VAR_SEQ 1..36 FT /note="MTEVVPSSALSEVSLRLLCHDDIDTVKHLCGDWFPI -> MFPRRRTERRLG FT DTGTRKKIAYRKAVPGGRKCGASLSWEKSSR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044123" FT VAR_SEQ 113..242 FT /note="GSLLLESLKDHISTTAQDHCKAIYLHVLTTNNTAINFYENRDFKQHHYLPYY FT YSIRGVLKDGFTYVLYINGGHPPWTILDYIQHLGSALASLSPCSIPHRVYRQAHSLLCS FT FLPWSGISSKSGIEYSRTM -> ESTARPTACSAASCHGRASLPRVASSTAGPCDVGWA FT AATRPHPSAARRARLPVHLTPSVFCKELPAI (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044124" FT VAR_SEQ 113..242 FT /note="GSLLLESLKDHISTTAQDHCKAIYLHVLTTNNTAINFYENRDFKQHHYLPYY FT YSIRGVLKDGFTYVLYINGGHPPWTILDYIQHLGSALASLSPCSIPHRVYRQAHSLLCS FT FLPWSGISSKSGIEYSRTM -> EPHGLHPAPGLCTSQPEPLLHSAQSLPPGPQPALQL FT PAMVGHLFQEWHRVQPDHVMSAGQPPPGPTLRPPAEPAFLSI (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044125" FT VARIANT 17 FT /note="L -> R (in IBGC9; uncertain significance; when FT transfected RPE-1 cells, does not affect subcellular FT localization to the Golgi apparatus)" FT /evidence="ECO:0000269|PubMed:38480682" FT /id="VAR_089549" FT VARIANT 44 FT /note="R -> C (in IBGC9; uncertain significance; decreased FT activity of N-terminal protein amino acid acetylation; when FT transfected RPE-1 cells, does not affect subcellular FT localization to the Golgi apparatus)" FT /evidence="ECO:0000269|PubMed:38480682" FT /id="VAR_089550" FT VARIANT 131 FT /note="H -> Y (in IBGC9; uncertain significance; decreased FT activity of N-terminal protein amino acid acetylation; when FT transfected RPE-1 cells, does not affect subcellular FT localization to the Golgi apparatus)" FT /evidence="ECO:0000269|PubMed:38480682" FT /id="VAR_089551" FT VARIANT 143 FT /note="N -> T (in IBGC9; uncertain significance; may FT strongly decrease protein expression levels; when FT transfected RPE-1 cells, does not affect subcellular FT localization to the Golgi apparatus)" FT /evidence="ECO:0000269|PubMed:38480682" FT /id="VAR_089552" FT VARIANT 218 FT /note="H -> Q (in dbSNP:rs34464545)" FT /id="VAR_060995" FT MUTAGEN 19 FT /note="C->S: Does not affect localization to the Golgi FT apparatus; when associated with S-30; S-132; S-207 and S- FT 222." FT /evidence="ECO:0000269|PubMed:25732826" FT MUTAGEN 30 FT /note="C->S: Does not affect localization to the Golgi FT apparatus; when associated with S-19; S-132; S-207 and S- FT 222." FT /evidence="ECO:0000269|PubMed:25732826" FT MUTAGEN 34 FT /note="F->A: Abolished acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 35 FT /note="P->A: Reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 36 FT /note="I->A: Reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 37 FT /note="E->A,F: Only slightly affects acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 38 FT /note="Y->A: Strongly reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT MUTAGEN 79 FT /note="K->A: Slightly reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 79 FT /note="K->R,Q: Increased acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 79 FT /note="K->R: Decreased acetyltransferase activity; when FT associated with R-105, R-109, R-121 and R-156." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 80 FT /note="E->A: Slightly increased acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 81 FT /note="D->A: Slightly increased acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT MUTAGEN 83 FT /note="D->A: Slightly increased acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 84 FT /note="I->A: Slightly altered acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 97 FT /note="Y->A,F: Abolished acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT MUTAGEN 105 FT /note="K->R: Decreased acetyltransferase activity; when FT associated with R-79, R-109, R-121 and R-156." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 109 FT /note="K->R: Decreased acetyltransferase activity; when FT associated with R-79, R-105, R-121 and R-156." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 111 FT /note="G->A: Abolishes acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 121 FT /note="K->R: Decreased acetyltransferase activity; when FT associated with R-79, R-105, R-109 and R-156." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 132 FT /note="C->S: Does not affect localization to the Golgi FT apparatus; when associated with S-19; S-30; S-207 and S- FT 222." FT /evidence="ECO:0000269|PubMed:25732826" FT MUTAGEN 138 FT /note="H->A,F: Abolished acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT MUTAGEN 140 FT /note="L->A: Decreased acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 143 FT /note="N->A: Strongly reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27550639" FT MUTAGEN 156 FT /note="K->R: Decreased histone acetyltransferase activity; FT when associated with R-79, R-105, R-109 and R-121." FT /evidence="ECO:0000269|PubMed:21981917" FT MUTAGEN 164 FT /note="Y->A,F: Slightly altered acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 165 FT /note="Y->A,F: Strongly reduced acetyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27320834, FT ECO:0000269|PubMed:27550639" FT MUTAGEN 167 FT /note="I->A: Reduced acetyltransferase activity." FT /evidence="ECO:0000269|PubMed:27320834" FT MUTAGEN 207 FT /note="C->S: Does not affect localization to the Golgi FT apparatus; when associated with S-19; S-30; S-132 and S- FT 222." FT /evidence="ECO:0000269|PubMed:25732826" FT MUTAGEN 220..221 FT /note="LL->AA: Does not affect localization to the Golgi FT apparatus." FT /evidence="ECO:0000269|PubMed:25732826" FT MUTAGEN 222 FT /note="C->S: Does not affect localization to the Golgi FT apparatus; when associated with S-19; S-30; S-132 and S- FT 207." FT /evidence="ECO:0000269|PubMed:25732826" FT CONFLICT 87 FT /note="S -> T (in Ref. 1; AAQ88907)" FT /evidence="ECO:0000305" FT CONFLICT 242 FT /note="M -> I (in Ref. 3; CAG33605)" FT /evidence="ECO:0000305" FT HELIX 3..9 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 12..17 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 20..22 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 23..33 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 40..48 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 52..59 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 62..73 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 74..76 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 79..81 FT /evidence="ECO:0007829|PDB:5HGZ" FT TURN 82..87 FT /evidence="ECO:0007829|PDB:5ICV" FT STRAND 94..103 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 112..128 FT /evidence="ECO:0007829|PDB:5HGZ" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 132..140 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 144..151 FT /evidence="ECO:0007829|PDB:5HGZ" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 156..167 FT /evidence="ECO:0007829|PDB:5HGZ" FT STRAND 170..180 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 190..201 FT /evidence="ECO:0007829|PDB:5HGZ" FT HELIX 206..208 FT /evidence="ECO:0007829|PDB:5HGZ" FT CONFLICT Q9H7X0-5:180 FT /note="R -> Q (in Ref. 2; BAG60760)" FT /evidence="ECO:0000305" SQ SEQUENCE 242 AA; 27451 MW; 11234F2C51DF55DE CRC64; MTEVVPSSAL SEVSLRLLCH DDIDTVKHLC GDWFPIEYPD SWYRDITSNK KFFSLAATYR GAIVGMIVAE IKNRTKIHKE DGDILASNFS VDTQVAYILS LGVVKEFRKH GIGSLLLESL KDHISTTAQD HCKAIYLHVL TTNNTAINFY ENRDFKQHHY LPYYYSIRGV LKDGFTYVLY INGGHPPWTI LDYIQHLGSA LASLSPCSIP HRVYRQAHSL LCSFLPWSGI SSKSGIEYSR TM // ID PARK7_HUMAN Reviewed; 189 AA. AC Q99497; B2R4Z1; O14805; Q6DR95; Q7LFU2; DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 2. DT 28-JAN-2026, entry version 231. DE RecName: Full=Parkinson disease protein 7 {ECO:0000305}; DE AltName: Full=Maillard deglycase {ECO:0000303|PubMed:28596309}; DE AltName: Full=Oncogene DJ1 {ECO:0000305}; DE AltName: Full=Parkinsonism-associated deglycase {ECO:0000312|HGNC:HGNC:16369}; DE AltName: Full=Protein DJ-1 {ECO:0000305}; DE Short=DJ-1; DE AltName: Full=Protein/nucleic acid deglycase DJ-1 {ECO:0000305|PubMed:25416785, ECO:0000305|PubMed:28596309}; DE EC=3.1.2.- {ECO:0000269|PubMed:25416785}; DE EC=3.5.1.- {ECO:0000269|PubMed:28596309}; DE EC=3.5.1.124 {ECO:0000269|PubMed:25416785}; DE Flags: Precursor; GN Name=PARK7 {ECO:0000312|HGNC:HGNC:16369}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Cervix carcinoma; RX PubMed=9070310; DOI=10.1006/bbrc.1997.6132; RA Nagakubo D., Taita T., Kitaura H., Ikeda M., Tamai K., Iguchi-Ariga S.M.M., RA Ariga H.; RT "DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation RT with ras."; RL Biochem. Biophys. Res. Commun. 231:509-513(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Lung; RA Beaudoin R., Hod Y.; RT "Homo sapiens RNA-binding protein regulatory subunit mRNA."; RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Ariga H., Niki T.; RT "Human DJ-1 cDNA from PC3 cells."; RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cervix; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6. RC TISSUE=Kidney; RX PubMed=11223268; DOI=10.1016/s0378-1119(00)00590-4; RA Taira T., Takahashi K., Kitagawa R., Iguchi-Ariga S.M.M., Ariga H.; RT "Molecular cloning of human and mouse DJ-1 genes and identification of Sp1- RT dependent activation of the human DJ-1 promoter."; RL Gene 263:285-292(2001). RN [9] RP PROTEIN SEQUENCE OF 6-27; 33-89; 99-122 AND 149-175, AND IDENTIFICATION BY RP MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 138-189, AND VARIANT SER-150. RA Zou H.Q., Chan P.; RT "DJ-1 gene G150S mutation."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [11] RP INTERACTION WITH PIAS2, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=11477070; DOI=10.1074/jbc.m101730200; RA Takahashi K., Taira T., Niki T., Seino C., Iguchi-Ariga S.M.M., Ariga H.; RT "DJ-1 positively regulates the androgen receptor by impairing the binding RT of PIASx alpha to the receptor."; RL J. Biol. Chem. 276:37556-37563(2001). RN [12] RP DEGRADATION BY THE PROTEASOME, SUBCELLULAR LOCATION, INTERACTION WITH RP PIAS2, HOMODIMERIZATION, MUTAGENESIS OF LYS-130, AND CHARACTERIZATION OF RP VARIANT PARK7 PRO-166. RX PubMed=12851414; DOI=10.1074/jbc.m304272200; RA Miller D.W., Ahmad R., Hague S., Baptista M.J., Canet-Aviles R., RA McLendon C., Carter D.M., Zhu P.-P., Stadler J., Chandran J., RA Klinefelter G.R., Blackstone C., Cookson M.R.; RT "L166P mutant DJ-1, causative for recessive Parkinson's disease, is RT degraded through the ubiquitin-proteasome system."; RL J. Biol. Chem. 278:36588-36595(2003). RN [13] RP DEGRADATION BY THE PROTEASOME, AND CHARACTERIZATION OF VARIANTS PARK7 RP ILE-26 AND PRO-166. RX PubMed=14713311; DOI=10.1111/j.1471-4159.2003.02265.x; RA Moore D.J., Zhang L., Dawson T.M., Dawson V.L.; RT "A missense mutation (L166P) in DJ-1, linked to familial Parkinson's RT disease, confers reduced protein stability and impairs homo- RT oligomerization."; RL J. Neurochem. 87:1558-1567(2003). RN [14] RP FUNCTION, INTERACTION WITH EFCAB6, AND COMPONENT OF A COMPLEX COMPOSED OF RP AR; EFCAB6 AND PARK7. RX PubMed=12612053; RA Niki T., Takahashi-Niki K., Taira T., Iguchi-Ariga S.M.M., Ariga H.; RT "DJBP: a novel DJ-1-binding protein, negatively regulates the androgen RT receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes RT this inhibition by abrogation of this complex."; RL Mol. Cancer Res. 1:247-261(2003). RN [15] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=14579415; DOI=10.1002/mrd.10360; RA Yoshida K., Sato Y., Yoshiike M., Nozawa S., Ariga H., Iwamoto T.; RT "Immunocytochemical localization of DJ-1 in human male reproductive RT tissue."; RL Mol. Reprod. Dev. 66:391-397(2003). RN [16] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=14705119; DOI=10.1002/ana.10782; RA Rizzu P., Hinkle D.A., Zhukareva V., Bonifati V., Severijnen L.-A., RA Martinez D., Ravid R., Kamphorst W., Eberwine J.H., Lee V.M.-Y., RA Trojanowski J.Q., Heutink P.; RT "DJ-1 colocalizes with tau inclusions: a link between parkinsonism and RT dementia."; RL Ann. Neurol. 55:113-118(2004). RN [17] RP TISSUE SPECIFICITY. RX PubMed=14662519; DOI=10.1093/brain/awh054; RA Bandopadhyay R., Kingsbury A.E., Cookson M.R., Reid A.R., Evans I.M., RA Hope A.D., Pittman A.M., Lashley T., Canet-Aviles R., Miller D.W., RA McLendon C., Strand C., Leonard A.J., Abou-Sleiman P.M., Healy D.G., RA Ariga H., Wood N.W., de Silva R., Revesz T., Hardy J.A., Lees A.J.; RT "The expression of DJ-1 (PARK7) in normal human CNS and idiopathic RT Parkinson's disease."; RL Brain 127:420-430(2004). RN [18] RP FUNCTION, INDUCTION, AND MUTAGENESIS OF VAL-51 AND CYS-53. RX PubMed=14749723; DOI=10.1038/sj.embor.7400074; RA Taira T., Saito Y., Niki T., Iguchi-Ariga S.M., Takahashi K., Ariga H.; RT "DJ-1 has a role in antioxidative stress to prevent cell death."; RL EMBO Rep. 5:213-218(2004). RN [19] RP FUNCTION, AND MUTAGENESIS OF CYS-46; CYS-53 AND CYS-106. RX PubMed=15502874; DOI=10.1371/journal.pbio.0020362; RA Shendelman S., Jonason A., Martinat C., Leete T., Abeliovich A.; RT "DJ-1 is a redox-dependent molecular chaperone that inhibits alpha- RT synuclein aggregate formation."; RL PLoS Biol. 2:1-10(2004). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-67, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [21] RP SUMOYLATION AT LYS-130, OXIDATION, SUBCELLULAR LOCATION, INDUCTION, AND RP FUNCTION. RX PubMed=15976810; DOI=10.1038/sj.cdd.4401704; RA Shinbo Y., Niki T., Taira T., Ooe H., Takahashi-Niki K., Maita C., RA Seino C., Iguchi-Ariga S.M.M., Ariga H.; RT "Proper SUMO-1 conjugation is essential to DJ-1 to exert its full RT activities."; RL Cell Death Differ. 13:96-108(2006). RN [22] RP FUNCTION, INTERACTION WITH HIPK1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP CYS-106. RX PubMed=16390825; DOI=10.1080/10715760500456847; RA Sekito A., Koide-Yoshida S., Niki T., Taira T., Iguchi-Ariga S.M.M., RA Ariga H.; RT "DJ-1 interacts with HIPK1 and affects H2O2-induced cell death."; RL Free Radic. Res. 40:155-165(2006). RN [23] RP FUNCTION. RX PubMed=17015834; DOI=10.1073/pnas.0607260103; RA Clements C.M., McNally R.S., Conti B.J., Mak T.W., Ting J.P.; RT "DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the RT antioxidant transcriptional master regulator Nrf2."; RL Proc. Natl. Acad. Sci. U.S.A. 103:15091-15096(2006). RN [24] RP FUNCTION. RX PubMed=18626009; DOI=10.1073/pnas.0708518105; RA van der Brug M.P., Blackinton J., Chandran J., Hao L.Y., Lal A., RA Mazan-Mamczarz K., Martindale J., Xie C., Ahmad R., Thomas K.J., RA Beilina A., Gibbs J.R., Ding J., Myers A.J., Zhan M., Cai H., Bonini N.M., RA Gorospe M., Cookson M.R.; RT "RNA binding activity of the recessive parkinsonism protein DJ-1 supports RT involvement in multiple cellular pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10244-10249(2008). RN [25] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT PARK7 PRO-166. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-46; CYS-53 AND RP CYS-106. RX PubMed=18711745; DOI=10.1002/jnr.21831; RA Junn E., Jang W.H., Zhao X., Jeong B.S., Mouradian M.M.; RT "Mitochondrial localization of DJ-1 leads to enhanced neuroprotection."; RL J. Neurosci. Res. 87:123-129(2009). RN [27] RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVE SITES, AND MUTAGENESIS OF RP CYS-106 AND HIS-126. RX PubMed=20304780; DOI=10.1093/hmg/ddq113; RA Chen J., Li L., Chin L.S.; RT "Parkinson disease protein DJ-1 converts from a zymogen to a protease by RT carboxyl-terminal cleavage."; RL Hum. Mol. Genet. 19:2395-2408(2010). RN [28] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [29] RP FUNCTION, INTERACTION WITH BBS1; CLCF1; MTERF AND OTUD7B, AND MUTAGENESIS RP OF CYS-106. RX PubMed=21097510; DOI=10.1074/jbc.m110.147371; RA McNally R.S., Davis B.K., Clements C.M., Accavitti-Loper M.A., Mak T.W., RA Ting J.P.; RT "DJ-1 enhances cell survival through the binding of cezanne, a negative RT regulator of NF-{kappa}B."; RL J. Biol. Chem. 286:4098-4106(2011). RN [30] RP FUNCTION, CAUTION, MUTAGENESIS OF GLU-18; CYS-106 AND HIS-126, AND RP CHARACTERIZATION OF VARIANT PARK7 PRO-166. RX PubMed=22523093; DOI=10.1093/hmg/dds155; RA Lee J.Y., Song J., Kwon K., Jang S., Kim C., Baek K., Kim J., Park C.; RT "Human DJ-1 and its homologs are novel glyoxalases."; RL Hum. Mol. Genet. 21:3215-3225(2012). RN [31] RP FUNCTION, DEVELOPMENTAL STAGE, INDUCTION BY HYPERGLYCEMIC CONDITIONS, RP TISSUE SPECIFICITY, AND INVOLVEMENT IN DISEASE. RX PubMed=22611253; DOI=10.1093/jmcb/mjs025; RA Jain D., Jain R., Eberhard D., Eglinger J., Bugliani M., Piemonti L., RA Marchetti P., Lammert E.; RT "Age- and diet-dependent requirement of DJ-1 for glucose homeostasis in RT mice with implications for human type 2 diabetes."; RL J. Mol. Cell Biol. 4:221-230(2012). RN [32] RP FUNCTION, PALMITOYLATION AT CYS-46; CYS-53 AND CYS-106, SUBCELLULAR RP LOCATION, MUTAGENESIS OF CYS-46 AND CYS-106, AND CHARACTERIZATION OF RP VARIANT PARK7 PRO-166. RX PubMed=23847046; DOI=10.1093/hmg/ddt332; RA Kim K.S., Kim J.S., Park J.Y., Suh Y.H., Jou I., Joe E.H., Park S.M.; RT "DJ-1 associates with lipid rafts by palmitoylation and regulates lipid RT rafts-dependent endocytosis in astrocytes."; RL Hum. Mol. Genet. 22:4805-4817(2013). RN [33] RP FUNCTION, COPPER-BINDING, CHARACTERIZATION OF VARIANTS PARK7 THR-104 AND RP ALA-149, AND MUTAGENESIS OF CYS-106. RX PubMed=23792957; DOI=10.1074/jbc.m113.482091; RA Bjorkblom B., Adilbayeva A., Maple-Grodem J., Piston D., Okvist M., RA Xu X.M., Brede C., Larsen J.P., Moller S.G.; RT "Parkinson disease protein DJ-1 binds metals and protects against metal- RT induced cytotoxicity."; RL J. Biol. Chem. 288:22809-22820(2013). RN [34] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [35] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, CAUTION, RP MUTAGENESIS OF CYS-46; CYS-53 AND CYS-106, AND COFACTOR. RX PubMed=25416785; DOI=10.1074/jbc.m114.597815; RA Richarme G., Mihoub M., Dairou J., Bui L.C., Leger T., Lamouri A.; RT "Parkinsonism-associated protein DJ-1/Park7 is a major protein deglycase RT that repairs methylglyoxal- and glyoxal-glycated cysteine, arginine and RT lysine residues."; RL J. Biol. Chem. 290:1885-1897(2015). RN [36] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [37] RP CAUTION. RX PubMed=27903648; DOI=10.1074/jbc.m116.743823; RA Pfaff D.H., Fleming T., Nawroth P., Teleman A.A.; RT "Evidence against a role for the Parkinsonism-associated protein DJ-1 in RT methylglyoxal detoxification."; RL J. Biol. Chem. 292:685-690(2017). RN [38] RP FUNCTION, AND CAUTION. RX PubMed=28013050; DOI=10.1016/j.bbrc.2016.12.134; RA Richarme G., Dairou J.; RT "Parkinsonism-associated protein DJ-1 is a bona fide deglycase."; RL Biochem. Biophys. Res. Commun. 483:387-391(2017). RN [39] RP FUNCTION, AND INDUCTION BY SULFORAPHANE. RX PubMed=26995087; DOI=10.1016/j.bbrc.2016.03.056; RA Advedissian T., Deshayes F., Poirier F., Viguier M., Richarme G.; RT "The Parkinsonism-associated protein DJ-1/Park7 prevents glycation damage RT in human keratinocyte."; RL Biochem. Biophys. Res. Commun. 473:87-91(2016). RN [40] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-106, SUBCELLULAR LOCATION, RP AND CAUTION. RX PubMed=28596309; DOI=10.1126/science.aag1095; RA Richarme G., Liu C., Mihoub M., Abdallah J., Leger T., Joly N., RA Liebart J.C., Jurkunas U.V., Nadal M., Bouloc P., Dairou J., Lamouri A.; RT "Guanine glycation repair by DJ-1/Park7 and its bacterial homologs."; RL Science 357:208-211(2017). RN [41] RP FUNCTION, MUTAGENESIS OF LEU-10; GLU-18; CYS-106 AND ALA-179, RP CHARACTERIZATION OF VARIANTS PARK7 ILE-26; ASP-64; THR-104; ALA-149; RP LYS-163 AND PRO-166, AND CHARACTERIZATION OF VARIANT SER-39. RX PubMed=28993701; DOI=10.1038/s41598-017-13146-0; RA Matsuda N., Kimura M., Queliconi B.B., Kojima W., Mishima M., Takagi K., RA Koyano F., Yamano K., Mizushima T., Ito Y., Tanaka K.; RT "Parkinson's disease-related DJ-1 functions in thiol quality control RT against aldehyde attack in vitro."; RL Sci. Rep. 7:12816-12816(2017). RN [42] RP FUNCTION. RX PubMed=30150385; DOI=10.1073/pnas.1802901115; RA Galligan J.J., Wepy J.A., Streeter M.D., Kingsley P.J., Mitchener M.M., RA Wauchope O.R., Beavers W.N., Rose K.L., Wang T., Spiegel D.A., RA Marnett L.J.; RT "Methylglyoxal-derived posttranslational arginine modifications are RT abundant histone marks."; RL Proc. Natl. Acad. Sci. U.S.A. 115:9228-9233(2018). RN [43] RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH NENF, AND SUBCELLULAR RP LOCATION. RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057; RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A., RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J., RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G., RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y., RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.; RT "Rewiring of the Human Mitochondrial Interactome during Neuronal RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis."; RL IScience 19:1114-1132(2019). RN [44] RP FUNCTION, CATALYTIC ACTIVITY, CAUTION, BIOPHYSICOCHEMICAL PROPERTIES, AND RP SUBUNIT. RX PubMed=31653696; DOI=10.1074/jbc.ra119.011237; RA Andreeva A., Bekkhozhin Z., Omertassova N., Baizhumanov T., Yeltay G., RA Akhmetali M., Toibazar D., Utepbergenov D.; RT "The apparent deglycase activity of DJ-1 results from the conversion of RT free methylglyoxal present in fast equilibrium with hemithioacetals and RT hemiaminals."; RL J. Biol. Chem. 294:18863-18872(2019). RN [45] RP FUNCTION, AND MUTAGENESIS OF CYS-106. RX PubMed=30894531; DOI=10.1038/s41467-019-09192-z; RA Zheng Q., Omans N.D., Leicher R., Osunsade A., Agustinus A.S., RA Finkin-Groner E., D'Ambrosio H., Liu B., Chandarlapaty S., Liu S., RA David Y.; RT "Reversible histone glycation is associated with disease-related changes in RT chromatin architecture."; RL Nat. Commun. 10:1289-1289(2019). RN [46] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS), AND HOMODIMERIZATION. RX PubMed=12914946; DOI=10.1016/s0014-5793(03)00764-6; RA Huai Q., Sun Y., Wang H., Chin L.-S., Li L., Robinson H., Ke H.; RT "Crystal structure of DJ-1/RS and implication on familial Parkinson's RT disease."; RL FEBS Lett. 549:171-175(2003). RN [47] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF WILD-TYPE AND MUTANT ARG-130, AND RP HOMODIMERIZATION. RX PubMed=12761214; DOI=10.1074/jbc.m304221200; RA Tao X., Tong L.; RT "Crystal structure of human DJ-1, a protein associated with early onset RT Parkinson's disease."; RL J. Biol. Chem. 278:31372-31379(2003). RN [48] RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS), AND HOMODIMERIZATION. RX PubMed=12796482; DOI=10.1074/jbc.m305878200; RA Honbou K., Suzuki N.N., Horiuchi M., Niki T., Taira T., Ariga H., RA Inagaki F.; RT "The crystal structure of DJ-1, a protein related to male fertility and RT Parkinson's disease."; RL J. Biol. Chem. 278:31380-31384(2003). RN [49] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), FUNCTION, OXIDATION AT CYS-106, AND RP HOMODIMERIZATION. RX PubMed=12939276; DOI=10.1074/jbc.m304517200; RA Lee S.-J., Kim S.J., Kim I.-K., Ko J., Jeong C.-S., Kim G.-H., Park C., RA Kang S.-O., Suh P.-G., Lee H.-S., Cha S.-S.; RT "Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share RT an evolutionarily conserved domain."; RL J. Biol. Chem. 278:44552-44559(2003). RN [50] RP X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS), HOMODIMERIZATION, OXIDATION, AND RP LACK OF PROTEOLYTIC ACTIVITY. RX PubMed=12855764; DOI=10.1073/pnas.1133288100; RA Wilson M.A., Collins J.L., Hod Y., Ringe D., Petsko G.A.; RT "The 1.1-A resolution crystal structure of DJ-1, the protein mutated in RT autosomal recessive early onset Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 100:9256-9261(2003). RN [51] RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS), MUTAGENESIS OF CYS-46; CYS-53 AND RP CYS-106, OXIDATION, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=15181200; DOI=10.1073/pnas.0402959101; RA Canet-Aviles R.M., Wilson M.A., Miller D.W., Ahmad R., McLendon C., RA Bandyopadhyay S., Baptista M.J., Ringe D., Petsko G.A., Cookson M.R.; RT "The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine- RT sulfinic acid-driven mitochondrial localization."; RL Proc. Natl. Acad. Sci. U.S.A. 101:9103-9108(2004). RN [52] RP VARIANTS PARK7 ILE-26 AND ALA-149, AND VARIANT GLN-98. RX PubMed=12953260; DOI=10.1002/ana.10675; RA Abou-Sleiman P.M., Healy D.G., Quinn N., Lees A.J., Wood N.W.; RT "The role of pathogenic DJ-1 mutations in Parkinson's disease."; RL Ann. Neurol. 54:283-286(2003). RN [53] RP VARIANT PARK7 PRO-166, AND SUBCELLULAR LOCATION. RX PubMed=12446870; DOI=10.1126/science.1077209; RA Bonifati V., Rizzu P., van Baren M.J., Schaap O., Breedveld G.J., RA Krieger E., Dekker M.C.J., Squitieri F., Ibanez P., Joosse M., RA van Dongen J.W., Vanacore N., van Swieten J.C., Brice A., Meco G., RA van Duijn C.M., Oostra B.A., Heutink P.; RT "Mutations in the DJ-1 gene associated with autosomal recessive early-onset RT Parkinsonism."; RL Science 299:256-259(2003). RN [54] RP VARIANT GLN-98. RX PubMed=14705128; DOI=10.1002/ana.10816; RA Hedrich K., Schaefer N., Hering R., Hagenah J., Lanthaler A.J., RA Schwinger E., Kramer P.L., Ozelius L.J., Bressman S.B., Abbruzzese G., RA Martinelli P., Kostic V., Pramstaller P.P., Vieregge P., Riess O., RA Klein C.; RT "The R98Q variation in DJ-1 represents a rare polymorphism."; RL Ann. Neurol. 55:145-146(2004). RN [55] RP VARIANT PARK7 ASP-64, AND X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS). RX PubMed=15365989; DOI=10.1002/humu.20089; RA Hering R., Strauss K.M., Tao X., Bauer A., Woitalla D., Mietz E.M., RA Petrovic S., Bauer P., Schaible W., Mueller T., Schoels L., Klein C., RA Berg D., Meyer P.T., Schulz J.B., Wollnik B., Tong L., Krueger R., RA Riess O.; RT "Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease RT (PARK7)."; RL Hum. Mutat. 24:321-329(2004). RN [56] RP CHARACTERIZATION OF VARIANTS PARK7 ASP-64 AND PRO-166. RX PubMed=14607841; DOI=10.1074/jbc.m309204200; RA Goerner K., Holtorf E., Odoy S., Nuscher B., Yamamoto A., Regula J.T., RA Beyer K., Haass C., Kahle P.J.; RT "Differential effects of Parkinson's disease-associated mutations on RT stability and folding of DJ-1."; RL J. Biol. Chem. 279:6943-6951(2004). RN [57] RP VARIANT PARK7 THR-104, AND VARIANTS GLN-98 AND SER-171. RX PubMed=15254937; DOI=10.1002/mds.20131; RA Clark L.N., Afridi S., Mejia-Santana H., Harris J., Louis E.D., Cote L.J., RA Andrews H., Singleton A., Wavrant De-Vrieze F., Hardy J., Mayeux R., RA Fahn S., Waters C., Ford B., Frucht S., Ottman R., Marder K.; RT "Analysis of an early-onset Parkinson's disease cohort for DJ-1 RT mutations."; RL Mov. Disord. 19:796-800(2004). RN [58] RP VARIANT GLN-98. RX PubMed=14872018; DOI=10.1212/01.wnl.0000113022.51739.88; RA Hedrich K., Djarmati A., Schafer N., Hering R., Wellenbrock C., Weiss P.H., RA Hilker R., Vieregge P., Ozelius L.J., Heutink P., Bonifati V., RA Schwinger E., Lang A.E., Noth J., Bressman S.B., Pramstaller P.P., RA Riess O., Klein C.; RT "DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in RT early-onset Parkinson disease."; RL Neurology 62:389-394(2004). RN [59] RP VARIANT PARK7 LYS-163. RX PubMed=16240358; DOI=10.1002/ana.20666; RA Annesi G., Savettieri G., Pugliese P., D'Amelio M., Tarantino P., RA Ragonese P., La Bella V., Piccoli T., Civitelli D., Annesi F., Fierro B., RA Piccoli F., Arabia G., Caracciolo M., Ciro Candiano I.C., Quattrone A.; RT "DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis RT complex."; RL Ann. Neurol. 58:803-807(2005). RN [60] RP VARIANT SER-39. RX PubMed=16632486; DOI=10.1093/hmg/ddl104; RA Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q., RA Xia J.-H., Xia K., Zhang Z.; RT "Association of PINK1 and DJ-1 confers digenic inheritance of early-onset RT Parkinson's disease."; RL Hum. Mol. Genet. 15:1816-1825(2006). RN [61] RP CHARACTERIZATION OF VARIANT PARK7 PRO-166. RX PubMed=17846173; DOI=10.1083/jcb.200611128; RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D., RA Chin L.S.; RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to RT aggresomes via binding to HDAC6."; RL J. Cell Biol. 178:1025-1038(2007). RN [62] RP VARIANT PARK7 PRO-10. RX PubMed=18785233; DOI=10.1002/mds.22156; RA Guo J.F., Xiao B., Liao B., Zhang X.W., Nie L.L., Zhang Y.H., Shen L., RA Jiang H., Xia K., Pan Q., Yan X.X., Tang B.S.; RT "Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese RT patients with autosomal recessive early-onset Parkinsonism."; RL Mov. Disord. 23:2074-2079(2008). RN [63] RP VARIANT ASP-64, AND FUNCTION. RX PubMed=20186336; DOI=10.1371/journal.pone.0009367; RA Krebiehl G., Ruckerbauer S., Burbulla L.F., Kieper N., Maurer B., Waak J., RA Wolburg H., Gizatullina Z., Gellerich F.N., Woitalla D., Riess O., RA Kahle P.J., Proikas-Cezanne T., Kruger R.; RT "Reduced basal autophagy and impaired mitochondrial dynamics due to loss of RT Parkinson's disease-associated protein DJ-1."; RL PLoS ONE 5:E9367-E9367(2010). RN [64] RP VARIANT PARK7 GLN-45 DEL. RX PubMed=26972524; DOI=10.1016/j.parkreldis.2016.03.001; RA Hanagasi H.A., Giri A., Kartal E., Guven G., Bilgic B., Hauser A.K., RA Emre M., Heutink P., Basak N., Gasser T., Simon-Sanchez J., Lohmann E.; RT "A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish RT family."; RL Parkinsonism Relat. Disord. 29:117-120(2016). RN [65] RP INVOLVEMENT IN PARK7. RX PubMed=30928208; DOI=10.1016/j.parkreldis.2019.03.013; RA Stephenson S.E., Djaldetti R., Rafehi H., Wilson G.R., Gillies G., RA Bahlo M., Lockhart P.J.; RT "Familial early onset Parkinson's disease caused by a homozygous frameshift RT variant in PARK7: Clinical features and literature update."; RL Parkinsonism Relat. Disord. 64:308-311(2019). CC -!- FUNCTION: Multifunctional protein with controversial molecular function CC which plays an important role in cell protection against oxidative CC stress and cell death acting as oxidative stress sensor and redox- CC sensitive chaperone and protease (PubMed:12796482, PubMed:17015834, CC PubMed:18711745, PubMed:19229105, PubMed:20304780, PubMed:25416785, CC PubMed:26995087, PubMed:28993701). It is involved in neuroprotective CC mechanisms like the stabilization of NFE2L2 and PINK1 proteins, male CC fertility as a positive regulator of androgen signaling pathway as well CC as cell growth and transformation through, for instance, the modulation CC of NF-kappa-B signaling pathway (PubMed:12612053, PubMed:14749723, CC PubMed:15502874, PubMed:17015834, PubMed:18711745, PubMed:21097510). CC Has been described as a protein and nucleotide deglycase that catalyzes CC the deglycation of the Maillard adducts formed between amino groups of CC proteins or nucleotides and reactive carbonyl groups of glyoxals CC (PubMed:25416785, PubMed:28596309). But this function is rebuted by CC other works (PubMed:27903648, PubMed:31653696). As a protein deglycase, CC repairs methylglyoxal- and glyoxal-glycated proteins, and releases CC repaired proteins and lactate or glycolate, respectively. Deglycates CC cysteine, arginine and lysine residues in proteins, and thus CC reactivates these proteins by reversing glycation by glyoxals. Acts on CC early glycation intermediates (hemithioacetals and aminocarbinols), CC preventing the formation of advanced glycation endproducts (AGE) that CC cause irreversible damage (PubMed:25416785, PubMed:26995087, CC PubMed:28013050). Also functions as a nucleotide deglycase able to CC repair glycated guanine in the free nucleotide pool (GTP, GDP, GMP, CC dGTP) and in DNA and RNA. Is thus involved in a major nucleotide repair CC system named guanine glycation repair (GG repair), dedicated to CC reversing methylglyoxal and glyoxal damage via nucleotide sanitization CC and direct nucleic acid repair (PubMed:28596309). Protects histones CC from adduction by methylglyoxal, controls the levels of methylglyoxal- CC derived argininine modifications on chromatin (PubMed:30150385). Able CC to remove the glycations and restore histone 3, histone glycation CC disrupts both local and global chromatin architecture by altering CC histone-DNA interactions as well as histone acetylation and CC ubiquitination levels (PubMed:30150385, PubMed:30894531). Displays a CC very low glyoxalase activity that may reflect its deglycase activity CC (PubMed:22523093, PubMed:28993701, PubMed:31653696). Eliminates CC hydrogen peroxide and protects cells against hydrogen peroxide-induced CC cell death (PubMed:16390825). Required for correct mitochondrial CC morphology and function as well as for autophagy of dysfunctional CC mitochondria (PubMed:16632486, PubMed:19229105). Plays a role in CC regulating expression or stability of the mitochondrial uncoupling CC proteins SLC25A14 and SLC25A27 in dopaminergic neurons of the CC substantia nigra pars compacta and attenuates the oxidative stress CC induced by calcium entry into the neurons via L-type channels during CC pacemaking (PubMed:18711745). Regulates astrocyte inflammatory CC responses, may modulate lipid rafts-dependent endocytosis in astrocytes CC and neuronal cells (PubMed:23847046). In pancreatic islets, involved in CC the maintenance of mitochondrial reactive oxygen species (ROS) levels CC and glucose homeostasis in an age- and diet dependent manner. Protects CC pancreatic beta cells from cell death induced by inflammatory and CC cytotoxic setting (By similarity). Binds to a number of mRNAs CC containing multiple copies of GG or CC motifs and partially inhibits CC their translation but dissociates following oxidative stress CC (PubMed:18626009). Metal-binding protein able to bind copper as well as CC toxic mercury ions, enhances the cell protection mechanism against CC induced metal toxicity (PubMed:23792957). In macrophages, interacts CC with the NADPH oxidase subunit NCF1 to direct NADPH oxidase-dependent CC ROS production, and protects against sepsis (By similarity). CC {ECO:0000250|UniProtKB:Q99LX0, ECO:0000269|PubMed:11477070, CC ECO:0000269|PubMed:12612053, ECO:0000269|PubMed:12855764, CC ECO:0000269|PubMed:12939276, ECO:0000269|PubMed:14749723, CC ECO:0000269|PubMed:15181200, ECO:0000269|PubMed:15502874, CC ECO:0000269|PubMed:15976810, ECO:0000269|PubMed:16390825, CC ECO:0000269|PubMed:17015834, ECO:0000269|PubMed:18626009, CC ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:20186336, ECO:0000269|PubMed:20304780, CC ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:22523093, CC ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:23847046, CC ECO:0000269|PubMed:25416785, ECO:0000269|PubMed:26995087, CC ECO:0000269|PubMed:28013050, ECO:0000269|PubMed:28596309, CC ECO:0000269|PubMed:28993701, ECO:0000269|PubMed:30150385, CC ECO:0000269|PubMed:30894531, ECO:0000269|PubMed:9070310}. CC -!- CATALYTIC ACTIVITY: CC Reaction=N(omega)-(1-hydroxy-2-oxopropyl)-L-arginyl-[protein] + H2O = CC lactate + L-arginyl-[protein] + H(+); Xref=Rhea:RHEA:49548, CC Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:12428, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:24996, ChEBI:CHEBI:29965, CC ChEBI:CHEBI:131708; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(6)-(1-hydroxy-2-oxopropyl)-L-lysyl-[protein] + H2O = lactate CC + L-lysyl-[protein] + H(+); Xref=Rhea:RHEA:49552, Rhea:RHEA- CC COMP:9752, Rhea:RHEA-COMP:12429, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:24996, ChEBI:CHEBI:29969, CC ChEBI:CHEBI:131709; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=S-(1-hydroxy-2-oxopropyl)-L-cysteinyl-[protein] + H2O = CC lactate + L-cysteinyl-[protein] + H(+); Xref=Rhea:RHEA:49556, CC Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:12430, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:24996, ChEBI:CHEBI:29950, CC ChEBI:CHEBI:131710; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(omega)-(1-hydroxy-2-oxoethyl)-L-arginyl-[protein] + H2O = L- CC arginyl-[protein] + glycolate + H(+); Xref=Rhea:RHEA:57188, CC Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:14844, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29805, ChEBI:CHEBI:29965, CC ChEBI:CHEBI:141553; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(6)-(1-hydroxy-2-oxoethyl)-L-lysyl-[protein] + H2O = CC glycolate + L-lysyl-[protein] + H(+); Xref=Rhea:RHEA:57192, CC Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:14845, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29805, ChEBI:CHEBI:29969, CC ChEBI:CHEBI:141554; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=S-(1-hydroxy-2-oxoethyl)-L-cysteinyl-[protein] + H2O = CC glycolate + L-cysteinyl-[protein] + H(+); Xref=Rhea:RHEA:57196, CC Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:14846, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29805, ChEBI:CHEBI:29950, CC ChEBI:CHEBI:141555; EC=3.5.1.124; CC Evidence={ECO:0000269|PubMed:25416785}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxopropyl)-dGTP + H2O = lactate + dGTP + CC H(+); Xref=Rhea:RHEA:57244, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:24996, ChEBI:CHEBI:61429, ChEBI:CHEBI:141569; CC Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxopropyl)-GTP + H2O = lactate + GTP + H(+); CC Xref=Rhea:RHEA:57256, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:24996, ChEBI:CHEBI:37565, ChEBI:CHEBI:141570; CC Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxopropyl)-GDP + H2O = lactate + GDP + H(+); CC Xref=Rhea:RHEA:57260, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:24996, ChEBI:CHEBI:58189, ChEBI:CHEBI:141573; CC Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxopropyl)-GMP + H2O = lactate + GMP + H(+); CC Xref=Rhea:RHEA:57268, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:24996, ChEBI:CHEBI:58115, ChEBI:CHEBI:141575; CC Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxoethyl)-dGTP + H2O = dGTP + glycolate + CC H(+); Xref=Rhea:RHEA:57248, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29805, ChEBI:CHEBI:61429, ChEBI:CHEBI:141572; CC Evidence={ECO:0000305|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxoethyl)-GTP + H2O = glycolate + GTP + CC H(+); Xref=Rhea:RHEA:57252, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29805, ChEBI:CHEBI:37565, ChEBI:CHEBI:141571; CC Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxoethyl)-GDP + H2O = glycolate + GDP + CC H(+); Xref=Rhea:RHEA:57264, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29805, ChEBI:CHEBI:58189, ChEBI:CHEBI:141574; CC Evidence={ECO:0000305|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=N(2)-(1-hydroxy-2-oxoethyl)-GMP + H2O = glycolate + GMP + CC H(+); Xref=Rhea:RHEA:57304, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29805, ChEBI:CHEBI:58115, ChEBI:CHEBI:141576; CC Evidence={ECO:0000305|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=an N(2)-(1-hydroxy-2-oxopropyl)-guanosine in RNA + H2O = a CC guanosine in RNA + lactate + H(+); Xref=Rhea:RHEA:57288, Rhea:RHEA- CC COMP:14855, Rhea:RHEA-COMP:14858, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:24996, ChEBI:CHEBI:74269, CC ChEBI:CHEBI:141580; Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=an N(2)-(1-hydroxy-2-oxopropyl)-2'-deoxyguanosine in DNA + H2O CC = a 2'-deoxyguanosine in DNA + lactate + H(+); Xref=Rhea:RHEA:57300, CC Rhea:RHEA-COMP:11367, Rhea:RHEA-COMP:14856, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:24996, ChEBI:CHEBI:85445, CC ChEBI:CHEBI:141578; Evidence={ECO:0000269|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=an N(2)-(1-hydroxy-2-oxoethyl)-guanosine in RNA + H2O = a CC guanosine in RNA + glycolate + H(+); Xref=Rhea:RHEA:57292, Rhea:RHEA- CC COMP:14855, Rhea:RHEA-COMP:14859, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29805, ChEBI:CHEBI:74269, CC ChEBI:CHEBI:141581; Evidence={ECO:0000305|PubMed:28596309}; CC -!- CATALYTIC ACTIVITY: CC Reaction=an N(2)-(1-hydroxy-2-oxoethyl)-2'-deoxyguanosine in DNA + H2O CC = a 2'-deoxyguanosine in DNA + glycolate + H(+); CC Xref=Rhea:RHEA:57296, Rhea:RHEA-COMP:11367, Rhea:RHEA-COMP:14857, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29805, CC ChEBI:CHEBI:85445, ChEBI:CHEBI:141579; CC Evidence={ECO:0000305|PubMed:28596309}; CC -!- COFACTOR: CC Note=Deglycase activity does not require glutathione as a cofactor, CC however, glycated glutathione constitutes a PARK7 substrate. CC {ECO:0000269|PubMed:25416785, ECO:0000269|PubMed:28993701}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=173.4 uM for casein {ECO:0000269|PubMed:20304780}; CC KM=0.44 mM for glycated N-acetylarginine (at pH 7.0 and 22 degrees CC Celsius) {ECO:0000269|PubMed:25416785}; CC KM=0.35 mM for glycated N-acetyllysine (at pH 7.0 and 22 degrees CC Celsius) {ECO:0000269|PubMed:25416785}; CC KM=0.32 mM for glycated N-acetylcysteine (at pH 7.0 and 22 degrees CC Celsius) {ECO:0000269|PubMed:25416785}; CC Note=kcat is 0.27 sec(-1) for the deglycation of glycated N- CC acetylarginine. kcat is 0.28 sec(-1) for the deglycation of glycated CC N-acetyllysine. kcat is 0.42 sec(-1) for the deglycation of glycated CC N-acetylcysteine. kcat is 0.02 sec(-1) for glyoxalase activity CC (PubMed:31653696). {ECO:0000269|PubMed:25416785, CC ECO:0000269|PubMed:31653696}; CC -!- SUBUNIT: Homodimer (PubMed:12796482, PubMed:12851414, PubMed:12855764, CC PubMed:31653696). Binds EFCAB6/DJBP and PIAS2 (PubMed:11477070, CC PubMed:12612053, PubMed:12851414). Part of a ternary complex containing CC PARK7, EFCAB6/DJBP and AR (PubMed:12612053). Interacts (via N-terminus) CC with OTUD7B (PubMed:21097510). Interacts with BBS1, HIPK1, CLCF1 and CC MTERF (PubMed:16390825, PubMed:21097510). Forms a complex with PINK1 CC and PRKN (PubMed:19229105). Interacts (via C-terminus) with NCF1; the CC interaction is enhanced by LPS and modulates NCF1 phosphorylation and CC membrane translocation (By similarity). Interacts with NENF CC (PubMed:31536960). {ECO:0000250|UniProtKB:Q99LX0, CC ECO:0000269|PubMed:11477070, ECO:0000269|PubMed:12612053, CC ECO:0000269|PubMed:12796482, ECO:0000269|PubMed:12851414, CC ECO:0000269|PubMed:12855764, ECO:0000269|PubMed:16390825, CC ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:31536960, CC ECO:0000269|PubMed:31653696}. CC -!- INTERACTION: CC Q99497; P01023: A2M; NbExp=3; IntAct=EBI-1164361, EBI-640741; CC Q99497; P63010-2: AP2B1; NbExp=3; IntAct=EBI-1164361, EBI-11529439; CC Q99497; P05067: APP; NbExp=3; IntAct=EBI-1164361, EBI-77613; CC Q99497; P10275: AR; NbExp=6; IntAct=EBI-1164361, EBI-608057; CC Q99497; Q8NFJ9: BBS1; NbExp=4; IntAct=EBI-1164361, EBI-1805484; CC Q99497; Q8N5S9-2: CAMKK1; NbExp=3; IntAct=EBI-1164361, EBI-25850646; CC Q99497; Q9UER7: DAXX; NbExp=6; IntAct=EBI-1164361, EBI-77321; CC Q99497; P50570-2: DNM2; NbExp=3; IntAct=EBI-1164361, EBI-10968534; CC Q99497; Q13158: FADD; NbExp=9; IntAct=EBI-1164361, EBI-494804; CC Q99497; P06241-3: FYN; NbExp=3; IntAct=EBI-1164361, EBI-10691738; CC Q99497; Q9HD26: GOPC; NbExp=3; IntAct=EBI-1164361, EBI-349832; CC Q99497; P42858: HTT; NbExp=6; IntAct=EBI-1164361, EBI-466029; CC Q99497; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-1164361, EBI-21911304; CC Q99497; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-1164361, EBI-1044640; CC Q99497; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-1164361, EBI-1108377; CC Q99497; O94776: MTA2; NbExp=3; IntAct=EBI-1164361, EBI-1783035; CC Q99497; Q8NFH3: NUP43; NbExp=3; IntAct=EBI-1164361, EBI-1059321; CC Q99497; Q96FW1: OTUB1; NbExp=4; IntAct=EBI-1164361, EBI-1058491; CC Q99497; Q6GQQ9: OTUD7B; NbExp=3; IntAct=EBI-1164361, EBI-527784; CC Q99497; Q99497: PARK7; NbExp=3; IntAct=EBI-1164361, EBI-1164361; CC Q99497; P32322: PYCR1; NbExp=5; IntAct=EBI-1164361, EBI-848624; CC Q99497; P63244: RACK1; NbExp=4; IntAct=EBI-1164361, EBI-296739; CC Q99497; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-1164361, EBI-21535400; CC Q99497; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-1164361, EBI-25829984; CC Q99497; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-1164361, EBI-358545; CC Q99497; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-1164361, EBI-2510414; CC Q99497; O14656-2: TOR1A; NbExp=3; IntAct=EBI-1164361, EBI-25847109; CC Q99497; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-1164361, EBI-11141397; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q99LX0}; CC Lipid-anchor {ECO:0000250|UniProtKB:Q99LX0}. Cytoplasm CC {ECO:0000269|PubMed:12851414, ECO:0000269|PubMed:14579415, CC ECO:0000269|PubMed:15976810, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:28596309}. Nucleus {ECO:0000269|PubMed:12851414, CC ECO:0000269|PubMed:14579415, ECO:0000269|PubMed:15976810, CC ECO:0000269|PubMed:16390825, ECO:0000269|PubMed:28596309}. Membrane CC raft {ECO:0000250|UniProtKB:O88767}. Mitochondrion CC {ECO:0000269|PubMed:15181200, ECO:0000269|PubMed:18711745, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:31536960}. Endoplasmic CC reticulum {ECO:0000269|PubMed:31536960}. Note=Under normal conditions, CC located predominantly in the cytoplasm and, to a lesser extent, in the CC nucleus and mitochondrion. Translocates to the mitochondrion and CC subsequently to the nucleus in response to oxidative stress and exerts CC an increased cytoprotective effect against oxidative damage CC (PubMed:18711745). Detected in tau inclusions in brains from CC neurodegenerative disease patients (PubMed:14705119). Membrane raft CC localization in astrocytes and neuronal cells requires palmitoylation. CC {ECO:0000269|PubMed:14705119, ECO:0000269|PubMed:18711745}. CC -!- TISSUE SPECIFICITY: Highly expressed in pancreas, kidney, skeletal CC muscle, liver, testis and heart. Detected at slightly lower levels in CC placenta and brain (at protein level). Detected in astrocytes, Sertoli CC cells, spermatogonia, spermatids and spermatozoa. Expressed by CC pancreatic islets at higher levels than surrounding exocrine tissues CC (PubMed:22611253). {ECO:0000269|PubMed:14579415, CC ECO:0000269|PubMed:14662519, ECO:0000269|PubMed:14705119, CC ECO:0000269|PubMed:22611253, ECO:0000269|PubMed:9070310}. CC -!- DEVELOPMENTAL STAGE: In pancreatic islets, expression increases during CC aging. {ECO:0000269|PubMed:22611253}. CC -!- INDUCTION: By hydrogen peroxide and UV irradiation (PubMed:14749723, CC PubMed:15976810). In pancreatic islets, expression increases under CC hyperglycemic conditions (PubMed:22611253). Expression is also induced CC by sulforaphane, an isothiocyanate obtained from cruciferous vegetables CC (PubMed:26995087). {ECO:0000269|PubMed:14749723, CC ECO:0000269|PubMed:15976810, ECO:0000269|PubMed:22611253, CC ECO:0000269|PubMed:26995087}. CC -!- PTM: Sumoylated on Lys-130 by PIAS2 or PIAS4; which is enhanced after CC ultraviolet irradiation and essential for cell-growth promoting CC activity and transforming activity. {ECO:0000269|PubMed:15976810}. CC -!- PTM: Cys-106 is easily oxidized to sulfinic acid. CC {ECO:0000269|PubMed:12939276, ECO:0000269|PubMed:15976810}. CC -!- PTM: Undergoes cleavage of a C-terminal peptide and subsequent CC activation of protease activity in response to oxidative stress. CC {ECO:0000269|PubMed:20304780}. CC -!- DISEASE: Parkinson disease 7 (PARK7) [MIM:606324]: A neurodegenerative CC disorder characterized by resting tremor, postural tremor, CC bradykinesia, muscular rigidity, anxiety and psychotic episodes. PARK7 CC has onset before 40 years, slow progression and initial good response CC to levodopa. Some patients may show traits reminiscent of amyotrophic CC lateral sclerosis-parkinsonism/dementia complex (Guam disease). CC {ECO:0000269|PubMed:12446870, ECO:0000269|PubMed:12851414, CC ECO:0000269|PubMed:12953260, ECO:0000269|PubMed:14607841, CC ECO:0000269|PubMed:14713311, ECO:0000269|PubMed:15254937, CC ECO:0000269|PubMed:15365989, ECO:0000269|PubMed:16240358, CC ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:18785233, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:22523093, CC ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:23847046, CC ECO:0000269|PubMed:26972524, ECO:0000269|PubMed:28993701, CC ECO:0000269|PubMed:30928208}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase C56 family. {ECO:0000305}. CC -!- CAUTION: Glyoxalase activity has been reported (PubMed:22523093, CC PubMed:31653696). It may however reflect its deglycase activity CC (PubMed:25416785). {ECO:0000269|PubMed:22523093, CC ECO:0000269|PubMed:25416785, ECO:0000269|PubMed:31653696}. CC -!- CAUTION: The protein deglycation activity is controversial. It has been CC ascribed to a TRIS buffer artifact by a publication (PubMed:27903648) CC and as a result of the removal of methylglyoxal by glyoxalase activity CC that leads to a subsequent decomposition of hemithioacetals and CC hemianimals due to the shift in equilibrium position by another one CC (PubMed:31653696). However, biochemical experiments showing that PARK7 CC is a bona fide deglycase have been performed (PubMed:25416785, CC PubMed:28013050, PubMed:28596309). {ECO:0000269|PubMed:25416785, CC ECO:0000269|PubMed:27903648, ECO:0000269|PubMed:28013050, CC ECO:0000269|PubMed:28596309, ECO:0000269|PubMed:31653696}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D61380; BAA09603.2; -; mRNA. DR EMBL; AF021819; AAC12806.1; -; mRNA. DR EMBL; AB073864; BAB71782.1; -; mRNA. DR EMBL; AK312000; BAG34938.1; -; mRNA. DR EMBL; AL034417; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471130; EAW71591.1; -; Genomic_DNA. DR EMBL; BC008188; AAH08188.1; -; mRNA. DR EMBL; AB045294; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AY648999; AAT68961.1; -; Genomic_DNA. DR CCDS; CCDS93.1; -. DR PIR; JC5394; JC5394. DR RefSeq; NP_001116849.1; NM_001123377.2. DR RefSeq; NP_009193.2; NM_007262.4. DR RefSeq; XP_005263481.1; XM_005263424.4. DR RefSeq; XP_054190021.1; XM_054334046.1. DR PDB; 1J42; X-ray; 2.50 A; A=1-189. DR PDB; 1P5F; X-ray; 1.10 A; A=1-189. DR PDB; 1PDV; X-ray; 1.80 A; A=1-189. DR PDB; 1PDW; X-ray; 2.20 A; A/B/C/D/E/F/G/H=1-189. DR PDB; 1PE0; X-ray; 1.70 A; A/B=1-189. DR PDB; 1Q2U; X-ray; 1.60 A; A=1-189. DR PDB; 1SOA; X-ray; 1.20 A; A=1-189. DR PDB; 1UCF; X-ray; 1.95 A; A/B=1-189. DR PDB; 2OR3; X-ray; 1.20 A; A/B=1-189. DR PDB; 2R1T; X-ray; 1.70 A; A/B=2-188. DR PDB; 2R1U; X-ray; 1.50 A; A/B=2-188. DR PDB; 2R1V; X-ray; 1.70 A; A/B=2-188. DR PDB; 2RK3; X-ray; 1.05 A; A=1-189. DR PDB; 2RK4; X-ray; 1.15 A; A=1-189. DR PDB; 2RK6; X-ray; 1.15 A; A=1-189. DR PDB; 3B36; X-ray; 1.50 A; A=1-189. DR PDB; 3B38; X-ray; 1.85 A; A=1-189. DR PDB; 3B3A; X-ray; 1.50 A; A=1-189. DR PDB; 3BWE; X-ray; 2.40 A; A/B/C/D/E/F/G=1-189. DR PDB; 3CY6; X-ray; 1.35 A; A=1-189. DR PDB; 3CYF; X-ray; 1.60 A; A=1-189. DR PDB; 3CZ9; X-ray; 1.15 A; A=1-189. DR PDB; 3CZA; X-ray; 1.20 A; A=1-189. DR PDB; 3EZG; X-ray; 1.15 A; A=1-189. DR PDB; 3F71; X-ray; 1.20 A; A=1-189. DR PDB; 3SF8; X-ray; 1.56 A; A/B=1-189. DR PDB; 4BTE; X-ray; 1.38 A; A=1-189. DR PDB; 4MNT; X-ray; 1.58 A; A=1-189. DR PDB; 4MTC; X-ray; 1.47 A; A=1-189. DR PDB; 4N0M; X-ray; 1.95 A; A=1-189. DR PDB; 4N12; X-ray; 1.48 A; A=1-189. DR PDB; 4OGF; X-ray; 1.60 A; A=2-188. DR PDB; 4OQ4; X-ray; 1.49 A; A=1-189. DR PDB; 4P2G; X-ray; 1.35 A; A=1-189. DR PDB; 4P34; X-ray; 1.55 A; A=1-189. DR PDB; 4P35; X-ray; 1.75 A; A=1-189. DR PDB; 4P36; X-ray; 1.18 A; A=1-189. DR PDB; 4RKW; X-ray; 1.50 A; A=1-189. DR PDB; 4RKY; X-ray; 1.50 A; A=1-189. DR PDB; 4S0Z; X-ray; 1.45 A; A=1-189. DR PDB; 4ZGG; X-ray; 1.23 A; A=1-189. DR PDB; 5IP5; X-ray; 1.66 A; A=1-189. DR PDB; 5SY6; X-ray; 1.15 A; A=1-189. DR PDB; 5SY9; X-ray; 1.10 A; A=1-189. DR PDB; 5SYA; X-ray; 1.10 A; A=1-189. DR PDB; 6AF5; X-ray; 1.65 A; A=1-189. DR PDB; 6AF7; X-ray; 1.30 A; A=1-189. DR PDB; 6AF9; X-ray; 1.39 A; A=1-189. DR PDB; 6AFA; X-ray; 1.65 A; A=1-189. DR PDB; 6AFB; X-ray; 1.60 A; A=1-189. DR PDB; 6AFC; X-ray; 1.45 A; A=1-189. DR PDB; 6AFD; X-ray; 1.48 A; A=1-189. DR PDB; 6AFE; X-ray; 1.50 A; A=1-189. DR PDB; 6AFF; X-ray; 1.60 A; A=1-189. DR PDB; 6AFG; X-ray; 1.50 A; A=1-189. DR PDB; 6AFH; X-ray; 1.65 A; A=1-189. DR PDB; 6AFI; X-ray; 1.65 A; A=1-189. DR PDB; 6AFJ; X-ray; 1.48 A; A=1-189. DR PDB; 6AFL; X-ray; 1.60 A; A=1-189. DR PDB; 6E5Z; X-ray; 1.35 A; A=1-189. DR PDB; 6M8Z; X-ray; 1.83 A; A=1-189. DR PDB; 7C62; X-ray; 2.03 A; A=1-189. DR PDB; 7PA2; X-ray; 1.21 A; AAA=1-189. DR PDB; 7PA3; X-ray; 1.42 A; AAA=1-189. DR PDB; 8PPW; X-ray; 1.53 A; A=1-189. DR PDB; 8PQ0; X-ray; 1.48 A; A=1-189. DR PDB; 9CEI; X-ray; 1.77 A; A=1-189. DR PDB; 9CFI; X-ray; 1.77 A; A=1-189. DR PDB; 9CFM; X-ray; 1.77 A; A=1-189. DR PDB; 9CFO; X-ray; 1.77 A; A=1-189. DR PDB; 9CFQ; X-ray; 1.90 A; A=1-189. DR PDB; 9CFY; X-ray; 1.77 A; A=1-189. DR PDB; 9CFZ; X-ray; 1.77 A; A=1-189. DR PDB; 9CG0; X-ray; 1.77 A; A=1-189. DR PDB; 9CGA; X-ray; 2.01 A; A=1-189. DR PDB; 9CGB; X-ray; 2.01 A; A=1-189. DR PDB; 9CGD; X-ray; 1.97 A; A=1-189. DR PDB; 9CGE; X-ray; 1.90 A; A=1-189. DR PDB; 9CGF; X-ray; 2.06 A; A=1-189. DR PDB; 9CGG; X-ray; 2.01 A; A=1-189. DR PDB; 9CMX; X-ray; 1.63 A; A=1-189. DR PDB; 9CMY; X-ray; 1.69 A; A=1-189. DR PDBsum; 1J42; -. DR PDBsum; 1P5F; -. DR PDBsum; 1PDV; -. DR PDBsum; 1PDW; -. DR PDBsum; 1PE0; -. DR PDBsum; 1Q2U; -. DR PDBsum; 1SOA; -. DR PDBsum; 1UCF; -. DR PDBsum; 2OR3; -. DR PDBsum; 2R1T; -. DR PDBsum; 2R1U; -. DR PDBsum; 2R1V; -. DR PDBsum; 2RK3; -. DR PDBsum; 2RK4; -. DR PDBsum; 2RK6; -. DR PDBsum; 3B36; -. DR PDBsum; 3B38; -. DR PDBsum; 3B3A; -. DR PDBsum; 3BWE; -. DR PDBsum; 3CY6; -. DR PDBsum; 3CYF; -. DR PDBsum; 3CZ9; -. DR PDBsum; 3CZA; -. DR PDBsum; 3EZG; -. DR PDBsum; 3F71; -. DR PDBsum; 3SF8; -. DR PDBsum; 4BTE; -. DR PDBsum; 4MNT; -. DR PDBsum; 4MTC; -. DR PDBsum; 4N0M; -. DR PDBsum; 4N12; -. DR PDBsum; 4OGF; -. DR PDBsum; 4OQ4; -. DR PDBsum; 4P2G; -. DR PDBsum; 4P34; -. DR PDBsum; 4P35; -. DR PDBsum; 4P36; -. DR PDBsum; 4RKW; -. DR PDBsum; 4RKY; -. DR PDBsum; 4S0Z; -. DR PDBsum; 4ZGG; -. DR PDBsum; 5IP5; -. DR PDBsum; 5SY6; -. DR PDBsum; 5SY9; -. DR PDBsum; 5SYA; -. DR PDBsum; 6AF5; -. DR PDBsum; 6AF7; -. DR PDBsum; 6AF9; -. DR PDBsum; 6AFA; -. DR PDBsum; 6AFB; -. DR PDBsum; 6AFC; -. DR PDBsum; 6AFD; -. DR PDBsum; 6AFE; -. DR PDBsum; 6AFF; -. DR PDBsum; 6AFG; -. DR PDBsum; 6AFH; -. DR PDBsum; 6AFI; -. DR PDBsum; 6AFJ; -. DR PDBsum; 6AFL; -. DR PDBsum; 6E5Z; -. DR PDBsum; 6M8Z; -. DR PDBsum; 7C62; -. DR PDBsum; 7PA2; -. DR PDBsum; 7PA3; -. DR PDBsum; 8PPW; -. DR PDBsum; 8PQ0; -. DR PDBsum; 9CEI; -. DR PDBsum; 9CFI; -. DR PDBsum; 9CFM; -. DR PDBsum; 9CFO; -. DR PDBsum; 9CFQ; -. DR PDBsum; 9CFY; -. DR PDBsum; 9CFZ; -. DR PDBsum; 9CG0; -. DR PDBsum; 9CGA; -. DR PDBsum; 9CGB; -. DR PDBsum; 9CGD; -. DR PDBsum; 9CGE; -. DR PDBsum; 9CGF; -. DR PDBsum; 9CGG; -. DR PDBsum; 9CMX; -. DR PDBsum; 9CMY; -. DR AlphaFoldDB; Q99497; -. DR BMRB; Q99497; -. DR SMR; Q99497; -. DR BioGRID; 116446; 356. DR CORUM; Q99497; -. DR DIP; DIP-35515N; -. DR FunCoup; Q99497; 1472. DR IntAct; Q99497; 163. DR MINT; Q99497; -. DR STRING; 9606.ENSP00000340278; -. DR BindingDB; Q99497; -. DR ChEMBL; CHEMBL5169188; -. DR DrugBank; DB09130; Copper. DR MEROPS; C56.002; -. DR GlyGen; Q99497; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q99497; -. DR MetOSite; Q99497; -. DR PhosphoSitePlus; Q99497; -. DR SwissPalm; Q99497; -. DR BioMuta; PARK7; -. DR DMDM; 56404943; -. DR OGP; Q99497; -. DR REPRODUCTION-2DPAGE; IPI00298547; -. DR jPOST; Q99497; -. DR MassIVE; Q99497; -. DR PaxDb; 9606-ENSP00000418770; -. DR PeptideAtlas; Q99497; -. DR ProteomicsDB; 78298; -. DR Pumba; Q99497; -. DR TopDownProteomics; Q99497; -. DR Antibodypedia; 1372; 902 antibodies from 52 providers. DR DNASU; 11315; -. DR Ensembl; ENST00000338639.10; ENSP00000340278.5; ENSG00000116288.14. DR Ensembl; ENST00000377488.5; ENSP00000366708.1; ENSG00000116288.14. DR Ensembl; ENST00000377491.5; ENSP00000366711.1; ENSG00000116288.14. DR Ensembl; ENST00000493373.5; ENSP00000465404.1; ENSG00000116288.14. DR Ensembl; ENST00000493678.5; ENSP00000418770.1; ENSG00000116288.14. DR GeneID; 11315; -. DR KEGG; hsa:11315; -. DR MANE-Select; ENST00000338639.10; ENSP00000340278.5; NM_007262.5; NP_009193.2. DR AGR; HGNC:16369; -. DR ClinPGx; PA32946; -. DR CTD; 11315; -. DR DisGeNET; 11315; -. DR GeneCards; PARK7; -. DR GeneReviews; PARK7; -. DR HGNC; HGNC:16369; PARK7. DR HPA; ENSG00000116288; Low tissue specificity. DR MalaCards; PARK7; -. DR MIM; 168600; phenotype. DR MIM; 602533; gene. DR MIM; 606324; phenotype. DR OpenTargets; ENSG00000116288; -. DR Orphanet; 90020; Parkinson-dementia complex of Guam. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000116288; -. DR eggNOG; KOG2764; Eukaryota. DR GeneTree; ENSGT00390000001231; -. DR HOGENOM; CLU_000445_44_2_1; -. DR InParanoid; Q99497; -. DR OMA; KATCYPG; -. DR OrthoDB; 543156at2759; -. DR PAN-GO; Q99497; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q99497; -. DR BioCyc; MetaCyc:ENSG00000116288-MONOMER; -. DR BRENDA; 3.5.1.124; 2681. DR BRENDA; 4.2.1.130; 2681. DR PathwayCommons; Q99497; -. DR Reactome; R-HSA-3899300; SUMOylation of transcription cofactors. DR Reactome; R-HSA-9613829; Chaperone Mediated Autophagy. DR Reactome; R-HSA-9615710; Late endosomal microautophagy. DR Reactome; R-HSA-9646399; Aggrephagy. DR SABIO-RK; Q99497; -. DR SignaLink; Q99497; -. DR SIGNOR; Q99497; -. DR Agora; ENSG00000116288; -. DR BioGRID-ORCS; 11315; 21 hits in 1167 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; PARK7; human. DR EvolutionaryTrace; Q99497; -. DR GeneWiki; PARK7; -. DR GenomeRNAi; 11315; -. DR Pharos; Q99497; Tbio. DR PRO; PR:Q99497; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q99497; protein. DR Bgee; ENSG00000116288; Expressed in adult organism and 209 other cell types or tissues. DR ExpressionAtlas; Q99497; baseline and differential. DR GO; GO:0005912; C:adherens junction; HDA:BHF-UCL. DR GO; GO:0030424; C:axon; ISS:ParkinsonsUK-UCL. DR GO; GO:0044297; C:cell body; IEA:Ensembl. DR GO; GO:0005814; C:centriole; IDA:HPA. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell. DR GO; GO:0005758; C:mitochondrial intermembrane space; IEA:Ensembl. DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:ParkinsonsUK-UCL. DR GO; GO:0097225; C:sperm midpiece; IDA:HPA. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903135; F:cupric ion binding; IDA:ParkinsonsUK-UCL. DR GO; GO:1903136; F:cuprous ion binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019955; F:cytokine binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008047; F:enzyme activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990422; F:glyoxalase (glycolic acid-forming) activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0036478; F:L-dopa decarboxylase activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0045340; F:mercury ion binding; IDA:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IDA:UniProtKB. DR GO; GO:0050681; F:nuclear androgen receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0016684; F:oxidoreductase activity, acting on peroxide as acceptor; IDA:ParkinsonsUK-UCL. DR GO; GO:0019826; F:oxygen sensor activity; IEA:Ensembl. DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB. DR GO; GO:0030414; F:peptidase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0051920; F:peroxiredoxin activity; IEA:Ensembl. DR GO; GO:0036524; F:protein deglycase activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0097110; F:scaffold protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0030546; F:signaling receptor activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB. DR GO; GO:0044388; F:small protein activating enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0016532; F:superoxide dismutase copper chaperone activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0003713; F:transcription coactivator activity; IGI:ParkinsonsUK-UCL. DR GO; GO:0036470; F:tyrosine 3-monooxygenase activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0044390; F:ubiquitin-like protein conjugating enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0055105; F:ubiquitin-protein transferase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:0030521; P:androgen receptor signaling pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0110095; P:cellular detoxification of aldehyde; IDA:UniProtKB. DR GO; GO:0140041; P:cellular detoxification of methylglyoxal; IDA:UniProtKB. DR GO; GO:0036471; P:cellular response to glyoxal; IDA:ParkinsonsUK-UCL. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0070994; P:detection of oxidative stress; IEA:Ensembl. DR GO; GO:0010273; P:detoxification of copper ion; IMP:UniProtKB. DR GO; GO:0061691; P:detoxification of hydrogen peroxide; IDA:UniProtKB. DR GO; GO:0050787; P:detoxification of mercury ion; IEA:Ensembl. DR GO; GO:0006281; P:DNA repair; IDA:UniProtKB. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0046295; P:glycolate biosynthetic process; IDA:ParkinsonsUK-UCL. DR GO; GO:1903189; P:glyoxal metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0106044; P:guanine deglycation; IDA:UniProtKB. DR GO; GO:0106046; P:guanine deglycation, glyoxal removal; IDA:UniProtKB. DR GO; GO:0106045; P:guanine deglycation, methylglyoxal removal; IDA:UniProtKB. DR GO; GO:0042743; P:hydrogen peroxide metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0030073; P:insulin secretion; ISS:UniProtKB. DR GO; GO:0019249; P:lactate biosynthetic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0051899; P:membrane depolarization; IEA:Ensembl. DR GO; GO:0060081; P:membrane hyperpolarization; IEA:Ensembl. DR GO; GO:0061727; P:methylglyoxal catabolic process to lactate; IDA:UniProtKB. DR GO; GO:0009438; P:methylglyoxal metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; ISS:UniProtKB. DR GO; GO:1903073; P:negative regulation of death-inducing signaling complex assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IGI:ParkinsonsUK-UCL. DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:ParkinsonsUK-UCL. DR GO; GO:1903384; P:negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway; IGI:ParkinsonsUK-UCL. DR GO; GO:1903751; P:negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide; IDA:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:BHF-UCL. DR GO; GO:1905259; P:negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0046826; P:negative regulation of protein export from nucleus; IGI:ParkinsonsUK-UCL. DR GO; GO:1903094; P:negative regulation of protein K48-linked deubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0033234; P:negative regulation of protein sumoylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; ISS:UniProtKB. DR GO; GO:1903122; P:negative regulation of TRAIL-activated apoptotic signaling pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0002866; P:positive regulation of acute inflammatory response to antigenic stimulus; ISS:UniProtKB. DR GO; GO:1903599; P:positive regulation of autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:1903181; P:positive regulation of dopamine biosynthetic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; TAS:ParkinsonsUK-UCL. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:ParkinsonsUK-UCL. DR GO; GO:1903197; P:positive regulation of L-dopa biosynthetic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1902958; P:positive regulation of mitochondrial electron transport, NADH to ubiquinone; IMP:ParkinsonsUK-UCL. DR GO; GO:1902177; P:positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:ParkinsonsUK-UCL. DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:ParkinsonsUK-UCL. DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IEA:Ensembl. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:0030091; P:protein repair; IDA:ParkinsonsUK-UCL. DR GO; GO:0050821; P:protein stabilization; IDA:ParkinsonsUK-UCL. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0007265; P:Ras protein signal transduction; TAS:ParkinsonsUK-UCL. DR GO; GO:0060765; P:regulation of androgen receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB. DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:0043523; P:regulation of neuron apoptotic process; IDA:UniProtKB. DR GO; GO:1903376; P:regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902903; P:regulation of supramolecular fiber organization; TAS:ParkinsonsUK-UCL. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:0019430; P:removal of superoxide radicals; IDA:ParkinsonsUK-UCL. DR GO; GO:0006979; P:response to oxidative stress; IBA:GO_Central. DR GO; GO:0007338; P:single fertilization; IEA:UniProtKB-KW. DR CDD; cd03135; GATase1_DJ-1; 1. DR FunFam; 3.40.50.880:FF:000057; Protein/nucleic acid deglycase DJ-1; 1. DR Gene3D; 3.40.50.880; -; 1. DR InterPro; IPR029062; Class_I_gatase-like. DR InterPro; IPR006287; DJ-1. DR InterPro; IPR002818; DJ-1/PfpI. DR InterPro; IPR050325; Prot/Nucl_acid_deglycase. DR NCBIfam; TIGR01383; not_thiJ; 1. DR PANTHER; PTHR48094:SF12; PARKINSON DISEASE PROTEIN 7 HOMOLOG; 1. DR PANTHER; PTHR48094; PROTEIN/NUCLEIC ACID DEGLYCASE DJ-1-RELATED; 1. DR Pfam; PF01965; DJ-1_PfpI; 1. DR SUPFAM; SSF52317; Class I glutamine amidotransferase-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Autophagy; Cell membrane; Chaperone; Copper; KW Cytoplasm; Direct protein sequencing; Disease variant; DNA damage; KW DNA repair; Endoplasmic reticulum; Fertilization; Hydrolase; KW Inflammatory response; Isopeptide bond; Lipoprotein; Membrane; KW Mitochondrion; Neurodegeneration; Nucleus; Oxidation; Palmitate; KW Parkinson disease; Parkinsonism; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; RNA-binding; KW Stress response; Tumor suppressor; Ubl conjugation; Zymogen. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:25944712" FT CHAIN 2..? FT /note="Parkinson disease protein 7" FT /id="PRO_0000157849" FT PROPEP ?..189 FT /note="Removed in mature form" FT /id="PRO_0000405558" FT ACT_SITE 106 FT /note="Nucleophile" FT /evidence="ECO:0000305|PubMed:20304780, FT ECO:0000305|PubMed:25416785" FT ACT_SITE 126 FT /evidence="ECO:0000305|PubMed:20304780" FT SITE 149..150 FT /note="Cleavage; by CASP6" FT /evidence="ECO:0000250|UniProtKB:Q99LX0" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:25944712" FT MOD_RES 67 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 106 FT /note="Cysteine sulfinic acid (-SO2H); alternate" FT /evidence="ECO:0000269|PubMed:12939276" FT MOD_RES 148 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q99LX0" FT MOD_RES 182 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:Q99LX0" FT LIPID 46 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:23847046" FT LIPID 53 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:23847046" FT LIPID 106 FT /note="S-palmitoyl cysteine; alternate" FT /evidence="ECO:0000269|PubMed:23847046" FT CROSSLNK 130 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:15976810" FT VARIANT 10 FT /note="L -> P (in PARK7; uncertain significance)" FT /evidence="ECO:0000269|PubMed:18785233" FT /id="VAR_084339" FT VARIANT 26 FT /note="M -> I (in PARK7; does not affect protein stability FT and degradation; does not interfere with homodimerization; FT decreased detoxification activity on methylglyocal-adducted FT CoA; dbSNP:rs74315351)" FT /evidence="ECO:0000269|PubMed:12953260, FT ECO:0000269|PubMed:14713311, ECO:0000269|PubMed:28993701" FT /id="VAR_020492" FT VARIANT 39 FT /note="A -> S (found in early-onset Parkinson disease with FT digenic inheritance; likely pathogenic; the patient also FT carries PINK1 mutation L-399; no effect on detoxification FT activity on methylglyocal-adducted CoA; dbSNP:rs137853051)" FT /evidence="ECO:0000269|PubMed:16632486, FT ECO:0000269|PubMed:28993701" FT /id="VAR_072589" FT VARIANT 45 FT /note="Missing (in PARK7)" FT /evidence="ECO:0000269|PubMed:26972524" FT /id="VAR_083277" FT VARIANT 64 FT /note="E -> D (in PARK7; no apparent effect on protein FT stability; impaired mitochondrial morphology; no effect on FT detoxification activity on methylglyocal-adducted CoA; FT dbSNP:rs74315353)" FT /evidence="ECO:0000269|PubMed:14607841, FT ECO:0000269|PubMed:15365989, ECO:0000269|PubMed:20186336, FT ECO:0000269|PubMed:28993701" FT /id="VAR_020493" FT VARIANT 98 FT /note="R -> Q (in dbSNP:rs71653619)" FT /evidence="ECO:0000269|PubMed:12953260, FT ECO:0000269|PubMed:14705128, ECO:0000269|PubMed:14872018, FT ECO:0000269|PubMed:15254937" FT /id="VAR_020494" FT VARIANT 104 FT /note="A -> T (in PARK7; loss of protection against metal FT cytotoxicity; decreased detoxification activity on FT methylglyocal-adducted CoA; dbSNP:rs774005786)" FT /evidence="ECO:0000269|PubMed:15254937, FT ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:28993701" FT /id="VAR_020495" FT VARIANT 149 FT /note="D -> A (in PARK7; loss of protection against metal FT cytotoxicity; decreased detoxification activity on FT methylglyocal-adducted CoA; dbSNP:rs74315352)" FT /evidence="ECO:0000269|PubMed:12953260, FT ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:28993701" FT /id="VAR_020496" FT VARIANT 150 FT /note="G -> S (in dbSNP:rs368420490)" FT /evidence="ECO:0000269|Ref.10" FT /id="VAR_020497" FT VARIANT 163 FT /note="E -> K (in PARK7; uncertain significance; no effect FT on detoxification activity on methylglyocal-adducted CoA; FT dbSNP:rs74315354)" FT /evidence="ECO:0000269|PubMed:16240358, FT ECO:0000269|PubMed:28993701" FT /id="VAR_034801" FT VARIANT 166 FT /note="L -> P (in PARK7; strongly decreases enzymatic FT activity; reduces protein stability and leads to increased FT degradation; ubiquitinated by PRKN leading to its FT recognition by HDAC6 and targeting to aggresome where is FT degraded; interferes with homodimerization; abolishes FT interaction with PIAS2; reduced localization in lipid FT rafts; almost abolished detoxification activity on FT methylglyocal-adducted CoA; dbSNP:rs28938172)" FT /evidence="ECO:0000269|PubMed:12446870, FT ECO:0000269|PubMed:12851414, ECO:0000269|PubMed:14607841, FT ECO:0000269|PubMed:14713311, ECO:0000269|PubMed:17846173, FT ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:22523093, FT ECO:0000269|PubMed:23847046, ECO:0000269|PubMed:28993701" FT /id="VAR_020498" FT VARIANT 171 FT /note="A -> S (in dbSNP:rs777026628)" FT /evidence="ECO:0000269|PubMed:15254937" FT /id="VAR_020499" FT MUTAGEN 10 FT /note="L->P: Abolishes detoxification activity on FT methylglyocal-adducted CoA." FT /evidence="ECO:0000269|PubMed:28993701" FT MUTAGEN 18 FT /note="E->A: Strongly decreases enzymatic activity. Almost FT abolishes detoxification activity on methylglyocal-adducted FT CoA." FT /evidence="ECO:0000269|PubMed:22523093, FT ECO:0000269|PubMed:28993701" FT MUTAGEN 18 FT /note="E->D: Strongly decreases enzymatic activity." FT /evidence="ECO:0000269|PubMed:22523093" FT MUTAGEN 18 FT /note="E->N: Strongly decreases enzymatic activity." FT /evidence="ECO:0000269|PubMed:22523093" FT MUTAGEN 18 FT /note="E->Q: Strongly decreases enzymatic activity." FT /evidence="ECO:0000269|PubMed:22523093" FT MUTAGEN 46 FT /note="C->A: Reduces protein stability. No effect on FT oxidation." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:18711745, FT ECO:0000269|PubMed:23847046" FT MUTAGEN 46 FT /note="C->A: Reduces protein stability. No effect on FT oxidation. Reduced localization in lipid rafts; when FT associated with A-106." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:18711745, FT ECO:0000269|PubMed:23847046" FT MUTAGEN 46 FT /note="C->S: No effect on mitochondrial translocation FT neither on deglycase activity." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:18711745, FT ECO:0000269|PubMed:23847046, ECO:0000269|PubMed:25416785" FT MUTAGEN 51 FT /note="V->A: Disrupts dimer formation and strongly reduces FT ability to eliminate hydrogen peroxide." FT /evidence="ECO:0000269|PubMed:14749723" FT MUTAGEN 53 FT /note="C->A: Strongly reduces chaperone activity and FT ability to eliminate hydrogen peroxide." FT /evidence="ECO:0000269|PubMed:14749723, FT ECO:0000269|PubMed:15181200, ECO:0000269|PubMed:15502874, FT ECO:0000269|PubMed:18711745" FT MUTAGEN 53 FT /note="C->S: No effect on mitochondrial translocation FT neither on deglycase activity." FT /evidence="ECO:0000269|PubMed:14749723, FT ECO:0000269|PubMed:15181200, ECO:0000269|PubMed:15502874, FT ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:25416785" FT MUTAGEN 106 FT /note="C->A: Abolishes enzymatic activity. Abolishes FT oxidation, association with mitochondria and protease FT activity. No effect on chaperone activity. Reduces binding FT to OTUD7B." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:16390825, FT ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:20304780, FT ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:22523093, FT ECO:0000269|PubMed:23847046" FT MUTAGEN 106 FT /note="C->A: Abolishes enzymatic activity. Abolishes FT oxidation, association with mitochondria and protease FT activity. No effect on chaperone activity. Reduces binding FT to OTUD7B. Removes the glycations and restores histone 3. FT Reduced localization in lipid rafts; when associated with FT A-46." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:16390825, FT ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:20304780, FT ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:22523093, FT ECO:0000269|PubMed:23847046, ECO:0000269|PubMed:30894531" FT MUTAGEN 106 FT /note="C->D: Abolishes oxidation and association with FT mitochondria. No effect on chaperone activity." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:16390825, FT ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:20304780, FT ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:23847046" FT MUTAGEN 106 FT /note="C->S: Loss of protein and nucleic acid deglycase FT activity. No effect on mitochondrial translocation. Reduced FT protease activity. No effect on protection against metal FT cytotoxicity. No effect on methylglyoxal-adducted FT glutathione or CoA." FT /evidence="ECO:0000269|PubMed:15181200, FT ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:16390825, FT ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:20304780, FT ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:23847046, FT ECO:0000269|PubMed:25416785, ECO:0000269|PubMed:28596309, FT ECO:0000269|PubMed:28993701" FT MUTAGEN 126 FT /note="H->A: Strongly decreases enzymatic activity." FT /evidence="ECO:0000269|PubMed:20304780, FT ECO:0000269|PubMed:22523093" FT MUTAGEN 130 FT /note="K->R: Partially compensates for loss of stability; FT when associated with P-166." FT /evidence="ECO:0000269|PubMed:12851414" FT MUTAGEN 179 FT /note="A->T: No effect on detoxification activity on FT methylglyocal-adducted CoA." FT /evidence="ECO:0000269|PubMed:28993701" FT CONFLICT 119 FT /note="F -> C (in Ref. 3; BAB71782)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 16..28 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:2RK3" FT TURN 38..41 FT /evidence="ECO:0007829|PDB:1PDW" FT STRAND 47..49 FT /evidence="ECO:0007829|PDB:4N0M" FT STRAND 51..53 FT /evidence="ECO:0007829|PDB:2OR3" FT STRAND 55..57 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 58..62 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 68..72 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 76..84 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 86..97 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 101..105 FT /evidence="ECO:0007829|PDB:2RK3" FT TURN 106..108 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 109..114 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 127..129 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 130..133 FT /evidence="ECO:0007829|PDB:2RK3" FT TURN 134..136 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 139..141 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 145..149 FT /evidence="ECO:0007829|PDB:2RK3" FT STRAND 152..155 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 158..160 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 161..173 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 175..182 FT /evidence="ECO:0007829|PDB:2RK3" FT HELIX 183..185 FT /evidence="ECO:0007829|PDB:2RK3" SQ SEQUENCE 189 AA; 19891 MW; 4B21661B3A76BC67 CRC64; MASKRALVIL AKGAEEMETV IPVDVMRRAG IKVTVAGLAG KDPVQCSRDV VICPDASLED AKKEGPYDVV VLPGGNLGAQ NLSESAAVKE ILKEQENRKG LIAAICAGPT ALLAHEIGFG SKVTTHPLAK DKMMNGGHYT YSENRVEKDG LILTSRGPGT SFEFALAIVE ALNGKEVAAQ VKAPLVLKD // ID PCS1N_HUMAN Reviewed; 260 AA. AC Q9UHG2; Q4VC04; DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 165. DE RecName: Full=ProSAAS; DE AltName: Full=Proprotein convertase subtilisin/kexin type 1 inhibitor; DE Short=Proprotein convertase 1 inhibitor; DE AltName: Full=pro-SAAS; DE Contains: DE RecName: Full=KEP; DE Contains: DE RecName: Full=Big SAAS; DE Short=b-SAAS; DE Contains: DE RecName: Full=Little SAAS; DE Short=l-SAAS; DE AltName: Full=N-proSAAS; DE Contains: DE RecName: Full=Big PEN-LEN; DE Short=b-PEN-LEN; DE AltName: Full=SAAS CT(1-49); DE Contains: DE RecName: Full=PEN; DE Contains: DE RecName: Full=Little LEN; DE Short=l-LEN; DE Contains: DE RecName: Full=Big LEN; DE Short=b-LEN; DE AltName: Full=SAAS CT(25-40); DE Flags: Precursor; GN Name=PCSK1N; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RX PubMed=10632593; DOI=10.1523/jneurosci.20-02-00639.2000; RA Fricker L., McKinzie A.A., Sun J., Curran E., Qian Y., Yan L., RA Patterson S.D., Courchesne P.L., Richards B., Levin N., Mzhavia N., RA Devi L.A., Douglass J.; RT "Identification and characterization of proSAAS, a granin-like RT neuroendocrine peptide precursor that inhibits prohormone processing."; RL J. Neurosci. 20:639-648(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-31. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP MUTAGENESIS OF VAL-235; LEU-236; GLY-237; LEU-240; ARG-241; VAL-242; RP LYS-243; ARG-244; LEU-245 AND GLU-246. RX PubMed=11435430; DOI=10.1074/jbc.m104064200; RA Basak A., Koch P., Dupelle M., Fricker L.D., Devi L.A., Chretien M., RA Seidah N.G.; RT "Inhibitory specificity and potency of proSAAS-derived peptides toward RT proprotein convertase 1."; RL J. Biol. Chem. 276:32720-32728(2001). RN [4] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS), AND PROTEOLYTIC PROCESSING. RX PubMed=12914799; DOI=10.1016/s0006-291x(03)01391-3; RA Kikuchi K., Arawaka S., Koyama S., Kimura H., Ren C.H., Wada M., RA Kawanami T., Kurita K., Daimon M., Kawakatsu S., Kadoya T., Goto K., RA Kato T.; RT "An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide RT precursor) is associated with tau inclusions in Pick's disease."; RL Biochem. Biophys. Res. Commun. 308:646-654(2003). RN [5] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS). RX PubMed=14746899; DOI=10.1016/j.neulet.2003.11.028; RA Wada M., Ren C.H., Koyama S., Arawaka S., Kawakatsu S., Kimura H., RA Nagasawa H., Kawanami T., Kurita K., Daimon M., Hirano A., Kato T.; RT "A human granin-like neuroendocrine peptide precursor (proSAAS) RT immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism- RT dementia complex on Guam."; RL Neurosci. Lett. 356:49-52(2004). RN [6] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-53 AND THR-247, AND STRUCTURE RP OF CARBOHYDRATES. RC TISSUE=Cerebrospinal fluid; RX PubMed=19838169; DOI=10.1038/nmeth.1392; RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., RA Larson G.; RT "Enrichment of glycopeptides for glycan structure and attachment site RT identification."; RL Nat. Methods 6:809-811(2009). RN [7] RP GLYCOSYLATION AT THR-53; SER-228 AND THR-247, STRUCTURE OF CARBOHYDRATES, RP AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.m111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of N- and RT O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 11:1-17(2012). RN [8] RP GLYCOSYLATION AT SER-228, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures RT of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). CC -!- FUNCTION: May function in the control of the neuroendocrine secretory CC pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS CC and Big PEN-LEN, both containing the C-terminal inhibitory domain, but CC not the further processed peptides reduce PCSK1 activity in the CC endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa CC form but not the autocatalytically derived 66 kDa form of PCSK1. CC Subsequent processing of proSAAS may eliminate the inhibition. Slows CC down convertase-mediated processing of proopiomelanocortin and CC proenkephalin. May control the intracellular timing of PCSK1 rather CC than its total level of activity (By similarity). CC {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [Big LEN]: Endogenous ligand for GPR171. Neuropeptide CC involved in the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [PEN]: Endogenous ligand for GPR83. Neuropeptide involved in CC the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- SUBUNIT: Interacts via the C-terminal inhibitory domain with PCSK1 66 CC kDa form. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9QXV0}. Golgi CC apparatus, trans-Golgi network {ECO:0000250|UniProtKB:Q9QXV0}. Note=A CC N-terminal processed peptide, probably Big SAAS or Little SAAS, is CC accumulated in cytoplasmic protein tau deposits in frontotemporal CC dementia and parkinsonism linked to chromosome 17 (Pick disease), CC Alzheimer disease and amyotrophic lateral sclerosis- CC parkinsonism/dementia complex 1 (Guam disease). CC {ECO:0000269|PubMed:12914799, ECO:0000269|PubMed:14746899}. CC -!- TISSUE SPECIFICITY: Expressed in brain and pancreas. CC {ECO:0000269|PubMed:10632593}. CC -!- DOMAIN: ProSAAS(1-180) increases secretion of enzymatically inactive CC PCSK1. {ECO:0000250}. CC -!- DOMAIN: The C-terminal inhibitory domain is involved in inhibition of CC PCSK1. It corresponds to the probable processing intermediate Big PEN- CC LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R, CC which, as a synthetic peptide, is sufficient for PCSK1 inhibition (By CC similarity). {ECO:0000250}. CC -!- DOMAIN: [Big LEN]: The four C-terminal amino acids of Big LEN are CC sufficient to bind and activate GPR171. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- PTM: Proteolytically cleaved in the Golgi. CC {ECO:0000269|PubMed:12914799}. CC -!- PTM: O-glycosylated with a core 1 or possibly core 8 glycan. CC {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:22171320, CC ECO:0000269|PubMed:23234360}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF181562; AAF22643.1; -; mRNA. DR EMBL; BC002851; AAH02851.1; -; mRNA. DR CCDS; CCDS14307.1; -. DR RefSeq; NP_037403.1; NM_013271.5. DR AlphaFoldDB; Q9UHG2; -. DR SMR; Q9UHG2; -. DR BioGRID; 118156; 18. DR FunCoup; Q9UHG2; 287. DR IntAct; Q9UHG2; 17. DR MINT; Q9UHG2; -. DR STRING; 9606.ENSP00000218230; -. DR MEROPS; I49.001; -. DR GlyConnect; 743; 1 O-Linked glycan (3 sites). DR GlyCosmos; Q9UHG2; 3 sites, 2 glycans. DR GlyGen; Q9UHG2; 4 sites, 4 O-linked glycans (4 sites). DR iPTMnet; Q9UHG2; -. DR PhosphoSitePlus; Q9UHG2; -. DR BioMuta; PCSK1N; -. DR DMDM; 74735013; -. DR jPOST; Q9UHG2; -. DR MassIVE; Q9UHG2; -. DR PaxDb; 9606-ENSP00000218230; -. DR PeptideAtlas; Q9UHG2; -. DR ProteomicsDB; 84349; -. DR Antibodypedia; 579; 87 antibodies from 19 providers. DR DNASU; 27344; -. DR Ensembl; ENST00000218230.6; ENSP00000218230.5; ENSG00000102109.10. DR GeneID; 27344; -. DR KEGG; hsa:27344; -. DR MANE-Select; ENST00000218230.6; ENSP00000218230.5; NM_013271.5; NP_037403.1. DR UCSC; uc004dkz.6; human. DR AGR; HGNC:17301; -. DR ClinPGx; PA33090; -. DR CTD; 27344; -. DR DisGeNET; 27344; -. DR GeneCards; PCSK1N; -. DR HGNC; HGNC:17301; PCSK1N. DR HPA; ENSG00000102109; Group enriched (brain, pituitary gland). DR MIM; 300399; gene. DR OpenTargets; ENSG00000102109; -. DR VEuPathDB; HostDB:ENSG00000102109; -. DR eggNOG; ENOG502RYS0; Eukaryota. DR GeneTree; ENSGT00390000013488; -. DR HOGENOM; CLU_100077_0_0_1; -. DR InParanoid; Q9UHG2; -. DR OMA; VWGAPRT; -. DR OrthoDB; 8962476at2759; -. DR PAN-GO; Q9UHG2; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHG2; -. DR PathwayCommons; Q9UHG2; -. DR SignaLink; Q9UHG2; -. DR Agora; ENSG00000102109; -. DR BioGRID-ORCS; 27344; 8 hits in 764 CRISPR screens. DR GenomeRNAi; 27344; -. DR Pharos; Q9UHG2; Tbio. DR PRO; PR:Q9UHG2; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q9UHG2; protein. DR Bgee; ENSG00000102109; Expressed in adenohypophysis and 138 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:0004866; F:endopeptidase inhibitor activity; IBA:GO_Central. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0016486; P:peptide hormone processing; IEA:Ensembl. DR GO; GO:0009409; P:response to cold; IEA:Ensembl. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR InterPro; IPR010832; ProSAAS. DR PANTHER; PTHR15531; PROSAAS; 1. DR PANTHER; PTHR15531:SF0; PROSAAS; 1. DR Pfam; PF07259; ProSAAS; 1. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Glycoprotein; Golgi apparatus; KW Neuropeptide; Proteomics identification; Reference proteome; Secreted; KW Signal. FT SIGNAL 1..33 FT /evidence="ECO:0000255" FT CHAIN 34..260 FT /note="ProSAAS" FT /id="PRO_0000259673" FT PEPTIDE 34..59 FT /note="Big SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259675" FT PEPTIDE 34..40 FT /note="KEP" FT /evidence="ECO:0000250" FT /id="PRO_0000259674" FT PEPTIDE 42..59 FT /note="Little SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259676" FT PEPTIDE 221..260 FT /note="Big PEN-LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259677" FT PEPTIDE 221..242 FT /note="PEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259678" FT PEPTIDE 245..260 FT /note="Big LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259679" FT PEPTIDE 245..254 FT /note="Little LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259680" FT REGION 34..215 FT /note="ProSAAS(1-180)" FT /evidence="ECO:0000250" FT REGION 165..188 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 221..260 FT /note="C-terminal inhibitory domain; interacts with PCSK1" FT /evidence="ECO:0000250" FT MOTIF 239..244 FT /note="Sufficient for inhibition of PCSK1" FT COMPBIAS 179..188 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 53 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT CARBOHYD 228 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:22171320, FT ECO:0000269|PubMed:23234360" FT CARBOHYD 247 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT VARIANT 31 FT /note="A -> T (in dbSNP:rs11538176)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_028971" FT MUTAGEN 235 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 236 FT /note="L->A: Greatly reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 237 FT /note="G->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 240 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 241 FT /note="R->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 242 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 243 FT /note="K->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 244 FT /note="R->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 245 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 246 FT /note="E->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" SQ SEQUENCE 260 AA; 27372 MW; FF8E2722784B7A5C CRC64; MAGSPLLWGP RAGGVGLLVL LLLGLFRPPP ALCARPVKEP RGLSAASPPL AETGAPRRFR RSVPRGEAAG AVQELARALA HLLEAERQER ARAEAQEAED QQARVLAQLL RVWGAPRNSD PALGLDDDPD APAAQLARAL LRARLDPAAL AAQLVPAPVP AAALRPRPPV YDDGPAGPDA EEAGDETPDV DPELLRYLLG RILAGSADSE GVAAPRRLRR AADHDVGSEL PPEGVLGALL RVKRLETPAP QVPARRLLPP // ID PDGFB_HUMAN Reviewed; 241 AA. AC P01127; G3XAG8; P78431; Q15354; Q6FHE7; Q9UF23; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 28-JAN-2026, entry version 261. DE RecName: Full=Platelet-derived growth factor subunit B; DE Short=PDGF subunit B; DE AltName: Full=PDGF-2; DE AltName: Full=Platelet-derived growth factor B chain; DE AltName: Full=Platelet-derived growth factor beta polypeptide; DE AltName: Full=Proto-oncogene c-Sis; DE AltName: INN=Becaplermin; DE Flags: Precursor; GN Name=PDGFB; Synonyms=PDGF2, SIS; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=6740330; DOI=10.1126/science.6740330; RA Josephs S.F., Ratner L., Clarke M.F., Westin E.H., Reitz M.S., RA Wong-Staal F.; RT "Transforming potential of human c-sis nucleotide sequences encoding RT platelet-derived growth factor."; RL Science 225:636-639(1984). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=4033772; DOI=10.1038/316748a0; RA Collins T., Ginsburg D., Boss J.M., Orkin S.H., Pober J.S.; RT "Cultured human endothelial cells express platelet-derived growth factor B RT chain: cDNA cloning and structural analysis."; RL Nature 316:748-750(1985). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2991848; DOI=10.1093/nar/13.14.5007; RA Ratner L., Josephs S.F., Jarrett R., Reitz M.S., Wong-Staal F.; RT "Nucleotide sequence of transforming human c-sis cDNA clones with homology RT to platelet-derived growth factor."; RL Nucleic Acids Res. 13:5007-5018(1985). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=3472769; DOI=10.1101/sqb.1986.051.01.109; RA Rao C.D., Igarashi H., Pech M.W., Robbins K.C., Aaronson S.A.; RT "Oncogenic potential of the human platelet-derived growth factor RT transcriptional unit."; RL Cold Spring Harb. Symp. Quant. Biol. 51:959-966(1986). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=3517869; DOI=10.1073/pnas.83.8.2392; RA Rao C.D., Igarashi H., Chiu I.-M., Robbins K.C., Aaronson S.A.; RT "Structure and sequence of the human c-sis/platelet-derived growth factor 2 RT (SIS/PDGF2) transcriptional unit."; RL Proc. Natl. Acad. Sci. U.S.A. 83:2392-2396(1986). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84; RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., RA Beare D.M., Dunham I.; RT "A genome annotation-driven approach to cloning the human ORFeome."; RL Genome Biol. 5:R84.1-R84.11(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10591208; DOI=10.1038/990031; RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M., RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C., RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E., RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C., RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G., RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V., RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E., RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F., RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M., RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A., RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D., RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S., RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E., RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A., RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L., RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P., RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P., RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q., RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J., RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J., RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D., RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T., RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L., RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J., RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E., RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P., RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y., RA Wright H.; RT "The DNA sequence of human chromosome 22."; RL Nature 402:489-495(1999). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, Lung, Pancreas, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-185 (ISOFORM 2). RC TISSUE=Choriocarcinoma; RX PubMed=7659502; DOI=10.1093/nar/23.15.2815; RA Dirks R.P.H., Onnekink C., Jansen H.J., de Jong A., Bloemers H.P.J.; RT "A novel human c-sis mRNA species is transcribed from a promoter in c-sis RT intron 1 and contains the code for an alternative PDGF B-like protein."; RL Nucleic Acids Res. 23:2815-2822(1995). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-53, AND CHROMOSOMAL TRANSLOCATION RP WITH COL1A1. RX PubMed=8988177; DOI=10.1038/ng0197-95; RA Simon M.-P., Pedeutour F., Sirvent N., Grosgeorge J., Minoletti F., RA Coindre J.-M., Terrier-Lacombe M.-J., Mandahl N., Craver R.D., Blin N., RA Sozzi G., Turc-Carel C., O'Brien K.P., Kedra D., Fransson I., Guilbaud C., RA Dumanski J.P.; RT "Deregulation of the platelet-derived growth factor B-chain gene via fusion RT with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell RT fibroblastoma."; RL Nat. Genet. 15:95-98(1997). RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 22-241. RX PubMed=6327048; DOI=10.1016/0092-8674(84)90307-6; RA Chiu I.-M., Reddy E.P., Givol D., Robbins K.C., Tronick S.R., RA Aaronson S.A.; RT "Nucleotide sequence analysis identifies the human c-sis proto-oncogene as RT a structural gene for platelet-derived growth factor."; RL Cell 37:123-129(1984). RN [14] RP NUCLEOTIDE SEQUENCE [MRNA] OF 26-241 (ISOFORM 1). RX PubMed=3456904; DOI=10.1016/0014-5793(86)80433-1; RA Weich H.A., Sebald W., Schairer H.U., Hoppe J.; RT "The human osteosarcoma cell line U-2 OS expresses a 3.8 kilobase mRNA RT which codes for the sequence of the PDGF-B chain."; RL FEBS Lett. 198:344-348(1986). RN [15] RP PROTEIN SEQUENCE OF 82-112. RX PubMed=6306471; DOI=10.1038/304035a0; RA Waterfield M.D., Scrace G.T., Whittle N., Stroobant P., Johnsson A., RA Wasteson A., Westermark B., Heldin C.H., Huang J.S., Deuel T.F.; RT "Platelet-derived growth factor is structurally related to the putative RT transforming protein p28sis of simian sarcoma virus."; RL Nature 304:35-39(1983). RN [16] RP PROTEIN SEQUENCE OF 82-110. RX PubMed=6844921; DOI=10.1126/science.6844921; RA Antoniades H.N., Hunkapiller M.W.; RT "Human platelet-derived growth factor (PDGF): amino-terminal amino acid RT sequence."; RL Science 220:963-965(1983). RN [17] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 153-200, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=6329745; DOI=10.1002/j.1460-2075.1984.tb01908.x; RA Johnsson A., Heldin C.H., Wasteson A., Westermark B., Deuel T.F., RA Huang J.S., Seeburg P.H., Gray A., Ullrich A., Scrace G., Stroobant P., RA Waterfield M.D.; RT "The c-sis gene encodes a precursor of the B chain of platelet-derived RT growth factor."; RL EMBO J. 3:921-928(1984). RN [18] RP MUTAGENESIS, AND IMPORTANCE OF ARG-108 AND ILE-111 FOR RECEPTOR BINDING. RX PubMed=1661670; DOI=10.1002/j.1460-2075.1991.tb04988.x; RA Clements J.M., Bawden L.J., Bloxidge R.E., Catlin G., Cook A.L., Craig S., RA Drummond A.H., Edwards R.M., Fallon A., Green D.R., Hellewell P.G., RA Kirwin P.M., Nayee P.D., Richardson S.J., Brown D., Chahwala S.B., RA Snarey M., Winslow D.; RT "Two PDGF-B chain residues, arginine 27 and isoleucine 30, mediate receptor RT binding and activation."; RL EMBO J. 10:4113-4120(1991). RN [19] RP INTERCHAIN DISULFIDE BONDS. RX PubMed=1317862; DOI=10.1016/s0021-9258(19)49905-5; RA Andersson M., Oestman A., Baeckstroem G., Hellman U., George-Nascimento C., RA Westermark B., Heldin C.-H.; RT "Assignment of interchain disulfide bonds in platelet-derived growth factor RT (PDGF) and evidence for agonist activity of monomeric PDGF."; RL J. Biol. Chem. 267:11260-11266(1992). RN [20] RP TISSUE SPECIFICITY. RX PubMed=11331882; DOI=10.1038/35074593; RA LaRochelle W.J., Jeffers M., McDonald W.F., Chillakuru R.A., Giese N.A., RA Lokker N.A., Sullivan C., Boldog F.L., Yang M., Vernet C., Burgess C.E., RA Fernandez E., Deegler L.L., Rittman B., Shimkets J., Shimkets R.A., RA Rothberg J.M., Lichenstein H.S.; RT "PDGF D, a novel protease-activated growth factor."; RL Nat. Cell Biol. 3:517-521(2001). RN [21] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH COL1A1. RX PubMed=12660034; DOI=10.1016/s0165-4608(02)00844-0; RA Sandberg A.A., Anderson W.D., Fredenberg C., Hashimoto H.; RT "Dermatofibrosarcoma protuberans of breast."; RL Cancer Genet. Cytogenet. 142:56-59(2003). RN [22] RP INTERACTION WITH LRP1 AND SORL1. RX PubMed=15053742; DOI=10.1042/bj20040149; RA Gliemann J., Hermey G., Nykjaer A., Petersen C.M., Jacobsen C., RA Andreasen P.A.; RT "The mosaic receptor sorLA/LR11 binds components of the plasminogen- RT activating system and platelet-derived growth factor-BB similarly to LRP1 RT (low-density lipoprotein receptor-related protein), but mediates slow RT internalization of bound ligand."; RL Biochem. J. 381:203-212(2004). RN [23] RP INTERACTION WITH SORL1. RX PubMed=16393139; DOI=10.1042/bj20051364; RA Hermey G., Sjoegaard S.S., Petersen C.M., Nykjaer A., Gliemann J.; RT "Tumour necrosis factor alpha-converting enzyme mediates ectodomain RT shedding of Vps10p-domain receptor family members."; RL Biochem. J. 395:285-293(2006). RN [24] RP CHARACTERIZATION OF VARIANTS IBGC5 ARG-9 AND PRO-119, AND FUNCTION. RX PubMed=26599395; DOI=10.1371/journal.pone.0143407; RA Vanlandewijck M., Lebouvier T., Andaloussi Maee M., Nahar K., Hornemann S., RA Kenkel D., Cunha S.I., Lennartsson J., Boss A., Heldin C.H., Keller A., RA Betsholtz C.; RT "Functional characterization of germline mutations in PDGFB and PDGFRB in RT primary familial brain calcification."; RL PLoS ONE 10:E0143407-E0143407(2015). RN [25] RP INTERACTION WITH CD82. RX PubMed=34530889; DOI=10.1186/s13045-021-01147-6; RA Lee J.W., Hur J., Kwon Y.W., Chae C.W., Choi J.I., Hwang I., Yun J.Y., RA Kang J.A., Choi Y.E., Kim Y.H., Lee S.E., Lee C., Jo D.H., Seok H., RA Cho B.S., Baek S.H., Kim H.S.; RT "KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic RT milieu to quiescent state."; RL J. Hematol. Oncol. 14:148-148(2021). RN [26] RP REVIEW ON FUNCTION IN DEVELOPMENT AND DISEASE. RX PubMed=18483217; DOI=10.1101/gad.1653708; RA Andrae J., Gallini R., Betsholtz C.; RT "Role of platelet-derived growth factors in physiology and medicine."; RL Genes Dev. 22:1276-1312(2008). RN [27] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS). RX PubMed=1396586; DOI=10.1002/j.1460-2075.1992.tb05485.x; RA Oefner C., D'Arcy A., Winkler F.K., Eggimann B., Hosang M.; RT "Crystal structure of human platelet-derived growth factor BB."; RL EMBO J. 11:3921-3926(1992). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 21-185 IN COMPLEX WITH PDGFRB, RP SUBUNIT, AND DISULFIDE BONDS. RX PubMed=20534510; DOI=10.1073/pnas.1000806107; RA Shim A.H., Liu H., Focia P.J., Chen X., Lin P.C., He X.; RT "Structures of a platelet-derived growth factor/propeptide complex and a RT platelet-derived growth factor/receptor complex."; RL Proc. Natl. Acad. Sci. U.S.A. 107:11307-11312(2010). RN [29] RP VARIANTS IBGC5 ARG-9 AND PRO-119. RX PubMed=23913003; DOI=10.1038/ng.2723; RA Keller A., Westenberger A., Sobrido M.J., Garcia-Murias M., Domingo A., RA Sears R.L., Lemos R.R., Ordonez-Ugalde A., Nicolas G., da Cunha J.E., RA Rushing E.J., Hugelshofer M., Wurnig M.C., Kaech A., Reimann R., RA Lohmann K., Dobricic V., Carracedo A., Petrovic I., Miyasaki J.M., RA Abakumova I., Mae M.A., Raschperger E., Zatz M., Zschiedrich K., RA Klepper J., Spiteri E., Prieto J.M., Navas I., Preuss M., Dering C., RA Jankovic M., Paucar M., Svenningsson P., Saliminejad K., Khorshid H.R., RA Novakovic I., Aguzzi A., Boss A., Le Ber I., Defer G., Hannequin D., RA Kostic V.S., Campion D., Geschwind D.H., Coppola G., Betsholtz C., RA Klein C., Oliveira J.R.; RT "Mutations in the gene encoding PDGF-B cause brain calcifications in humans RT and mice."; RL Nat. Genet. 45:1077-1082(2013). CC -!- FUNCTION: Growth factor that plays an essential role in the regulation CC of embryonic development, cell proliferation, cell migration, survival CC and chemotaxis. Potent mitogen for cells of mesenchymal origin CC (PubMed:26599395). Required for normal proliferation and recruitment of CC pericytes and vascular smooth muscle cells in the central nervous CC system, skin, lung, heart and placenta. Required for normal blood CC vessel development, and for normal development of kidney glomeruli. CC Plays an important role in wound healing. Signaling is modulated by the CC formation of heterodimers with PDGFA (By similarity). CC {ECO:0000250|UniProtKB:P31240, ECO:0000269|PubMed:26599395}. CC -!- SUBUNIT: Antiparallel homodimer; disulfide-linked. Antiparallel CC heterodimer with PDGFA; disulfide-linked. The PDGFB homodimer interacts CC with PDGFRA and PDGFRB homodimers, and with heterodimers formed by CC PDGFRA and PDGFRB. The heterodimer composed of PDGFA and PDGFB CC interacts with PDGFRB homodimers, and with heterodimers formed by CC PDGFRA and PDGFRB. Interacts with XLKD1 (By similarity). Interacts with CC LRP1 (PubMed:15053742). Interacts with SORL1 (via the N-terminal CC ectodomain) (PubMed:15053742, PubMed:16393139). Interacts with CD82; CC this interaction inhibits PDGFB-mediated signaling pathway CC (PubMed:34530889). {ECO:0000250, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:34530889}. CC -!- INTERACTION: CC P01127; Q9P287: BCCIP; NbExp=3; IntAct=EBI-1554925, EBI-711154; CC P01127; P01127: PDGFB; NbExp=3; IntAct=EBI-1554925, EBI-1554925; CC P01127; P16234: PDGFRA; NbExp=11; IntAct=EBI-1554925, EBI-2861522; CC P01127; P09619: PDGFRB; NbExp=16; IntAct=EBI-1554925, EBI-641237; CC -!- SUBCELLULAR LOCATION: Secreted. Note=Released by platelets upon CC wounding. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative promoter usage; Named isoforms=2; CC Name=1; CC IsoId=P01127-1; Sequence=Displayed; CC Name=2; CC IsoId=P01127-2; Sequence=VSP_044913; CC -!- TISSUE SPECIFICITY: Expressed at high levels in the heart, brain CC (sustantia nigra), placenta and fetal kidney. Expressed at moderate CC levels in the brain (hippocampus), skeletal muscle, kidney and lung. CC {ECO:0000269|PubMed:11331882}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 5 (IBGC5) CC [MIM:615483]: A form of basal ganglia calcification, an autosomal CC dominant condition characterized by symmetric calcification in the CC basal ganglia and other brain regions. Affected individuals can either CC be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, CC including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, CC seizures, and chronic headache. Serum levels of calcium, phosphate, CC alkaline phosphatase and parathyroid hormone are normal. The CC neuropathological hallmark of the disease is vascular and pericapillary CC calcification, mainly of calcium phosphate, in the affected brain CC areas. {ECO:0000269|PubMed:23913003, ECO:0000269|PubMed:26599395}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving PDGFB is found in CC dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with CC PDGFB. {ECO:0000269|PubMed:12660034}. CC -!- PHARMACEUTICAL: Available under the name Regranex (Ortho-McNeil). Used CC to promote healing in diabetic neuropathic foot ulcers. CC -!- SIMILARITY: Belongs to the PDGF/VEGF growth factor family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/155/PDGFB"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; K01401; AAA60552.1; -; Genomic_DNA. DR EMBL; K01918; AAA60552.1; JOINED; Genomic_DNA. DR EMBL; J00121; AAA60552.1; JOINED; Genomic_DNA. DR EMBL; K01398; AAA60552.1; JOINED; Genomic_DNA. DR EMBL; K01399; AAA60552.1; JOINED; Genomic_DNA. DR EMBL; K01400; AAA60552.1; JOINED; Genomic_DNA. DR EMBL; X02811; CAA26579.1; -; mRNA. DR EMBL; X02744; CAA26524.1; -; mRNA. DR EMBL; M12783; AAA60553.1; -; mRNA. DR EMBL; CR456538; CAG30424.1; -; mRNA. DR EMBL; Z81010; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CR541807; CAG46606.1; -; mRNA. DR EMBL; CH471095; EAW60306.1; -; Genomic_DNA. DR EMBL; CH471095; EAW60307.1; -; Genomic_DNA. DR EMBL; BC029822; AAH29822.1; -; mRNA. DR EMBL; BC077725; AAH77725.1; -; mRNA. DR EMBL; X83705; CAA58679.1; -; mRNA. DR EMBL; X98706; CAA67262.1; -; Genomic_DNA. DR EMBL; K01917; AAA98793.1; -; Genomic_DNA. DR EMBL; K01913; AAA98793.1; JOINED; Genomic_DNA. DR EMBL; K01914; AAA98793.1; JOINED; Genomic_DNA. DR EMBL; K01915; AAA98793.1; JOINED; Genomic_DNA. DR EMBL; K01916; AAA98793.1; JOINED; Genomic_DNA. DR EMBL; X03702; CAA27333.1; -; mRNA. DR EMBL; X00561; CAA25228.1; -; Genomic_DNA. DR EMBL; X00561; CAA25229.1; -; Genomic_DNA. DR CCDS; CCDS13987.1; -. [P01127-1] DR CCDS; CCDS33650.1; -. [P01127-2] DR PIR; A94276; PFHUG2. DR RefSeq; NP_002599.1; NM_002608.4. [P01127-1] DR RefSeq; NP_148937.1; NM_033016.3. [P01127-2] DR PDB; 1PDG; X-ray; 3.00 A; A/B/C=82-190. DR PDB; 3MJG; X-ray; 2.30 A; A/B=21-185. DR PDB; 4HQU; X-ray; 2.20 A; A=82-190. DR PDB; 4HQX; X-ray; 2.30 A; A=82-183. DR PDB; 4QCI; X-ray; 2.30 A; C/D=82-190. DR PDB; 6T9E; X-ray; 2.99 A; CCC/DDD=82-190. DR PDBsum; 1PDG; -. DR PDBsum; 3MJG; -. DR PDBsum; 4HQU; -. DR PDBsum; 4HQX; -. DR PDBsum; 4QCI; -. DR PDBsum; 6T9E; -. DR AlphaFoldDB; P01127; -. DR EMDB; EMD-6426; -. DR SMR; P01127; -. DR BioGRID; 111181; 93. DR ComplexPortal; CPX-1875; Platelet-derived growth factor AB complex. DR ComplexPortal; CPX-1876; Platelet-derived growth factor BB complex. DR ComplexPortal; CPX-2882; PDGF receptor beta - PDGF-BB complex. DR ComplexPortal; CPX-2883; PDGF receptor alpha-beta - PDGF-BB complex. DR ComplexPortal; CPX-2884; PDGF receptor alpha - PDGF-BB complex. DR ComplexPortal; CPX-2885; PDGF receptor alpha - PDGF-AB complex. DR ComplexPortal; CPX-2886; PDGF receptor beta - PDGF-AB complex. DR ComplexPortal; CPX-2892; PDGF receptor alpha-beta - PDGF-AB complex. DR CORUM; P01127; -. DR DIP; DIP-5737N; -. DR FunCoup; P01127; 1104. DR IntAct; P01127; 69. DR STRING; 9606.ENSP00000330382; -. DR BindingDB; P01127; -. DR ChEMBL; CHEMBL3108633; -. DR DrugBank; DB06325; Pegpleranib. DR GlyConnect; 754; 4 N-Linked glycans (1 site). DR GlyCosmos; P01127; 1 site, 5 glycans. DR GlyGen; P01127; 3 sites, 5 N-linked glycans (1 site), 1 O-linked glycan (2 sites). DR iPTMnet; P01127; -. DR PhosphoSitePlus; P01127; -. DR BioMuta; PDGFB; -. DR DMDM; 129724; -. DR MassIVE; P01127; -. DR PaxDb; 9606-ENSP00000330382; -. DR PeptideAtlas; P01127; -. DR ProteomicsDB; 33745; -. DR ProteomicsDB; 51325; -. [P01127-1] DR TopDownProteomics; P01127-2; -. [P01127-2] DR ABCD; P01127; 9 sequenced antibodies. DR Antibodypedia; 293; 734 antibodies from 42 providers. DR DNASU; 5155; -. DR Ensembl; ENST00000331163.11; ENSP00000330382.6; ENSG00000100311.18. [P01127-1] DR Ensembl; ENST00000381551.8; ENSP00000370963.4; ENSG00000100311.18. [P01127-2] DR GeneID; 5155; -. DR KEGG; hsa:5155; -. DR MANE-Select; ENST00000331163.11; ENSP00000330382.6; NM_002608.4; NP_002599.1. DR UCSC; uc003axe.4; human. [P01127-1] DR AGR; HGNC:8800; -. DR CIViC; 5155; 3 evidence items across 1 molecular profile. DR ClinPGx; PA33145; -. DR CTD; 5155; -. DR DisGeNET; 5155; -. DR GeneCards; PDGFB; -. DR GeneReviews; PDGFB; -. DR HGNC; HGNC:8800; PDGFB. DR HPA; ENSG00000100311; Low tissue specificity. DR MalaCards; PDGFB; -. DR MIM; 190040; gene. DR MIM; 607907; phenotype. DR MIM; 615483; phenotype. DR OpenTargets; ENSG00000100311; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR Orphanet; 31112; Dermatofibrosarcoma protuberans. DR Orphanet; 263662; Familial multiple meningioma. DR Orphanet; 2495; Meningioma. DR VEuPathDB; HostDB:ENSG00000100311; -. DR eggNOG; ENOG502S2VW; Eukaryota. DR GeneTree; ENSGT00940000157367; -. DR HOGENOM; CLU_094438_0_0_1; -. DR InParanoid; P01127; -. DR OMA; KHTHDKE; -. DR OrthoDB; 8878063at2759; -. DR PAN-GO; P01127; 9 GO annotations based on evolutionary models. DR PhylomeDB; P01127; -. DR PathwayCommons; P01127; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-186763; Downstream signal transduction. DR Reactome; R-HSA-186797; Signaling by PDGF. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-3000171; Non-integrin membrane-ECM interactions. DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR SignaLink; P01127; -. DR SIGNOR; P01127; -. DR Agora; ENSG00000100311; -. DR BioGRID-ORCS; 5155; 8 hits in 1145 CRISPR screens. DR ChiTaRS; PDGFB; human. DR EvolutionaryTrace; P01127; -. DR GeneWiki; PDGFB; -. DR GenomeRNAi; 5155; -. DR Pharos; P01127; Tbio. DR PRO; PR:P01127; -. DR Proteomes; UP000005640; Chromosome 22. DR RNAct; P01127; protein. DR Bgee; ENSG00000100311; Expressed in olfactory bulb and 189 other cell types or tissues. DR ExpressionAtlas; P01127; baseline and differential. DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0031012; C:extracellular matrix; HDA:BHF-UCL. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome. DR GO; GO:1990265; C:platelet-derived growth factor complex; IPI:ComplexPortal. DR GO; GO:0042056; F:chemoattractant activity; IDA:BHF-UCL. DR GO; GO:0005518; F:collagen binding; IDA:MGI. DR GO; GO:0008083; F:growth factor activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0048407; F:platelet-derived growth factor binding; IPI:BHF-UCL. DR GO; GO:0005161; F:platelet-derived growth factor receptor binding; IDA:BHF-UCL. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL. DR GO; GO:0016176; F:superoxide-generating NADPH oxidase activator activity; IDA:UniProtKB. DR GO; GO:0001525; P:angiogenesis; IBA:GO_Central. DR GO; GO:0060326; P:cell chemotaxis; IDA:UniProtKB. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IDA:BHF-UCL. DR GO; GO:0071506; P:cellular response to mycophenolic acid; ISS:UniProtKB. DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IDA:BHF-UCL. DR GO; GO:0001892; P:embryonic placenta development; ISS:UniProtKB. DR GO; GO:0010467; P:gene expression; IDA:UniProtKB. DR GO; GO:0007507; P:heart development; ISS:UniProtKB. DR GO; GO:0035655; P:interleukin-18-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0072255; P:metanephric glomerular mesangial cell development; ISS:UniProtKB. DR GO; GO:0002548; P:monocyte chemotaxis; IDA:BHF-UCL. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IDA:BHF-UCL. DR GO; GO:0010512; P:negative regulation of phosphatidylinositol biosynthetic process; IDA:BHF-UCL. DR GO; GO:0010544; P:negative regulation of platelet activation; IDA:BHF-UCL. DR GO; GO:1905064; P:negative regulation of vascular associated smooth muscle cell differentiation; IDA:BHF-UCL. DR GO; GO:0038001; P:paracrine signaling; ISS:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB. DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0090280; P:positive regulation of calcium ion import; IDA:UniProtKB. DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB. DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IDA:BHF-UCL. DR GO; GO:0050921; P:positive regulation of chemotaxis; IDA:UniProtKB. DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:BHF-UCL. DR GO; GO:0003104; P:positive regulation of glomerular filtration; ISS:UniProtKB. DR GO; GO:0072126; P:positive regulation of glomerular mesangial cell proliferation; IDA:UniProtKB. DR GO; GO:1900127; P:positive regulation of hyaluronan biosynthetic process; IDA:UniProtKB. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:2000591; P:positive regulation of metanephric mesenchymal cell migration; IDA:UniProtKB. DR GO; GO:0035793; P:positive regulation of metanephric mesenchymal cell migration by platelet-derived growth factor receptor-beta signaling pathway; IDA:UniProtKB. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IDA:BHF-UCL. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IDA:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:UniProtKB. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:UniProtKB. DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IDA:BHF-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL. DR GO; GO:1905176; P:positive regulation of vascular associated smooth muscle cell dedifferentiation; IDA:BHF-UCL. DR GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; IDA:UniProtKB. DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB. DR GO; GO:0009611; P:response to wounding; IDA:BHF-UCL. DR GO; GO:0014805; P:smooth muscle adaptation; NAS:BHF-UCL. DR CDD; cd00135; PDGF; 1. DR DisProt; DP02770; -. DR FunFam; 2.10.90.10:FF:000023; Platelet-derived growth factor subunit B; 1. DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR023581; PD_growth_factor_CS. DR InterPro; IPR000072; PDGF/VEGF_dom. DR InterPro; IPR006782; PDGF_N. DR PANTHER; PTHR11633; PLATELET-DERIVED GROWTH FACTOR; 1. DR PANTHER; PTHR11633:SF2; PLATELET-DERIVED GROWTH FACTOR SUBUNIT B; 1. DR Pfam; PF00341; PDGF; 1. DR Pfam; PF04692; PDGF_N; 1. DR SMART; SM00141; PDGF; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS00249; PDGF_1; 1. DR PROSITE; PS50278; PDGF_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative promoter usage; Chromosomal rearrangement; KW Cleavage on pair of basic residues; Developmental protein; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Growth factor; Mitogen; Pharmaceutical; Proteomics identification; KW Proto-oncogene; Reference proteome; Secreted; Signal. FT SIGNAL 1..20 FT PROPEP 21..81 FT /note="Removed in mature form" FT /id="PRO_0000023371" FT CHAIN 82..190 FT /note="Platelet-derived growth factor subunit B" FT /id="PRO_0000023372" FT PROPEP 191..241 FT /note="Removed in mature form" FT /id="PRO_0000023373" FT REGION 216..241 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 216..230 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 108 FT /note="Involved in receptor binding" FT SITE 111 FT /note="Involved in receptor binding" FT CARBOHYD 63 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 97..141 FT /evidence="ECO:0000269|PubMed:20534510" FT DISULFID 124 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:20534510" FT DISULFID 130..178 FT /evidence="ECO:0000269|PubMed:20534510" FT DISULFID 133 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:20534510" FT DISULFID 134..180 FT /evidence="ECO:0000269|PubMed:20534510" FT VAR_SEQ 1..21 FT /note="MNRCWALFLSLCCYLRLVSAE -> MFIMGL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7659502" FT /id="VSP_044913" FT VARIANT 9 FT /note="L -> R (in IBGC5; loss of protein expression)" FT /evidence="ECO:0000269|PubMed:23913003, FT ECO:0000269|PubMed:26599395" FT /id="VAR_070870" FT VARIANT 88 FT /note="I -> V (in dbSNP:rs17565)" FT /id="VAR_014578" FT VARIANT 119 FT /note="L -> P (in IBGC5; loss of protein expression; FT dbSNP:rs397515632)" FT /evidence="ECO:0000269|PubMed:23913003, FT ECO:0000269|PubMed:26599395" FT /id="VAR_070871" FT CONFLICT 101 FT /note="T -> E (in Ref. 16; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 105 FT /note="E -> C (in Ref. 16; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 107 FT /note="S -> C (in Ref. 16; AA sequence)" FT /evidence="ECO:0000305" FT STRAND 97..105 FT /evidence="ECO:0007829|PDB:4HQU" FT HELIX 108..111 FT /evidence="ECO:0007829|PDB:4HQU" FT STRAND 118..121 FT /evidence="ECO:0007829|PDB:4HQU" FT STRAND 123..131 FT /evidence="ECO:0007829|PDB:4HQU" FT STRAND 140..159 FT /evidence="ECO:0007829|PDB:4HQU" FT STRAND 162..181 FT /evidence="ECO:0007829|PDB:4HQU" SQ SEQUENCE 241 AA; 27283 MW; 9F9A3474CE203C0B CRC64; MNRCWALFLS LCCYLRLVSA EGDPIPEELY EMLSDHSIRS FDDLQRLLHG DPGEEDGAEL DLNMTRSHSG GELESLARGR RSLGSLTIAE PAMIAECKTR TEVFEISRRL IDRTNANFLV WPPCVEVQRC SGCCNNRNVQ CRPTQVQLRP VQVRKIEIVR KKPIFKKATV TLEDHLACKC ETVAAARPVT RSPGGSQEQR AKTPQTRVTI RTVRVRRPPK GKHRKFKHTH DKTALKETLG A // ID PGFRB_HUMAN Reviewed; 1106 AA. AC P09619; B5A957; Q8N5L4; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 28-JAN-2026, entry version 269. DE RecName: Full=Platelet-derived growth factor receptor beta; DE Short=PDGF-R-beta; DE Short=PDGFR-beta; DE EC=2.7.10.1; DE AltName: Full=Beta platelet-derived growth factor receptor; DE AltName: Full=Beta-type platelet-derived growth factor receptor; DE AltName: Full=CD140 antigen-like family member B; DE AltName: Full=Platelet-derived growth factor receptor 1; DE Short=PDGFR-1; DE AltName: CD_antigen=CD140b; DE Flags: Precursor; GN Name=PDGFRB; Synonyms=PDGFR, PDGFR1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION AS PDGFB RECEPTOR, RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, AND INTERACTION WITH PDGFB. RX PubMed=2835772; DOI=10.1073/pnas.85.10.3435; RA Gronwald R.G.K., Grant F.J., Haldeman B.A., Hart C.E., O'Hara P.J., RA Hagen F.S., Ross R., Bowen-Pope D.F., Murray M.J.; RT "Cloning and expression of a cDNA coding for the human platelet-derived RT growth factor receptor: evidence for more than one receptor class."; RL Proc. Natl. Acad. Sci. U.S.A. 85:3435-3439(1988). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION AS PDGFB RECEPTOR, RP SUBCELLULAR LOCATION, GLYCOSYLATION, AUTOPHOSPHORYLATION, AND INTERACTION RP WITH PDGFA AND PDGFB. RX PubMed=2850496; DOI=10.1128/mcb.8.8.3476-3486.1988; RA Claesson-Welsh L., Eriksson A., Moren A., Severinsson L., Ek B., RA Oestman A., Betsholtz C., Heldin C.-H.; RT "cDNA cloning and expression of a human platelet-derived growth factor RT (PDGF) receptor specific for B-chain-containing PDGF molecules."; RL Mol. Cell. Biol. 8:3476-3486(1988). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING. RX PubMed=18593464; DOI=10.1186/ar2447; RA Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D., RA Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.; RT "Novel splice variants derived from the receptor tyrosine kinase RT superfamily are potential therapeutics for rheumatoid arthritis."; RL Arthritis Res. Ther. 10:R73-R73(2008). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PHE-180. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 548-569. RX PubMed=9285559; DOI=10.1038/sj.onc.1201267; RA Chi K.D., McPhee R.A., Wagner A.S., Dietz J.J., Pantazis P., Goustin A.S.; RT "Integration of proviral DNA into the PDGF beta-receptor gene in HTLV-I- RT infected T-cells results in a novel tyrosine kinase product with RT transforming activity."; RL Oncogene 15:1051-1057(1997). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 559-1106 (ISOFORM 1), AND CHROMOSOMAL RP TRANSLOCATION WITH CEP85L. RX PubMed=21938754; DOI=10.1002/gcc.20930; RA Chmielecki J., Peifer M., Viale A., Hutchinson K., Giltnane J., Socci N.D., RA Hollis C.J., Dean R.S., Yenamandra A., Jagasia M., Kim A.S., Dave U.P., RA Thomas R.K., Pao W.; RT "Systematic screen for tyrosine kinase rearrangements identifies a novel RT C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated RT myeloproliferative neoplasm."; RL Genes Chromosomes Cancer 51:54-65(2012). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1046-1106. RX PubMed=2846185; DOI=10.1016/0092-8674(88)90224-3; RA Roberts W.M., Look A.T., Roussel M.F., Sherr C.J.; RT "Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes."; RL Cell 55:655-661(1988). RN [9] RP PROTEIN SEQUENCE OF 33-47. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [10] RP PHOSPHORYLATION AT TYR-751 AND TYR-857. RX PubMed=2550144; DOI=10.1016/0092-8674(89)90510-2; RA Kazlauskas A., Cooper J.A.; RT "Autophosphorylation of the PDGF receptor in the kinase insert region RT regulates interactions with cell proteins."; RL Cell 58:1121-1133(1989). RN [11] RP FUNCTION AS PDGFB RECEPTOR IN CELL PROLIFERATION AND CHEMOTAXIS, AND RP SUBCELLULAR LOCATION. RX PubMed=2554309; DOI=10.1073/pnas.86.21.8314; RA Matsui T., Pierce J.H., Fleming T.P., Greenberger J.S., LaRochelle W.J., RA Ruggiero M., Aaronson S.A.; RT "Independent expression of human alpha or beta platelet-derived growth RT factor receptor cDNAs in a naive hematopoietic cell leads to functional RT coupling with mitogenic and chemotactic signaling pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 86:8314-8318(1989). RN [12] RP FUNCTION IN CELL PROLIFERATION; ACTIVATION OF PLCG1 AND IN PHOSPHORYLATION RP OF PLCG1 AND RASA1/GAP, AND MUTAGENESIS OF TYR-751 AND TYR-857. RX PubMed=1653029; DOI=10.1091/mbc.2.6.413; RA Kazlauskas A., Durden D.L., Cooper J.A.; RT "Functions of the major tyrosine phosphorylation site of the PDGF receptor RT beta subunit."; RL Cell Regul. 2:413-425(1991). RN [13] RP INTERACTION WITH PDGFRA; PDGFA AND PDGFB, FUNCTION AS RECEPTOR FOR PDGFA RP AND PDGFB, AND PHOSPHORYLATION AT TYR-857 AND TYR-751. RX PubMed=1709159; DOI=10.1016/s0021-9258(18)31541-2; RA Kelly J.D., Haldeman B.A., Grant F.J., Murray M.J., Seifert R.A., RA Bowen-Pope D.F., Cooper J.A., Kazlauskas A.; RT "Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit RT dimerization and intersubunit trans-phosphorylation."; RL J. Biol. Chem. 266:8987-8992(1991). RN [14] RP FUNCTION AS RECEPTOR FOR PDGFA AND PDGFB, SUBCELLULAR LOCATION, CATALYTIC RP ACTIVITY, AND MUTAGENESIS OF LYS-634. RX PubMed=1846866; DOI=10.1083/jcb.112.3.469; RA Sorkin A., Westermark B., Heldin C.H., Claesson-Welsh L.; RT "Effect of receptor kinase inactivation on the rate of internalization and RT degradation of PDGF and the PDGF beta-receptor."; RL J. Cell Biol. 112:469-478(1991). RN [15] RP FUNCTION IN ACTIVATION OF PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY, RP INTERACTION WITH PIK3R1 AND RASA1, PHOSPHORYLATION AT TYR-740; TYR-751; RP TYR-771 AND TYR-857, AND MUTAGENESIS OF LYS-634; TYR-716; TYR-740; TYR-751; RP TYR-763; TYR-771; TYR-775; TYR-778 AND TYR-857. RX PubMed=1314164; DOI=10.1002/j.1460-2075.1992.tb05182.x; RA Kashishian A., Kazlauskas A., Cooper J.A.; RT "Phosphorylation sites in the PDGF receptor with different specificities RT for binding GAP and PI3 kinase in vivo."; RL EMBO J. 11:1373-1382(1992). RN [16] RP FUNCTION AS PDGFB RECEPTOR IN CELL PROLIFERATION AND PHOSPHORYLATION OF RP PLCG1, INTERACTION WITH PLCG1, PHOSPHORYLATION AT TYR-1009 AND TYR-1021, RP AND MUTAGENESIS OF TYR-1009 AND TYR-1021. RX PubMed=1396585; DOI=10.1002/j.1460-2075.1992.tb05484.x; RA Ronnstrand L., Mori S., Arridsson A.K., Eriksson A., Wernstedt C., RA Hellman U., Claesson-Welsh L., Heldin C.H.; RT "Identification of two C-terminal autophosphorylation sites in the PDGF RT beta-receptor: involvement in the interaction with phospholipase C-gamma."; RL EMBO J. 11:3911-3919(1992). RN [17] RP UBIQUITINATION, AND DEGRADATION. RX PubMed=1313434; DOI=10.1016/s0021-9258(18)42714-7; RA Mori S., Heldin C.H., Claesson-Welsh L.; RT "Ligand-induced polyubiquitination of the platelet-derived growth factor RT beta-receptor."; RL J. Biol. Chem. 267:6429-6434(1992). RN [18] RP INTERACTION WITH PIK3R1 AND RASA1, AND MUTAGENESIS OF TYR-740; TYR-751 AND RP TYR-771. RX PubMed=1375321; DOI=10.1128/mcb.12.6.2534-2544.1992; RA Kazlauskas A., Kashishian A., Cooper J.A., Valius M.; RT "GTPase-activating protein and phosphatidylinositol 3-kinase bind to RT distinct regions of the platelet-derived growth factor receptor beta RT subunit."; RL Mol. Cell. Biol. 12:2534-2544(1992). RN [19] RP FUNCTION AS PDGFB RECEPTOR IN CELL PROLIFERATION, PHOSPHORYLATION AT RP TYR-579 AND TYR-581; INTERACTION WITH SRC, CATALYTIC ACTIVITY, AND RP MUTAGENESIS OF TYR-579 AND TYR-581. RX PubMed=7685273; DOI=10.1002/j.1460-2075.1993.tb05879.x; RA Mori S., Ronnstrand L., Yokote K., Engstrom A., Courtneidge S.A., RA Claesson-Welsh L., Heldin C.H.; RT "Identification of two juxtamembrane autophosphorylation sites in the PDGF RT beta-receptor; involvement in the interaction with Src family tyrosine RT kinases."; RL EMBO J. 12:2257-2264(1993). RN [20] RP INTERACTION WITH DGFA AND PDGFB. RX PubMed=7679113; DOI=10.1016/s0021-9258(18)53739-x; RA Fretto L.J., Snape A.J., Tomlinson J.E., Seroogy J.J., Wolf D.L., RA LaRochelle W.J., Giese N.A.; RT "Mechanism of platelet-derived growth factor (PDGF) AA, AB, and BB binding RT to alpha and beta PDGF receptor."; RL J. Biol. Chem. 268:3625-3631(1993). RN [21] RP FUNCTION IN PHOSPHORYLATION AND ACTIVATION OF PTPN11, INTERACTION WITH RP PTPN11; PIK3R1; PLCG1 AND RASA1, AND MUTAGENESIS OF TYR-1009. RX PubMed=7691811; DOI=10.1016/s0021-9258(20)80562-6; RA Lechleider R.J., Sugimoto S., Bennett A.M., Kashishian A.S., Cooper J.A., RA Shoelson S.E., Walsh C.T., Neel B.G.; RT "Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by RT its binding site, phosphotyrosine 1009, on the human platelet-derived RT growth factor receptor."; RL J. Biol. Chem. 268:21478-21481(1993). RN [22] RP INTERACTION WITH NCK1 AND PIK3R1, FUNCTION IN PHOSPHORYLATION OF NCK1, AND RP MUTAGENESIS OF TYR-751. RX PubMed=7692233; DOI=10.1128/mcb.13.11.6889-6896.1993; RA Nishimura R., Li W., Kashishian A., Mondino A., Zhou M., Cooper J., RA Schlessinger J.; RT "Two signaling molecules share a phosphotyrosine-containing binding site in RT the platelet-derived growth factor receptor."; RL Mol. Cell. Biol. 13:6889-6896(1993). RN [23] RP INTERACTION WITH SHB. RX PubMed=8302579; RA Welsh M., Mares J., Karlsson T., Lavergne C., Breant B., Claesson-Welsh L.; RT "Shb is a ubiquitously expressed Src homology 2 protein."; RL Oncogene 9:19-27(1994). RN [24] RP INTERACTION WITH GRB7. RX PubMed=8940081; DOI=10.1074/jbc.271.48.30942; RA Yokote K., Margolis B., Heldin C.H., Claesson-Welsh L.; RT "Grb7 is a downstream signaling component of platelet-derived growth factor RT alpha- and beta-receptors."; RL J. Biol. Chem. 271:30942-30949(1996). RN [25] RP CHROMOSOMAL TRANSLOCATION WITH TRIP11. RX PubMed=9373237; RA Abe A., Emi N., Tanimoto M., Terasaki H., Marunouchi T., Saito H.; RT "Fusion of the platelet-derived growth factor receptor beta to a novel gene RT CEV14 in acute myelogenous leukemia after clonal evolution."; RL Blood 90:4271-4277(1997). RN [26] RP INTERACTION WITH GRB10, AND MUTAGENESIS OF TYR-579; TYR-581; TYR-716; RP TYR-740; TYR-751; TYR-771; TYR-857; TYR-1009 AND TYR-1021. RX PubMed=10454568; DOI=10.1128/mcb.19.9.6217; RA Wang J., Dai H., Yousaf N., Moussaif M., Deng Y., Boufelliga A., RA Swamy O.R., Leone M.E., Riedel H.; RT "Grb10, a positive, stimulatory signaling adapter in platelet-derived RT growth factor BB-, insulin-like growth factor I-, and insulin-mediated RT mitogenesis."; RL Mol. Cell. Biol. 19:6217-6228(1999). RN [27] RP INTERACTION WITH SH2B2/APS. RX PubMed=9989826; DOI=10.1038/sj.onc.1202326; RA Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., Sasaki A., RA Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.; RT "APS, an adaptor protein containing PH and SH2 domains, is associated with RT the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis."; RL Oncogene 18:759-767(1999). RN [28] RP PHOSPHORYLATION AT TYR-562; TYR-751; TYR-763; TYR-771; TYR-775; TYR-778; RP TYR-857; TYR-1009 AND TYR-1021, AND DEPHOSPHORYLATION AT TYR-751; TYR-857; RP TYR-1009 AND TYR-1021 BY PTPRJ. RX PubMed=10821867; DOI=10.1074/jbc.275.21.16219; RA Kovalenko M., Denner K., Sandstrom J., Persson C., Gross S., Jandt E., RA Vilella R., Bohmer F., Ostman A.; RT "Site-selective dephosphorylation of the platelet-derived growth factor RT beta-receptor by the receptor-like protein-tyrosine phosphatase DEP-1."; RL J. Biol. Chem. 275:16219-16226(2000). RN [29] RP INTERACTION WITH PIK3C2B. RX PubMed=10805725; DOI=10.1128/mcb.20.11.3817-3830.2000; RA Arcaro A., Zvelebil M.J., Wallasch C., Ullrich A., Waterfield M.D., RA Domin J.; RT "Class II phosphoinositide 3-kinases are downstream targets of activated RT polypeptide growth factor receptors."; RL Mol. Cell. Biol. 20:3817-3830(2000). RN [30] RP FUNCTION AS A RECEPTOR FOR PDGFC, AND INTERACTION WITH PDGFC. RX PubMed=11297552; DOI=10.1074/jbc.m101056200; RA Gilbertson D.G., Duff M.E., West J.W., Kelly J.D., Sheppard P.O., RA Hofstrand P.D., Gao Z., Shoemaker K., Bukowski T.R., Moore M., RA Feldhaus A.L., Humes J.M., Palmer T.E., Hart C.E.; RT "Platelet-derived growth factor C (PDGF-C), a novel growth factor that RT binds to PDGF alpha and beta receptor."; RL J. Biol. Chem. 276:27406-27414(2001). RN [31] RP FUNCTION AS A RECEPTOR FOR PDGFD. RX PubMed=11331881; DOI=10.1038/35074588; RA Bergsten E., Uutela M., Li X., Pietras K., Oestman A., Heldin C.-H., RA Alitalo K., Eriksson U.; RT "PDGF-D is a specific, protease-activated ligand for the PDGF beta- RT receptor."; RL Nat. Cell Biol. 3:512-516(2001). RN [32] RP CHROMOSOMAL TRANSLOCATION WITH ETV6. RX PubMed=12181402; DOI=10.1056/nejmoa020150; RA Apperley J.F., Gardembas M., Melo J.V., Russell-Jones R., Bain B.J., RA Baxter E.J., Chase A., Chessells J.M., Colombat M., Dearden C.E., RA Dimitrijevic S., Mahon F.-X., Marin D., Nikolova Z., Olavarria E., RA Silberman S., Schultheis B., Cross N.C.P., Goldman J.M.; RT "Response to imatinib mesylate in patients with chronic myeloproliferative RT diseases with rearrangements of the platelet-derived growth factor receptor RT beta."; RL N. Engl. J. Med. 347:481-487(2002). RN [33] RP CHROMOSOMAL TRANSLOCATION WITH PDE4DIP. RX PubMed=12907457; DOI=10.1182/blood-2003-04-1150; RA Wilkinson K., Velloso E.R.P., Lopes L.F., Lee C., Aster J.C., Shipp M.A., RA Aguiar R.C.T.; RT "Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated RT with eosinophilia: involvement of PDGFRB and response to imatinib."; RL Blood 102:4187-4190(2003). RN [34] RP CHROMOSOMAL TRANSLOCATION WITH SPECC1. RX PubMed=15087372; DOI=10.1158/0008-5472.can-03-4026; RA Morerio C., Acquila M., Rosanda C., Rapella A., Dufour C., Locatelli F., RA Maserati E., Pasquali F., Panarello C.; RT "HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic RT leukemia with t(5;17)(q33;p11.2)."; RL Cancer Res. 64:2649-2651(2004). RN [35] RP CHROMOSOMAL TRANSLOCATION WITH TP53BP1, AND ACTIVITY REGULATION. RX PubMed=15492236; DOI=10.1158/0008-5472.can-04-2005; RA Grand F.H., Burgstaller S., Kuhr T., Baxter E.J., Webersinke G., Thaler J., RA Chase A.J., Cross N.C.; RT "p53-Binding protein 1 is fused to the platelet-derived growth factor RT receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib- RT responsive eosinophilic myeloproliferative disorder."; RL Cancer Res. 64:7216-7219(2004). RN [36] RP PHOSPHORYLATION AT TYR-579; TYR-751; TYR-771 AND TYR-1021, AND RP DEPHOSPHORYLATION AT TYR-579 AND TYR-1021 BY PTPN2. RX PubMed=14966296; DOI=10.1128/mcb.24.5.2190-2201.2004; RA Persson C., Saevenhed C., Bourdeau A., Tremblay M.L., Markova B., RA Boehmer F.D., Haj F.G., Neel B.G., Elson A., Heldin C.H., Roennstrand L., RA Ostman A., Hellberg C.; RT "Site-selective regulation of platelet-derived growth factor beta receptor RT tyrosine phosphorylation by T-cell protein tyrosine phosphatase."; RL Mol. Cell. Biol. 24:2190-2201(2004). RN [37] RP PHOSPHORYLATION AT TYR-579; TYR-581; TYR-716; TYR-740; TYR-771; TYR-857; RP TYR-1009 AND TYR-1021. RX PubMed=15902258; DOI=10.1038/nature03587; RA Choi M.H., Lee I.K., Kim G.W., Kim B.U., Han Y.H., Yu D.Y., Park H.S., RA Kim K.Y., Lee J.S., Choi C., Bae Y.S., Lee B.I., Rhee S.G., Kang S.W.; RT "Regulation of PDGF signalling and vascular remodelling by peroxiredoxin RT II."; RL Nature 435:347-353(2005). RN [38] RP INTERACTION WITH CBL, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-1021, AND RP UBIQUITINATION. RX PubMed=17620338; DOI=10.1074/jbc.m701797200; RA Reddi A.L., Ying G., Duan L., Chen G., Dimri M., Douillard P., Druker B.J., RA Naramura M., Band V., Band H.; RT "Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived RT growth factor receptor beta provides a dual mechanism of negative RT regulation."; RL J. Biol. Chem. 282:29336-29347(2007). RN [39] RP FUNCTION AS PDGFD RECEPTOR. RX PubMed=21098708; DOI=10.1158/0008-5472.can-10-0511; RA Ustach C.V., Huang W., Conley-LaComb M.K., Lin C.Y., Che M., Abrams J., RA Kim H.R.; RT "A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate RT cancer."; RL Cancer Res. 70:9631-9640(2010). RN [40] RP FUNCTION IN PHOSPHORYLATION OF CBL; STAM; PDCD6IP/ALIX; PLCG1 AND PTPN11, RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF LYS-634 AND TYR-857. RX PubMed=20494825; DOI=10.1016/j.cellsig.2010.05.004; RA Wardega P., Heldin C.H., Lennartsson J.; RT "Mutation of tyrosine residue 857 in the PDGF beta-receptor affects cell RT proliferation but not migration."; RL Cell. Signal. 22:1363-1368(2010). RN [41] RP FUNCTION. RX PubMed=20529858; DOI=10.1074/jbc.m110.102566; RA Mendelson K., Swendeman S., Saftig P., Blobel C.P.; RT "Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) RT activates ADAM17 and promotes metalloproteinase-dependent cross-talk RT between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling RT pathways."; RL J. Biol. Chem. 285:25024-25032(2010). RN [42] RP FUNCTION IN SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION. RX PubMed=21733313; DOI=10.1017/s0007114511002571; RA Kim H.J., Cha B.Y., Choi B., Lim J.S., Woo J.T., Kim J.S.; RT "Glyceollins inhibit platelet-derived growth factor-mediated human arterial RT smooth muscle cell proliferation and migration."; RL Br. J. Nutr. 107:24-35(2012). RN [43] RP INTERACTION WITH SHC1 AND GRB2, AND FUNCTION IN PHOSPHORYLATION OF SHC1. RX PubMed=8195171; DOI=10.1016/s0021-9258(17)36611-5; RA Yokote K., Mori S., Hansen K., McGlade J., Pawson T., Heldin C.H., RA Claesson-Welsh L.; RT "Direct interaction between Shc and the platelet-derived growth factor RT beta-receptor."; RL J. Biol. Chem. 269:15337-15343(1994). RN [44] RP FUNCTION IN SMOOTH MUSCLE CELL MIGRATION AND NEOINTIMA FORMATION AFTER RP BLOOD VESSEL INJURY, AND MUTAGENESIS OF TYR-740; TYR-751 AND TYR-1021. RX PubMed=21679854; DOI=10.1016/j.jacc.2011.02.037; RA Caglayan E., Vantler M., Leppanen O., Gerhardt F., Mustafov L., RA Ten Freyhaus H., Kappert K., Odenthal M., Zimmermann W.H., Tallquist M.D., RA Rosenkranz S.; RT "Disruption of platelet-derived growth factor-dependent RT phosphatidylinositol 3-kinase and phospholipase Cgamma 1 activity abolishes RT vascular smooth muscle cell proliferation and migration and attenuates RT neointima formation in vivo."; RL J. Am. Coll. Cardiol. 57:2527-2538(2011). RN [45] RP INVOLVEMENT IN PENTT, VARIANT PENTT ALA-665, AND CHARACTERIZATION OF RP VARIANT PENTT ALA-665. RX PubMed=26279204; DOI=10.1016/j.ajhg.2015.07.009; RA Johnston J.J., Sanchez-Contreras M.Y., Keppler-Noreuil K.M., Sapp J., RA Crenshaw M., Finch N.A., Cormier-Daire V., Rademakers R., Sybert V.P., RA Biesecker L.G.; RT "A point mutation in PDGFRB causes autosomal-dominant Penttinen syndrome."; RL Am. J. Hum. Genet. 97:465-474(2015). RN [46] RP INVOLVEMENT IN KOGS, AND VARIANT KOGS ARG-584. RX PubMed=25454926; DOI=10.1016/j.jpeds.2014.10.015; RA Takenouchi T., Yamaguchi Y., Tanikawa A., Kosaki R., Okano H., Kosaki K.; RT "Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB RT mutation."; RL J. Pediatr. 166:483-486(2015). RN [47] RP CHARACTERIZATION OF VARIANTS IBGC4 PRO-658; TRP-987 AND VAL-1071, AND RP FUNCTION. RX PubMed=26599395; DOI=10.1371/journal.pone.0143407; RA Vanlandewijck M., Lebouvier T., Andaloussi Maee M., Nahar K., Hornemann S., RA Kenkel D., Cunha S.I., Lennartsson J., Boss A., Heldin C.H., Keller A., RA Betsholtz C.; RT "Functional characterization of germline mutations in PDGFB and PDGFRB in RT primary familial brain calcification."; RL PLoS ONE 10:E0143407-E0143407(2015). RN [48] RP REVIEW ON SIGNALING AND AUTOPHOSPHORYLATION. RX PubMed=9739761; DOI=10.1016/s0304-419x(98)00015-8; RA Heldin C.H., Ostman A., Ronnstrand L.; RT "Signal transduction via platelet-derived growth factor receptors."; RL Biochim. Biophys. Acta 1378:F79-113(1998). RN [49] RP REVIEW. RX PubMed=15207817; DOI=10.1016/j.cytogfr.2004.03.002; RA Ostman A.; RT "PDGF receptors-mediators of autocrine tumor growth and regulators of tumor RT vasculature and stroma."; RL Cytokine Growth Factor Rev. 15:275-286(2004). RN [50] RP REVIEW. RX PubMed=17419949; DOI=10.1016/s0065-230x(06)97011-0; RA Ostman A., Heldin C.H.; RT "PDGF receptors as targets in tumor treatment."; RL Adv. Cancer Res. 97:247-274(2007). RN [51] RP REVIEW ON FUNCTION; LIGANDS; ROLE IN DEVELOPMENT AND DISEASE AND ACTIVATION RP OF SIGNALING PATHWAYS. RX PubMed=18483217; DOI=10.1101/gad.1653708; RA Andrae J., Gallini R., Betsholtz C.; RT "Role of platelet-derived growth factors in physiology and medicine."; RL Genes Dev. 22:1276-1312(2008). RN [52] RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 751-755 IN COMPLEX WITH PIK3R1, RP AND COMPARISON WITH NMR ANALYSIS. RX PubMed=11567151; DOI=10.1107/s0907444901012434; RA Pauptit R.A., Dennis C.A., Derbyshire D.J., Breeze A.L., Weston S.A., RA Rowsell S., Murshudov G.N.; RT "NMR trial models: experiences with the colicin immunity protein Im7 and RT the p85alpha C-terminal SH2-peptide complex."; RL Acta Crystallogr. D 57:1397-1404(2001). RN [53] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1102-1106 IN COMPLEX WITH NHERF1, RP AND INTERACTION WITH NHERF1. RX PubMed=11882663; DOI=10.1074/jbc.m201507200; RA Karthikeyan S., Leung T., Ladias J.A.A.; RT "Structural determinants of the Na+/H+ exchanger regulatory factor RT interaction with the beta 2 adrenergic and platelet-derived growth factor RT receptors."; RL J. Biol. Chem. 277:18973-18978(2002). RN [54] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 33-314 IN COMPLEX WITH PDGFB, RP SUBUNIT, GLYCOSYLATION AT ASN-45; ASN-89; ASN-103; ASN-215; ASN-230; RP ASN-292 AND ASN-307, AND DISULFIDE BONDS. RX PubMed=20534510; DOI=10.1073/pnas.1000806107; RA Shim A.H., Liu H., Focia P.J., Chen X., Lin P.C., He X.; RT "Structures of a platelet-derived growth factor/propeptide complex and a RT platelet-derived growth factor/receptor complex."; RL Proc. Natl. Acad. Sci. U.S.A. 107:11307-11312(2010). RN [55] RP VARIANTS [LARGE SCALE ANALYSIS] PHE-29; LYS-282; LYS-485; HIS-589; TYR-718 RP AND ILE-882. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [56] RP VARIANT IMF1 THR-660, AND INVOLVEMENT IN IMF1. RX PubMed=23731542; DOI=10.1016/j.ajhg.2013.04.024; RA Martignetti J.A., Tian L., Li D., Ramirez M.C., Camacho-Vanegas O., RA Camacho S.C., Guo Y., Zand D.J., Bernstein A.M., Masur S.K., Kim C.E., RA Otieno F.G., Hou C., Abdel-Magid N., Tweddale B., Metry D., Fournet J.C., RA Papp E., McPherson E.W., Zabel C., Vaksmann G., Morisot C., Keating B., RA Sleiman P.M., Cleveland J.A., Everman D.B., Zackai E., Hakonarson H.; RT "Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis."; RL Am. J. Hum. Genet. 92:1001-1007(2013). RN [57] RP VARIANT IMF1 CYS-561, AND INVOLVEMENT IN IMF1. RX PubMed=23731537; DOI=10.1016/j.ajhg.2013.04.026; RA Cheung Y.H., Gayden T., Campeau P.M., Leduc C.A., Russo D., Nguyen V.H., RA Guo J., Qi M., Guan Y., Albrecht S., Moroz B., Eldin K.W., Lu J.T., RA Schwartzentruber J., Malkin D., Berghuis A.M., Emil S., Gibbs R.A., RA Burk D.L., Vanstone M., Lee B.H., Orchard D., Boycott K.M., Chung W.K., RA Jabado N.; RT "A recurrent PDGFRB mutation causes familial infantile myofibromatosis."; RL Am. J. Hum. Genet. 92:996-1000(2013). RN [58] RP VARIANTS IBGC4 PRO-658; TRP-987 AND VAL-1071, AND INVOLVEMENT IN IBGC4. RX PubMed=24065723; DOI=10.1093/brain/awt255; RG French IBGC Study Group; RA Nicolas G., Pottier C., Charbonnier C., Guyant-Marechal L., Le Ber I., RA Pariente J., Labauge P., Ayrignac X., Defebvre L., Maltete D., RA Martinaud O., Lefaucheur R., Guillin O., Wallon D., Chaumette B., RA Rondepierre P., Derache N., Fromager G., Schaeffer S., Krystkowiak P., RA Verny C., Jurici S., Sauvee M., Verin M., Lebouvier T., Rouaud O., RA Thauvin-Robinet C., Rousseau S., Rovelet-Lecrux A., Frebourg T., RA Campion D., Hannequin D.; RT "Phenotypic spectrum of probable and genetically-confirmed idiopathic basal RT ganglia calcification."; RL Brain 136:3395-3407(2013). RN [59] RP VARIANTS IBGC4 PRO-658 AND TRP-987, AND INVOLVEMENT IN IBGC4. RX PubMed=23255827; DOI=10.1212/wnl.0b013e31827ccf34; RA Nicolas G., Pottier C., Maltete D., Coutant S., Rovelet-Lecrux A., RA Legallic S., Rousseau S., Vaschalde Y., Guyant-Marechal L., Augustin J., RA Martinaud O., Defebvre L., Krystkowiak P., Pariente J., Clanet M., RA Labauge P., Ayrignac X., Lefaucheur R., Le Ber I., Frebourg T., RA Hannequin D., Campion D.; RT "Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia RT calcification."; RL Neurology 80:181-187(2013). RN [60] RP VARIANT PENTT SER-666, CHARACTERIZATION OF VARIANT PENTT SER-666, AND RP INVOLVEMENT IN PENTT. RX PubMed=30573803; DOI=10.1038/s41431-018-0323-z; RA Bredrup C., Stokowy T., McGaughran J., Lee S., Sapkota D., Cristea I., RA Xu L., Tveit K.S., Hoevding G., Steen V.M., Roedahl E., Bruland O., RA Houge G.; RT "A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a RT progeria-like condition in the severe end of Penttinen syndrome."; RL Eur. J. Hum. Genet. 27:574-581(2019). RN [61] RP VARIANT OPDKD TYR-666, CHARACTERIZATION OF VARIANT OPDKD TYR-666, AND RP INVOLVEMENT IN OPDKD. RX PubMed=33450762; DOI=10.1093/hmg/ddab014; RA Bredrup C., Cristea I., Safieh L.A., Di Maria E., Gjertsen B.T., RA Tveit K.S., Thu F., Bull N., Edward D.P., Hennekam R.C.M., Hoevding G., RA Haugen O.H., Houge G., Roedahl E., Bruland O.; RT "Temperature-dependent autoactivation associated with clinical variability RT of PDGFRB Asn666 substitutions."; RL Hum. Mol. Genet. 30:72-77(2021). CC -!- FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor CC for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA CC and PDGFB, and plays an essential role in the regulation of embryonic CC development, cell proliferation, survival, differentiation, chemotaxis CC and migration. Plays an essential role in blood vessel development by CC promoting proliferation, migration and recruitment of pericytes and CC smooth muscle cells to endothelial cells. Plays a role in the migration CC of vascular smooth muscle cells and the formation of neointima at CC vascular injury sites. Required for normal development of the CC cardiovascular system. Required for normal recruitment of pericytes CC (mesangial cells) in the kidney glomerulus, and for normal formation of CC a branched network of capillaries in kidney glomeruli. Promotes CC rearrangement of the actin cytoskeleton and the formation of membrane CC ruffles. Binding of its cognate ligands - homodimeric PDGFB, CC heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to CC the activation of several signaling cascades; the response depends on CC the nature of the bound ligand and is modulated by the formation of CC heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, CC PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the CC production of the cellular signaling molecules diacylglycerol and CC inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the CC activation of protein kinase C. Phosphorylation of PIK3R1, the CC regulatory subunit of phosphatidylinositol 3-kinase, leads to the CC activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or CC of the C-terminus of PTPN11, creates a binding site for GRB2, resulting CC in the activation of HRAS, RAF1 and down-stream MAP kinases, including CC MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation CC of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and CC STAM. Receptor signaling is down-regulated by protein phosphatases that CC dephosphorylate the receptor and its down-stream effectors, and by CC rapid internalization of the activated receptor. CC {ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:11331881, CC ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1396585, CC ECO:0000269|PubMed:1653029, ECO:0000269|PubMed:1709159, CC ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825, CC ECO:0000269|PubMed:20529858, ECO:0000269|PubMed:21098708, CC ECO:0000269|PubMed:21679854, ECO:0000269|PubMed:21733313, CC ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:26599395, CC ECO:0000269|PubMed:2835772, ECO:0000269|PubMed:2850496, CC ECO:0000269|PubMed:7685273, ECO:0000269|PubMed:7691811, CC ECO:0000269|PubMed:7692233, ECO:0000269|PubMed:8195171}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, ChEBI:CHEBI:456216; EC=2.7.10.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, CC ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825, CC ECO:0000269|PubMed:7685273}; CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence CC of bound ligand. Binding of PDGFB and/or PDGFD leads to dimerization CC and activation by autophosphorylation on tyrosine residues. Inhibited CC by imatinib. {ECO:0000269|PubMed:15492236}. CC -!- SUBUNIT: Interacts with homodimeric PDGFB and PDGFD, and with CC heterodimers formed by PDGFA and PDGFB. May also interact with CC homodimeric PDGFC. Monomer in the absence of bound ligand. Interaction CC with homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or CC homodimeric PDGFD, leads to receptor dimerization, where both PDGFRA CC homodimers and heterodimers with PDGFRB are observed. Interacts with CC SH2B2/APS. Interacts directly (tyrosine phosphorylated) with SHB. CC Interacts (tyrosine phosphorylated) with PIK3R1 and RASA1. Interacts CC (tyrosine phosphorylated) with CBL. Interacts (tyrosine phosphorylated) CC with SRC and SRC family kinases. Interacts (tyrosine phosphorylated) CC with PIK3C2B, maybe indirectly. Interacts (tyrosine phosphorylated) CC with SHC1, GRB7, GRB10 and NCK1. Interaction with GRB2 is mediated by CC SHC1. Interacts (via C-terminus) with NHERF1. CC {ECO:0000269|PubMed:10454568, ECO:0000269|PubMed:10805725, CC ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:11567151, CC ECO:0000269|PubMed:11882663, ECO:0000269|PubMed:1314164, CC ECO:0000269|PubMed:1375321, ECO:0000269|PubMed:1396585, CC ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:17620338, CC ECO:0000269|PubMed:20534510, ECO:0000269|PubMed:2835772, CC ECO:0000269|PubMed:2850496, ECO:0000269|PubMed:7679113, CC ECO:0000269|PubMed:7691811, ECO:0000269|PubMed:7692233, CC ECO:0000269|PubMed:8195171, ECO:0000269|PubMed:8302579, CC ECO:0000269|PubMed:8940081, ECO:0000269|PubMed:9989826}. CC -!- INTERACTION: CC P09619; P05067: APP; NbExp=3; IntAct=EBI-641237, EBI-77613; CC P09619; Q8TAP6: CEP76; NbExp=3; IntAct=EBI-641237, EBI-742887; CC P09619; P06241: FYN; NbExp=3; IntAct=EBI-641237, EBI-515315; CC P09619; Q14451: GRB7; NbExp=4; IntAct=EBI-641237, EBI-970191; CC P09619; P14778: IL1R1; NbExp=2; IntAct=EBI-641237, EBI-525905; CC P09619; P35968: KDR; NbExp=2; IntAct=EBI-641237, EBI-1005487; CC P09619; Q53G59: KLHL12; NbExp=6; IntAct=EBI-641237, EBI-740929; CC P09619; Q5T749: KPRP; NbExp=3; IntAct=EBI-641237, EBI-10981970; CC P09619; Q15323: KRT31; NbExp=3; IntAct=EBI-641237, EBI-948001; CC P09619; O76011: KRT34; NbExp=3; IntAct=EBI-641237, EBI-1047093; CC P09619; P60411: KRTAP10-9; NbExp=3; IntAct=EBI-641237, EBI-10172052; CC P09619; P60328: KRTAP12-3; NbExp=3; IntAct=EBI-641237, EBI-11953334; CC P09619; O94898: LRIG2; NbExp=3; IntAct=EBI-641237, EBI-2830372; CC P09619; O75581: LRP6; NbExp=3; IntAct=EBI-641237, EBI-910915; CC P09619; O14745: NHERF1; NbExp=5; IntAct=EBI-641237, EBI-349787; CC P09619; Q15599: NHERF2; NbExp=2; IntAct=EBI-641237, EBI-1149760; CC P09619; P01127: PDGFB; NbExp=16; IntAct=EBI-641237, EBI-1554925; CC P09619; P27986: PIK3R1; NbExp=21; IntAct=EBI-641237, EBI-79464; CC P09619; O00459: PIK3R2; NbExp=3; IntAct=EBI-641237, EBI-346930; CC P09619; P19174: PLCG1; NbExp=7; IntAct=EBI-641237, EBI-79387; CC P09619; P60484: PTEN; NbExp=3; IntAct=EBI-641237, EBI-696162; CC P09619; P18031: PTPN1; NbExp=3; IntAct=EBI-641237, EBI-968788; CC P09619; Q06124: PTPN11; NbExp=8; IntAct=EBI-641237, EBI-297779; CC P09619; Q05209: PTPN12; NbExp=3; IntAct=EBI-641237, EBI-2266035; CC P09619; P23470: PTPRG; NbExp=2; IntAct=EBI-641237, EBI-2258115; CC P09619; Q12913: PTPRJ; NbExp=4; IntAct=EBI-641237, EBI-2264500; CC P09619; P20936: RASA1; NbExp=3; IntAct=EBI-641237, EBI-1026476; CC P09619; Q13239: SLA; NbExp=4; IntAct=EBI-641237, EBI-726214; CC P09619; Q15654: TRIP6; NbExp=3; IntAct=EBI-641237, EBI-742327; CC P09619; P07947: YES1; NbExp=3; IntAct=EBI-641237, EBI-515331; CC P09619; P0CK45: E5; Xeno; NbExp=2; IntAct=EBI-641237, EBI-7015490; CC P09619; P35918: Kdr; Xeno; NbExp=4; IntAct=EBI-641237, EBI-1555005; CC P09619; Q28619: NHERF1; Xeno; NbExp=3; IntAct=EBI-641237, EBI-7073613; CC P09619; P23727: PIK3R1; Xeno; NbExp=6; IntAct=EBI-641237, EBI-520244; CC P09619; P08487: PLCG1; Xeno; NbExp=3; IntAct=EBI-641237, EBI-8013886; CC P09619; P41499: Ptpn11; Xeno; NbExp=4; IntAct=EBI-641237, EBI-7180604; CC P09619; P25020: V-SRC; Xeno; NbExp=4; IntAct=EBI-641237, EBI-8636140; CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane CC protein. Cytoplasmic vesicle. Lysosome lumen. Note=After ligand CC binding, the autophosphorylated receptor is ubiquitinated and CC internalized, leading to its degradation. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P09619-1; Sequence=Displayed; CC Name=2; CC IsoId=P09619-2; Sequence=VSP_056008, VSP_056009; CC -!- PTM: Autophosphorylated on tyrosine residues upon ligand binding. CC Autophosphorylation occurs in trans, i.e. one subunit of the dimeric CC receptor phosphorylates tyrosine residues on the other subunit. CC Phosphorylation at Tyr-579, and to a lesser degree, at Tyr-581, is CC important for interaction with SRC family kinases. Phosphorylation at CC Tyr-740 and Tyr-751 is important for interaction with PIK3R1. CC Phosphorylation at Tyr-751 is important for interaction with NCK1. CC Phosphorylation at Tyr-771 and Tyr-857 is important for interaction CC with RASA1/GAP. Phosphorylation at Tyr-857 is important for efficient CC phosphorylation of PLCG1 and PTPN11, resulting in increased CC phosphorylation of AKT1, MAPK1/ERK2 and/or MAPK3/ERK1, PDCD6IP/ALIX and CC STAM, and in increased cell proliferation. Phosphorylation at Tyr-1009 CC is important for interaction with PTPN11. Phosphorylation at Tyr-1009 CC and Tyr-1021 is important for interaction with PLCG1. Phosphorylation CC at Tyr-1021 is important for interaction with CBL; PLCG1 and CBL CC compete for the same binding site. Dephosphorylated by PTPRJ at Tyr- CC 751, Tyr-857, Tyr-1009 and Tyr-1021. Dephosphorylated by PTPN2 at Tyr- CC 579 and Tyr-1021. {ECO:0000269|PubMed:10821867, CC ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1396585, CC ECO:0000269|PubMed:14966296, ECO:0000269|PubMed:15902258, CC ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:2550144, CC ECO:0000269|PubMed:7685273}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:20534510, CC ECO:0000269|PubMed:2850496}. CC -!- PTM: Ubiquitinated. After autophosphorylation, the receptor is CC polyubiquitinated, leading to its degradation. CC {ECO:0000269|PubMed:1313434, ECO:0000269|PubMed:17620338}. CC -!- DISEASE: Note=A chromosomal aberration involving PDGFRB is found in a CC form of chronic myelomonocytic leukemia (CMML). Translocation CC t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal CC myeloid proliferation and by progression to acute myelogenous leukemia CC (AML). CC -!- DISEASE: Myeloproliferative disorder chronic with eosinophilia (MPE) CC [MIM:131440]: A hematologic disorder characterized by malignant CC eosinophils proliferation. Note=The gene represented in this entry may CC be involved in disease pathogenesis. Chromosomal aberrations involving CC PDGFRB have been found in many instances of chronic myeloproliferative CC disorder with eosinophilia. Translocation t(5;12) with ETV6 on CC chromosome 12 creating an PDGFRB-ETV6 fusion protein (PubMed:12181402). CC Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 CC fusion protein (PubMed:15492236). Translocation t(1;5)(q23;q33) that CC forms a PDE4DIP-PDGFRB fusion protein (PubMed:12907457). Translocation CC t(5;6)(q33-34;q23) with CEP85L that fuses the 5'-end of CEP85L (isoform CC 4) to the 3'-end of PDGFRB (PubMed:21938754). CC {ECO:0000269|PubMed:12181402, ECO:0000269|PubMed:12907457, CC ECO:0000269|PubMed:15492236, ECO:0000269|PubMed:21938754}. CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of CC acute leukemia, a cancer of the white blood cells. AML is a malignant CC disease of bone marrow characterized by maturational arrest of CC hematopoietic precursors at an early stage of development. Clonal CC expansion of myeloid blasts occurs in bone marrow, blood, and other CC tissue. Myelogenous leukemias develop from changes in cells that CC normally produce neutrophils, basophils, eosinophils and monocytes. CC Note=The gene represented in this entry may be involved in disease CC pathogenesis. A chromosomal aberration involving PDGFRB has been found CC in a patient with AML. Translocation t(5;14)(q33;q32) with TRIP11 CC (PubMed:9373237). {ECO:0000269|PubMed:9373237}. CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An CC aggressive pediatric myelodysplastic syndrome/myeloproliferative CC disorder characterized by malignant transformation in the hematopoietic CC stem cell compartment with proliferation of differentiated progeny. CC Patients have splenomegaly, enlarged lymph nodes, rashes, and CC hemorrhages. Note=The gene represented in this entry may be involved in CC disease pathogenesis. A chromosomal aberration involving PDGFRB has CC been found in a patient with JMML. Translocation t(5;17)(q33;p11.2) CC with SPECC1 (PubMed:15087372). {ECO:0000269|PubMed:15087372}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 4 (IBGC4) CC [MIM:615007]: A form of basal ganglia calcification, an autosomal CC dominant condition characterized by symmetric calcification in the CC basal ganglia and other brain regions. Affected individuals can either CC be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, CC including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, CC seizures, and chronic headache. Serum levels of calcium, phosphate, CC alkaline phosphatase and parathyroid hormone are normal. The CC neuropathological hallmark of the disease is vascular and pericapillary CC calcification, mainly of calcium phosphate, in the affected brain CC areas. {ECO:0000269|PubMed:23255827, ECO:0000269|PubMed:24065723, CC ECO:0000269|PubMed:26599395}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Myofibromatosis, infantile 1 (IMF1) [MIM:228550]: A rare CC mesenchymal disorder characterized by the development of benign tumors CC in the skin, striated muscles, bones, and, more rarely, visceral CC organs. Subcutaneous or soft tissue nodules commonly involve the skin CC of the head, neck, and trunk. Skeletal and muscular lesions occur in CC about half of the patients. Lesions may be solitary or multicentric, CC and they may be present at birth or become apparent in early infancy or CC occasionally in adult life. Visceral lesions are associated with high CC morbidity and mortality. {ECO:0000269|PubMed:23731537, CC ECO:0000269|PubMed:23731542}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Kosaki overgrowth syndrome (KOGS) [MIM:616592]: A syndrome CC characterized by somatic overgrowth, distinctive facial features, CC hyperelastic and fragile skin, and progressive neurologic deterioration CC with white matter lesions on brain imaging. CC {ECO:0000269|PubMed:25454926}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Premature aging syndrome, Penttinen type (PENTT) [MIM:601812]: CC An autosomal dominant syndrome characterized by a prematurely aged CC appearance with lipoatrophy, epidermal and dermal atrophy along with CC hypertrophic lesions that resemble scars, thin hair, proptosis, CC underdeveloped cheekbones, and marked acro-osteolysis. CC {ECO:0000269|PubMed:26279204, ECO:0000269|PubMed:30573803}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Ocular pterygium-digital keloid dysplasia syndrome (OPDKD) CC [MIM:621091]: An autosomal dominant disorder that presents in childhood CC with aggressive ingrowth of vascularized connective tissue on the CC cornea, ultimately leading to loss of vision. Later, affected CC individuals develop keloids on digits after minor trauma, but are CC otherwise healthy. {ECO:0000269|PubMed:33450762}. Note=The disease may CC be caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. CSF-1/PDGF receptor subfamily. {ECO:0000255|PROSITE- CC ProRule:PRU00159}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/21/PDGFRB"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J03278; AAA60049.1; -; mRNA. DR EMBL; M21616; AAA36427.1; -; mRNA. DR EMBL; EU826595; ACF47631.1; -; mRNA. DR EMBL; AC005895; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC011382; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC032224; AAH32224.1; -; mRNA. DR EMBL; U33172; AAC51675.1; -; Genomic_DNA. DR CCDS; CCDS4303.1; -. [P09619-1] DR PIR; A28206; PFHUGB. DR RefSeq; NP_002600.1; NM_002609.4. [P09619-1] DR PDB; 1GQ5; X-ray; 2.20 A; A=1102-1106. DR PDB; 1H9O; X-ray; 1.79 A; B=751-755. DR PDB; 1SHA; X-ray; 1.50 A; B=751-755. DR PDB; 2IUI; X-ray; 2.40 A; C/D=748-758. DR PDB; 2L6W; NMR; -; A/B=526-563. DR PDB; 2PLD; NMR; -; B=1018-1029. DR PDB; 2PLE; NMR; -; B=1018-1029. DR PDB; 3MJG; X-ray; 2.30 A; X/Y=33-314. DR PDBsum; 1GQ5; -. DR PDBsum; 1H9O; -. DR PDBsum; 1SHA; -. DR PDBsum; 2IUI; -. DR PDBsum; 2L6W; -. DR PDBsum; 2PLD; -. DR PDBsum; 2PLE; -. DR PDBsum; 3MJG; -. DR AlphaFoldDB; P09619; -. DR BMRB; P09619; -. DR EMDB; EMD-6426; -. DR SMR; P09619; -. DR BioGRID; 111185; 211. DR ComplexPortal; CPX-2882; PDGF receptor beta - PDGF-BB complex. DR ComplexPortal; CPX-2883; PDGF receptor alpha-beta - PDGF-BB complex. DR ComplexPortal; CPX-2886; PDGF receptor beta - PDGF-AB complex. DR ComplexPortal; CPX-2888; PDGF receptor alpha-beta - PDGF-CC complex. DR ComplexPortal; CPX-2889; PDGF receptor beta - PDGF-DD complex. DR ComplexPortal; CPX-2890; PDGF receptor alpha-beta - PDGF-DD complex. DR ComplexPortal; CPX-2891; PDGF receptor beta - PDGF-CC complex. DR ComplexPortal; CPX-2892; PDGF receptor alpha-beta - PDGF-AB complex. DR CORUM; P09619; -. DR DIP; DIP-558N; -. DR FunCoup; P09619; 1764. DR IntAct; P09619; 390. DR MINT; P09619; -. DR STRING; 9606.ENSP00000261799; -. DR BindingDB; P09619; -. DR ChEMBL; CHEMBL1913; -. DR DrugBank; DB00102; Becaplermin. DR DrugBank; DB01254; Dasatinib. DR DrugBank; DB12147; Erdafitinib. DR DrugBank; DB11741; Famitinib. DR DrugBank; DB10770; Foreskin fibroblast (neonatal). DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB00619; Imatinib. DR DrugBank; DB11845; Lucitanib. DR DrugBank; DB06595; Midostaurin. DR DrugBank; DB09079; Nintedanib. DR DrugBank; DB06589; Pazopanib. DR DrugBank; DB08339; PD-166326. DR DrugBank; DB17041; PD-173952. DR DrugBank; DB02567; PD173955. DR DrugBank; DB12978; Pexidartinib. DR DrugBank; DB09221; Polaprezinc. DR DrugBank; DB15822; Pralsetinib. DR DrugBank; DB08896; Regorafenib. DR DrugBank; DB14840; Ripretinib. DR DrugBank; DB06436; Semaxanib. DR DrugBank; DB00398; Sorafenib. DR DrugBank; DB08009; SU-11652. DR DrugBank; DB01268; Sunitinib. DR DrugBank; DB13093; TAK-593. DR DrugBank; DB11800; Tivozanib. DR DrugBank; DB09283; Trapidil. DR DrugBank; DB05146; XL820. DR DrugBank; DB05014; XL999. DR DrugCentral; P09619; -. DR GuidetoPHARMACOLOGY; 1804; -. DR TCDB; 8.A.23.1.37; the basigin (basigin) family. DR GlyConnect; 1967; 4 N-Linked glycans (3 sites). DR GlyCosmos; P09619; 11 sites, 4 glycans. DR GlyGen; P09619; 13 sites, 4 N-linked glycans (3 sites), 1 O-linked glycan (1 site). DR iPTMnet; P09619; -. DR PhosphoSitePlus; P09619; -. DR BioMuta; PDGFRB; -. DR DMDM; 129890; -. DR CPTAC; CPTAC-1630; -. DR CPTAC; CPTAC-3063; -. DR jPOST; P09619; -. DR MassIVE; P09619; -. DR PaxDb; 9606-ENSP00000261799; -. DR PeptideAtlas; P09619; -. DR ProteomicsDB; 52253; -. [P09619-1] DR Pumba; P09619; -. DR ABCD; P09619; 7 sequenced antibodies. DR Antibodypedia; 3424; 2244 antibodies from 49 providers. DR DNASU; 5159; -. DR Ensembl; ENST00000261799.9; ENSP00000261799.4; ENSG00000113721.15. [P09619-1] DR GeneID; 5159; -. DR KEGG; hsa:5159; -. DR MANE-Select; ENST00000261799.9; ENSP00000261799.4; NM_002609.4; NP_002600.1. DR UCSC; uc003lro.4; human. [P09619-1] DR AGR; HGNC:8804; -. DR CIViC; 5159; 2 evidence items across 3 molecular profiles. DR ClinPGx; PA33148; -. DR CTD; 5159; -. DR DisGeNET; 5159; -. DR GeneCards; PDGFRB; -. DR GeneReviews; PDGFRB; -. DR HGNC; HGNC:8804; PDGFRB. DR HPA; ENSG00000113721; Low tissue specificity. DR MalaCards; PDGFRB; -. DR MIM; 131440; phenotype. DR MIM; 173410; gene. DR MIM; 228550; phenotype. DR MIM; 601626; phenotype. DR MIM; 601812; phenotype. DR MIM; 607785; phenotype. DR MIM; 615007; phenotype. DR MIM; 616592; phenotype. DR MIM; 621091; phenotype. DR OpenTargets; ENSG00000113721; -. DR Orphanet; 363665; Acroosteolysis-keloid-like lesions-premature aging syndrome. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR Orphanet; 86830; Chronic myeloproliferative disease, unclassifiable. DR Orphanet; 2591; Infantile myofibromatosis. DR Orphanet; 477831; Kosaki overgrowth syndrome. DR Orphanet; 168950; Myeloid/lymphoid neoplasm associated with PDGFRB rearrangement. DR Orphanet; 314950; Primary hypereosinophilic syndrome. DR VEuPathDB; HostDB:ENSG00000113721; -. DR eggNOG; KOG0200; Eukaryota. DR GeneTree; ENSGT00940000157138; -. DR HOGENOM; CLU_000288_49_0_1; -. DR InParanoid; P09619; -. DR OMA; WPEDQEF; -. DR OrthoDB; 9936425at2759; -. DR PAN-GO; P09619; 10 GO annotations based on evolutionary models. DR PhylomeDB; P09619; -. DR BRENDA; 2.7.10.1; 2681. DR PathwayCommons; P09619; -. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-186763; Downstream signal transduction. DR Reactome; R-HSA-186797; Signaling by PDGF. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR SignaLink; P09619; -. DR SIGNOR; P09619; -. DR Agora; ENSG00000113721; -. DR BioGRID-ORCS; 5159; 18 hits in 1194 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR ChiTaRS; PDGFRB; human. DR EvolutionaryTrace; P09619; -. DR GeneWiki; PDGFRB; -. DR GenomeRNAi; 5159; -. DR Pharos; P09619; Tclin. DR PRO; PR:P09619; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; P09619; protein. DR Bgee; ENSG00000113721; Expressed in stromal cell of endometrium and 182 other cell types or tissues. DR ExpressionAtlas; P09619; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0043202; C:lysosomal lumen; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0043235; C:receptor complex; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL. DR GO; GO:0005096; F:GTPase activator activity; IMP:UniProtKB. DR GO; GO:0160185; F:phospholipase C activator activity; IMP:UniProtKB. DR GO; GO:0004992; F:platelet activating factor receptor activity; TAS:ProtInc. DR GO; GO:0005019; F:platelet-derived growth factor beta-receptor activity; IDA:UniProtKB. DR GO; GO:0048407; F:platelet-derived growth factor binding; IDA:UniProtKB. DR GO; GO:0005017; F:platelet-derived growth factor receptor activity; TAS:ProtInc. DR GO; GO:0005161; F:platelet-derived growth factor receptor binding; IPI:BHF-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB. DR GO; GO:0038085; F:vascular endothelial growth factor binding; IPI:BHF-UCL. DR GO; GO:0001525; P:angiogenesis; IBA:GO_Central. DR GO; GO:0035909; P:aorta morphogenesis; ISS:BHF-UCL. DR GO; GO:0055003; P:cardiac myofibril assembly; ISS:UniProtKB. DR GO; GO:0060326; P:cell chemotaxis; IDA:UniProtKB. DR GO; GO:0060981; P:cell migration involved in coronary angiogenesis; ISS:UniProtKB. DR GO; GO:0035441; P:cell migration involved in vasculogenesis; ISS:UniProtKB. DR GO; GO:0007169; P:cell surface receptor protein tyrosine kinase signaling pathway; IBA:GO_Central. DR GO; GO:0072277; P:metanephric glomerular capillary formation; ISS:UniProtKB. DR GO; GO:0072262; P:metanephric glomerular mesangial cell proliferation involved in metanephros development; ISS:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB. DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0035791; P:platelet-derived growth factor receptor-beta signaling pathway; IMP:UniProtKB. DR GO; GO:0090280; P:positive regulation of calcium ion import; ISS:UniProtKB. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IMP:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:UniProtKB. DR GO; GO:0038091; P:positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0050921; P:positive regulation of chemotaxis; ISS:UniProtKB. DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; ISS:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB. DR GO; GO:0035793; P:positive regulation of metanephric mesenchymal cell migration by platelet-derived growth factor receptor-beta signaling pathway; ISS:UniProtKB. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISS:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:UniProtKB. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; ISS:UniProtKB. DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IMP:UniProtKB. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISS:BHF-UCL. DR GO; GO:0061298; P:retina vasculature development in camera-type eye; ISS:UniProtKB. DR GO; GO:0007165; P:signal transduction; IDA:UniProtKB. DR GO; GO:0014805; P:smooth muscle adaptation; NAS:BHF-UCL. DR GO; GO:0071670; P:smooth muscle cell chemotaxis; ISS:BHF-UCL. DR CDD; cd00096; Ig; 1. DR CDD; cd05859; Ig4_PDGFR; 1. DR CDD; cd05861; IgI_PDGFR-alphabeta; 1. DR CDD; cd05107; PTKc_PDGFR_beta; 1. DR FunFam; 3.30.200.20:FF:000025; Platelet-derived growth factor receptor alpha; 1. DR FunFam; 1.10.510.10:FF:000140; Platelet-derived growth factor receptor beta; 1. DR FunFam; 2.60.40.10:FF:000223; Platelet-derived growth factor receptor beta; 1. DR FunFam; 2.60.40.10:FF:000572; Platelet-derived growth factor receptor beta; 1. DR FunFam; 2.60.40.10:FF:000715; Platelet-derived growth factor receptor beta; 1. DR FunFam; 2.60.40.10:FF:000814; Platelet-derived growth factor receptor beta; 1. DR FunFam; 2.60.40.10:FF:000982; Platelet-derived growth factor receptor beta; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 5. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR003599; Ig_sub. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR013151; Immunoglobulin_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR027288; PGFRB. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR050122; RTK. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS. DR PANTHER; PTHR24416:SF53; PLATELET-DERIVED GROWTH FACTOR RECEPTOR BETA; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. DR Pfam; PF00047; ig; 1. DR Pfam; PF13927; Ig_3; 1. DR Pfam; PF25305; Ig_PDGFR_d4; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR PIRSF; PIRSF500948; Beta-PDGF_receptor; 1. DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1. DR PRINTS; PR01832; VEGFRECEPTOR. DR SMART; SM00409; IG; 3. DR SMART; SM00408; IGc2; 3. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF48726; Immunoglobulin; 3. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50835; IG_LIKE; 2. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; Chemotaxis; KW Chromosomal rearrangement; Cytoplasmic vesicle; Developmental protein; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Immunoglobulin domain; Kinase; Lysosome; Membrane; Nucleotide-binding; KW Phosphoprotein; Proteomics identification; Proto-oncogene; Receptor; KW Reference proteome; Repeat; Signal; Transferase; Transmembrane; KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation. FT SIGNAL 1..32 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 33..1106 FT /note="Platelet-derived growth factor receptor beta" FT /id="PRO_0000016757" FT TOPO_DOM 33..532 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 533..553 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 554..1106 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 33..120 FT /note="Ig-like C2-type 1" FT DOMAIN 129..210 FT /note="Ig-like C2-type 2" FT DOMAIN 214..309 FT /note="Ig-like C2-type 3" FT DOMAIN 331..403 FT /note="Ig-like C2-type 4" FT DOMAIN 416..524 FT /note="Ig-like C2-type 5" FT DOMAIN 600..962 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 1019..1106 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1043..1060 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1066..1088 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 826 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10028" FT BINDING 606..614 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 634 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305" FT SITE 527..528 FT /note="Breakpoint for insertion to form PDE4DIP-PDGFRB FT fusion protein" FT SITE 527..528 FT /note="Breakpoint for translocation to form TRIP11-PDGFRB" FT SITE 558..559 FT /note="Breakpoint for translocation to form the CEP85L- FT PDGFRB fusion protein" FT MOD_RES 562 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867" FT MOD_RES 579 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:14966296, FT ECO:0000269|PubMed:15902258, ECO:0000269|PubMed:7685273" FT MOD_RES 581 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15902258, FT ECO:0000269|PubMed:7685273" FT MOD_RES 686 FT /note="Phosphotyrosine; by ABL1 and ABL2" FT /evidence="ECO:0000250|UniProtKB:P05622" FT MOD_RES 716 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15902258" FT MOD_RES 740 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:1314164, FT ECO:0000269|PubMed:15902258" FT MOD_RES 751 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:14966296, FT ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:2550144" FT MOD_RES 763 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867" FT MOD_RES 771 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:14966296, FT ECO:0000269|PubMed:15902258" FT MOD_RES 775 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867" FT MOD_RES 778 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867" FT MOD_RES 857 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:15902258, FT ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:2550144" FT MOD_RES 934 FT /note="Phosphotyrosine; by ABL1 and ABL2" FT /evidence="ECO:0000250|UniProtKB:P05622" FT MOD_RES 970 FT /note="Phosphotyrosine; by ABL1 and ABL2" FT /evidence="ECO:0000250|UniProtKB:P05622" FT MOD_RES 1009 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867, FT ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:15902258" FT MOD_RES 1021 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:10821867, FT ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:14966296, FT ECO:0000269|PubMed:15902258" FT CARBOHYD 45 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 89 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 103 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 215 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 230 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 292 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 307 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20534510" FT CARBOHYD 354 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 371 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 468 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 479 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 54..100 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:20534510" FT DISULFID 149..190 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:20534510" FT DISULFID 235..291 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:20534510" FT DISULFID 436..508 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT VAR_SEQ 311..336 FT /note="VESGYVRLLGEVGTLQFAELHRSRTL -> RAATCGSWERWAHYNLLSCIGA FT GHCR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:18593464" FT /id="VSP_056008" FT VAR_SEQ 337..1106 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:18593464" FT /id="VSP_056009" FT VARIANT 29 FT /note="I -> F (in dbSNP:rs17110944)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_034377" FT VARIANT 180 FT /note="S -> F (in dbSNP:rs17853027)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_035125" FT VARIANT 282 FT /note="E -> K (in dbSNP:rs34586048)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042027" FT VARIANT 345 FT /note="P -> S (in dbSNP:rs2229558)" FT /id="VAR_049717" FT VARIANT 485 FT /note="E -> K (in dbSNP:rs41287110)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042028" FT VARIANT 561 FT /note="R -> C (in IMF1; dbSNP:rs367543286)" FT /evidence="ECO:0000269|PubMed:23731537" FT /id="VAR_069925" FT VARIANT 584 FT /note="P -> R (in KOGS; dbSNP:rs863224946)" FT /evidence="ECO:0000269|PubMed:25454926" FT /id="VAR_075865" FT VARIANT 589 FT /note="Y -> H (in a gastric adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042029" FT VARIANT 658 FT /note="L -> P (in IBGC4; no effect on protein abundance; FT loss of PDGF beta receptor activity; dbSNP:rs397509381)" FT /evidence="ECO:0000269|PubMed:23255827, FT ECO:0000269|PubMed:24065723, ECO:0000269|PubMed:26599395" FT /id="VAR_069320" FT VARIANT 660 FT /note="P -> T (in IMF1; dbSNP:rs144050370)" FT /evidence="ECO:0000269|PubMed:23731542" FT /id="VAR_069926" FT VARIANT 665 FT /note="V -> A (in PENTT; gain of function in protein FT tyrosine kinase activity; shows ligand-independent FT constitutive signaling; dbSNP:rs1554108211)" FT /evidence="ECO:0000269|PubMed:26279204" FT /id="VAR_075866" FT VARIANT 666 FT /note="N -> S (in PENTT; likely pathogenic; gain-of- FT function variant resulting in constitutive FT autophosphorylation and increased phosphorylation of FT downstream signaling proteins; levels of protein FT phosphorylation are similar at 32 and 37 degrees Celsius; FT dbSNP:rs2113894766)" FT /evidence="ECO:0000269|PubMed:30573803" FT /id="VAR_090402" FT VARIANT 666 FT /note="N -> Y (in OPDKD; likely pathogenic; gain-of- FT function variant resulting in temperature-dependent FT constitutive autophosphorylation and increased FT phosphorylation of downstream signaling proteins; levels of FT protein phosphorylation at 32 degrees Celsius are higher FT than at 37 degrees; dbSNP:rs797044887)" FT /evidence="ECO:0000269|PubMed:33450762" FT /id="VAR_090403" FT VARIANT 718 FT /note="N -> Y (in dbSNP:rs35322465)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042030" FT VARIANT 882 FT /note="T -> I (in a breast infiltrating ductal carcinoma FT sample; somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042031" FT VARIANT 987 FT /note="R -> W (in IBGC4; decreased protein abundance; no FT effect on receptor activity; decreased PDGF signaling FT pathway; dbSNP:rs397509382)" FT /evidence="ECO:0000269|PubMed:23255827, FT ECO:0000269|PubMed:24065723, ECO:0000269|PubMed:26599395" FT /id="VAR_069321" FT VARIANT 1071 FT /note="E -> V (in IBGC4; no effect on protein abundance; no FT effect on receptor activity; decreased PDGF signaling FT pathway)" FT /evidence="ECO:0000269|PubMed:24065723, FT ECO:0000269|PubMed:26599395" FT /id="VAR_075395" FT MUTAGEN 579 FT /note="Y->F: Loss of kinase activity; when associated with FT F-581. Strongly reduces interaction with SRC family FT kinases. No effect on interaction with GRB10." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:7685273" FT MUTAGEN 581 FT /note="Y->F: Loss of kinase activity; when associated with FT F-579. No effect on interaction with GRB10." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:7685273" FT MUTAGEN 634 FT /note="K->A,R: Loss of kinase activity. Abolishes FT interaction with RASA1. No effect on phosphatidylinositol FT 3-kinase activity." FT /evidence="ECO:0000269|PubMed:1314164, FT ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825" FT MUTAGEN 716 FT /note="Y->F: No effect neither on interaction with GRB10 FT and RASA1 nor on phosphatidylinositol 3-kinase activity." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1314164" FT MUTAGEN 740 FT /note="Y->F: Strongly reduces up-regulation of cell FT proliferation; when associated with F-751. Strongly FT decreases phosphatidylinositol 3-kinase activity. No effect FT on interaction with GRB10 and RASA1." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1375321, FT ECO:0000269|PubMed:21679854" FT MUTAGEN 751 FT /note="Y->F: Strongly reduces up-regulation of cell FT proliferation; when associated with F-740. Abolishes FT phosphatidylinositol 3-kinase activity and interaction with FT NCK1, and slightly reduces interaction with RASA1. No FT effect on interaction with GRB10." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1375321, FT ECO:0000269|PubMed:1653029, ECO:0000269|PubMed:21679854, FT ECO:0000269|PubMed:7692233" FT MUTAGEN 763 FT /note="Y->F: No effect on interaction with RASA1 and on FT phosphatidylinositol 3-kinase activity." FT /evidence="ECO:0000269|PubMed:1314164" FT MUTAGEN 771 FT /note="Y->F: Loss of interaction with GRB10. Abolishes FT interaction with RASA1. No effect on phosphatidylinositol FT 3-kinase activity." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1375321" FT MUTAGEN 775 FT /note="Y->F: No effect on interaction with RASA1 and on FT phosphatidylinositol 3-kinase activity." FT /evidence="ECO:0000269|PubMed:1314164" FT MUTAGEN 778 FT /note="Y->F: Strongly reduces expression levels." FT /evidence="ECO:0000269|PubMed:1314164" FT MUTAGEN 857 FT /note="Y->F: Reduces kinase activity. No effect on FT interaction with GRB10. Abolishes interaction with RASA1. FT No effect on phosphatidylinositol 3-kinase activity." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1653029, FT ECO:0000269|PubMed:20494825" FT MUTAGEN 1009 FT /note="Y->F: No effect on interaction with GRB10. Abolishes FT interaction with PLCG1; when associated with F-1021." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:7691811" FT MUTAGEN 1021 FT /note="Y->F: Strongly reduces up-regulation of cell FT proliferation. Abolishes interaction with PLCG1; when FT associated with F-1009. No effect on interaction with FT GRB10." FT /evidence="ECO:0000269|PubMed:10454568, FT ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:17620338, FT ECO:0000269|PubMed:21679854" FT CONFLICT 241 FT /note="E -> D (in Ref. 2; AAA36427)" FT /evidence="ECO:0000305" FT STRAND 40..43 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 50..58 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 61..64 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 70..75 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 81..87 FT /evidence="ECO:0007829|PDB:3MJG" FT HELIX 92..94 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 96..101 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 114..119 FT /evidence="ECO:0007829|PDB:3MJG" FT HELIX 132..135 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 136..141 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 158..164 FT /evidence="ECO:0007829|PDB:3MJG" FT TURN 175..177 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 178..181 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 185..194 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 197..200 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 204..208 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 217..221 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 223..226 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 231..239 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 241..248 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 252..255 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 261..265 FT /evidence="ECO:0007829|PDB:3MJG" FT TURN 267..270 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 271..280 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 287..295 FT /evidence="ECO:0007829|PDB:3MJG" FT TURN 296..299 FT /evidence="ECO:0007829|PDB:3MJG" FT STRAND 300..311 FT /evidence="ECO:0007829|PDB:3MJG" FT HELIX 530..556 FT /evidence="ECO:0007829|PDB:2L6W" SQ SEQUENCE 1106 AA; 123968 MW; 038C15E531D6E89D CRC64; MRLPGAMPAL ALKGELLLLS LLLLLEPQIS QGLVVTPPGP ELVLNVSSTF VLTCSGSAPV VWERMSQEPP QEMAKAQDGT FSSVLTLTNL TGLDTGEYFC THNDSRGLET DERKRLYIFV PDPTVGFLPN DAEELFIFLT EITEITIPCR VTDPQLVVTL HEKKGDVALP VPYDHQRGFS GIFEDRSYIC KTTIGDREVD SDAYYVYRLQ VSSINVSVNA VQTVVRQGEN ITLMCIVIGN EVVNFEWTYP RKESGRLVEP VTDFLLDMPY HIRSILHIPS AELEDSGTYT CNVTESVNDH QDEKAINITV VESGYVRLLG EVGTLQFAEL HRSRTLQVVF EAYPPPTVLW FKDNRTLGDS SAGEIALSTR NVSETRYVSE LTLVRVKVAE AGHYTMRAFH EDAEVQLSFQ LQINVPVRVL ELSESHPDSG EQTVRCRGRG MPQPNIIWSA CRDLKRCPRE LPPTLLGNSS EEESQLETNV TYWEEEQEFE VVSTLRLQHV DRPLSVRCTL RNAVGQDTQE VIVVPHSLPF KVVVISAILA LVVLTIISLI ILIMLWQKKP RYEIRWKVIE SVSSDGHEYI YVDPMQLPYD STWELPRDQL VLGRTLGSGA FGQVVEATAH GLSHSQATMK VAVKMLKSTA RSSEKQALMS ELKIMSHLGP HLNVVNLLGA CTKGGPIYII TEYCRYGDLV DYLHRNKHTF LQHHSDKRRP PSAELYSNAL PVGLPLPSHV SLTGESDGGY MDMSKDESVD YVPMLDMKGD VKYADIESSN YMAPYDNYVP SAPERTCRAT LINESPVLSY MDLVGFSYQV ANGMEFLASK NCVHRDLAAR NVLICEGKLV KICDFGLARD IMRDSNYISK GSTFLPLKWM APESIFNSLY TTLSDVWSFG ILLWEIFTLG GTPYPELPMN EQFYNAIKRG YRMAQPAHAS DEIYEIMQKC WEEKFEIRPP FSQLVLLLER LLGEGYKKKY QQVDEEFLRS DHPAILRSQA RLPGFHGLRS PLDTSSVLYT AVQPNEGDND YIIPLPDPKP EVADEGPLEG SPSLASSTLN EVNTSSTISC DSPLEPQDEP EPEPQLELQV EPEPELEQLP DSGCPAPRAE AEDSFL // ID PINK1_HUMAN Reviewed; 581 AA. AC Q9BXM7; Q8N6T9; Q8NBU3; Q96DE4; DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 212. DE RecName: Full=Serine/threonine-protein kinase PINK1, mitochondrial; DE EC=2.7.11.1 {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:32484300}; DE AltName: Full=BRPK; DE AltName: Full=PTEN-induced putative kinase protein 1; DE Flags: Precursor; GN Name=PINK1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAK28062.1}; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Endometrium {ECO:0000269|PubMed:11494141}; RX PubMed=11494141; DOI=10.1038/sj.onc.1204608; RA Unoki M., Nakamura Y.; RT "Growth-suppressive effects of BPOZ and EGR2, two genes involved in the RT PTEN signaling pathway."; RL Oncogene 20:4457-4465(2001). RN [2] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND AUTOPHOSPHORYLATION. RC TISSUE=Placenta {ECO:0000312|EMBL:AAK28062.1}; RX PubMed=14607334; DOI=10.1016/s0304-3835(03)00443-9; RA Nakajima A., Kataoka K., Hong M., Sakaguchi M., Huh N.-H.; RT "BRPK, a novel protein kinase showing increased expression in mouse cancer RT cell lines with higher metastatic potential."; RL Cancer Lett. 201:195-201(2003). RN [3] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANTS THR-340 RP AND THR-521. RC TISSUE=Placenta {ECO:0000312|EMBL:BAC11484.1}; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Leukocyte {ECO:0000312|EMBL:AAH28215.1}, and RC Lung {ECO:0000312|EMBL:AAH09534.1}; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP SUBCELLULAR LOCATION. RX PubMed=16672980; DOI=10.1038/nature04788; RA Park J., Lee S.B., Lee S., Kim Y., Song S., Kim S., Bae E., Kim J., RA Shong M., Kim J.M., Chung J.; RT "Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by RT parkin."; RL Nature 441:1157-1161(2006). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND RP MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [8] RP FUNCTION. RX PubMed=18443288; DOI=10.1073/pnas.0711845105; RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RT "Pink1 regulates mitochondrial dynamics through interaction with the RT fission/fusion machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 105:7070-7075(2008). RN [9] RP ERRATUM OF PUBMED:18443288. RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RT "Pink1 regulates mitochondrial dynamics through interaction with the RT fission/fusion machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 105:17585-17585(2008). RN [10] RP SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY. RX PubMed=18687899; DOI=10.1073/pnas.0802814105; RA Zhou C., Huang Y., Shao Y., May J., Prou D., Perier C., Dauer W., RA Schon E.A., Przedborski S.; RT "The kinase domain of mitochondrial PINK1 faces the cytoplasm."; RL Proc. Natl. Acad. Sci. U.S.A. 105:12022-12027(2008). RN [11] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, CHARACTERIZATION OF VARIANTS RP PARK6 ASP-309 AND MET-313, AND CHARACTERIZATION OF VARIANT LEU-399. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [12] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PRKN, AND CHARACTERIZATION OF VARIANTS PARK6 PRO-126; ASP-309 AND PRO-347. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [13] RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 492-ARG--LYS-581 DEL. RX PubMed=20547144; DOI=10.1016/j.brainres.2010.06.005; RA Yuan X.L., Guo J.F., Shi Z.H., Xiao Z.Q., Yan X.X., Zhao B.L., Tang B.S.; RT "R492X mutation in PTEN-induced putative kinase 1 induced cellular RT mitochondrial dysfunction and oxidative stress."; RL Brain Res. 1351:229-237(2010). RN [14] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND PHOSPHORYLATION. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [15] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND INTERACTION WITH PRKN. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [16] RP INVOLVEMENT IN PARK6. RX PubMed=22043288; DOI=10.1371/journal.pone.0025622; RA Abramov A.Y., Gegg M., Grunewald A., Wood N.W., Klein C., Schapira A.H.; RT "Bioenergetic consequences of PINK1 mutations in Parkinson disease."; RL PLoS ONE 6:E25622-E25622(2011). RN [17] RP PROTEOLYTIC CLEAVAGE, AND SUBCELLULAR LOCATION. RX PubMed=22354088; DOI=10.1038/embor.2012.14; RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R., RA Haque M.E., McBride H.M., Park D.S., Fon E.A.; RT "Mitochondrial processing peptidase regulates PINK1 processing, import and RT Parkin recruitment."; RL EMBO Rep. 13:378-385(2012). RN [18] RP PHOSPHORYLATION AT SER-228 AND SER-402. RX PubMed=22910362; DOI=10.1038/ncomms2016; RA Okatsu K., Oka T., Iguchi M., Imamura K., Kosako H., Tani N., Kimura M., RA Go E., Koyano F., Funayama M., Shiba-Fukushima K., Sato S., Shimizu H., RA Fukunaga Y., Taniguchi H., Komatsu M., Hattori N., Mihara K., Tanaka K., RA Matsuda N.; RT "PINK1 autophosphorylation upon membrane potential dissipation is essential RT for Parkin recruitment to damaged mitochondria."; RL Nat. Commun. 3:1016-1016(2012). RN [19] RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 PRO-347. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [20] RP FUNCTION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [22] RP FUNCTION IN MITOPHAGY, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [23] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [24] RP FUNCTION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [25] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANTS PARK6 RP PRO-168 AND ALA-386. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [27] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [28] RP FUNCTION. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [29] RP VARIANTS PARK6 GLY-170 AND 456-GLN--LEU-581 DEL. RX PubMed=24652937; DOI=10.1126/science.1249161; RA Morais V.A., Haddad D., Craessaerts K., De Bock P.J., Swerts J., Vilain S., RA Aerts L., Overbergh L., Gruenewald A., Seibler P., Klein C., Gevaert K., RA Verstreken P., De Strooper B.; RT "PINK1 loss-of-function mutations affect mitochondrial complex I activity RT via NdufA10 ubiquinone uncoupling."; RL Science 344:203-207(2014). RN [30] RP FUNCTION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [31] RP PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 112-GLU--GLU-117. RX PubMed=30733118; DOI=10.1016/j.molcel.2019.01.002; RA Sekine S., Wang C., Sideris D.P., Bunker E., Zhang Z., Youle R.J.; RT "Reciprocal roles of Tom7 and OMA1 during mitochondrial import and RT activation of PINK1."; RL Mol. Cell 73:1028-1043(2019). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH NENF, AND SUBCELLULAR RP LOCATION. RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057; RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A., RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J., RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G., RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y., RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.; RT "Rewiring of the Human Mitochondrial Interactome during Neuronal RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis."; RL IScience 19:1114-1132(2019). RN [33] RP FUNCTION, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [34] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLY-309 AND ASP-384, AND RP CHARACTERIZATION OF VARIANTS ASP-309; MET-313 AND 492-ARG--LYS-581 DEL. RX PubMed=32484300; DOI=10.15252/embr.201948686; RA Han H., Tan J., Wang R., Wan H., He Y., Yan X., Guo J., Gao Q., Li J., RA Shang S., Chen F., Tian R., Liu W., Liao L., Tang B., Zhang Z.; RT "PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent RT mitochondrial dynamics."; RL EMBO Rep. 21:48686-48686(2020). RN [35] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=29123128; DOI=10.1038/s41467-017-01435-1; RA Huang E., Qu D., Huang T., Rizzi N., Boonying W., Krolak D., Ciana P., RA Woulfe J., Klein C., Slack R.S., Figeys D., Park D.S.; RT "PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium RT transport and protects neurons against mitochondrial stress."; RL Nat. Commun. 8:1399-1399(2017). RN [36] RP INTERACTION WITH TOMM70. RX PubMed=35391620; DOI=10.1007/s00109-022-02191-6; RA Maruszczak K.K., Jung M., Rasool S., Trempe J.F., Rapaport D.; RT "The role of the individual TOM subunits in the association of PINK1 with RT depolarized mitochondria."; RL J. Mol. Med. 100:747-762(2022). RN [37] RP INTERACTION WITH TIMM23, AND CHARACTERIZATION OF VARIANTS LEU-52; PHE-67; RP PRO-68; VAL-78; PHE-92; TRP-98; SER-111; LEU-115; VAL-124; GLY-125; RP PRO-126; MET-145; HIS-147; TRP-148; PRO-168; LYS-240; GLN-271; ASP-309; RP PRO-347; ALA-386; VAL-409; GLY-417 AND GLN-534 INS. RX PubMed=37160114; DOI=10.1016/j.celrep.2023.112454; RA Akabane S., Watanabe K., Kosako H., Yamashita S.I., Nishino K., Kato M., RA Sekine S., Kanki T., Matsuda N., Endo T., Oka T.; RT "TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated RT degradation in damaged mitochondria."; RL Cell Rep. 42:112454-112454(2023). RN [38] RP INTERACTION WITH TOM AND TIM23 COMPLEXES, INTERACTION WITH TOMM20, RP MUTAGENESIS OF ILE-131; ALA-536; LEU-540 AND ARG-543, AND CHARACTERIZATION RP OF VARIANTS SER-111; LEU-115; GLY-125 AND PRO-126. RX PubMed=38416681; DOI=10.1073/pnas.2313540121; RA Eldeeb M.A., Bayne A.N., Fallahi A., Goiran T., MacDougall E.J., RA Soumbasis A., Zorca C.E., Tabah J.J., Thomas R.A., Karpilovsky N., RA Mathur M., Durcan T.M., Trempe J.F., Fon E.A.; RT "Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 RT translocases upon mitochondrial stress."; RL Proc. Natl. Acad. Sci. U.S.A. 121:e2313540121-e2313540121(2024). RN [39] RP INTERACTION WITH TOMM20, MUTAGENESIS OF LEU-532; LEU-539 AND LEU-540, AND RP CHARACTERIZATION OF VARIANTS PRO-126; LYS-240; ASP-309 AND GLN-534 INS. RX PubMed=38848361; DOI=10.1126/sciadv.adn7191; RA Raimi O.G., Ojha H., Ehses K., Dederer V., Lange S.M., Rivera C.P., RA Deegan T.D., Chen Y., Wightman M., Toth R., Labib K.P.M., Mathea S., RA Ranson N., Fernandez-Busnadiego R., Muqit M.M.K.; RT "Mechanism of human PINK1 activation at the TOM complex in a reconstituted RT system."; RL Sci. Adv. 10:Eadn7191-Eadn7191(2024). RN [40] {ECO:0007744|PDB:9EIH, ECO:0007744|PDB:9EII, ECO:0007744|PDB:9EIJ} RP STRUCTURE BY ELECTRON MICROSCOPY (2.75 ANGSTROMS) IN COMPLEX WITH VDAC2 AND RP THE TOM COMPLEX, FUNCTION, INTERACTION WITH VDAC2 AND THE TOM COMPLEX, AND RP SUBCELLULAR LOCATION. RX PubMed=40080546; DOI=10.1126/science.adu6445; RA Callegari S., Kirk N.S., Gan Z.Y., Dite T., Cobbold S.A., Leis A., RA Dagley L.F., Glukhova A., Komander D.; RT "Structure of human PINK1 at a mitochondrial TOM-VDAC array."; RL Science 0:0-0(2025). RN [41] RP VARIANTS PARK6 PHE-92; PRO-168 AND HIS-464, AND VARIANTS LEU-296; THR-340; RP THR-442; LYS-476; THR-521 AND ASN-525. RX PubMed=15349860; DOI=10.1002/ana.20256; RA Valente E.M., Salvi S., Ialongo T., Marongiu R., Elia A.E., Caputo V., RA Romito L., Albanese A., Dallapiccola B., Bentivoglio A.R.; RT "PINK1 mutations are associated with sporadic early-onset parkinsonism."; RL Ann. Neurol. 56:336-341(2004). RN [42] RP VARIANTS PARK6 GLN-271; PRO-347 AND GLY-417. RX PubMed=15349870; DOI=10.1002/ana.20251; RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H., RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R., RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.; RT "Novel PINK1 mutations in early-onset parkinsonism."; RL Ann. Neurol. 56:424-427(2004). RN [43] RP ERRATUM OF PUBMED:15349870. RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H., RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R., RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.; RL Ann. Neurol. 56:603-603(2004). RN [44] RP VARIANTS PARK6 LYS-240; PRO-347 AND PRO-489, AND VARIANTS GLY-231; ILE-235; RP GLY-263; LEU-318; THR-339; THR-340; HIS-362; SER-425; LYS-476 AND THR-521. RX PubMed=15596610; DOI=10.1001/archneur.61.12.1898; RA Rogaeva E., Johnson J., Lang A.E., Gulick C., Gwinn-Hardy K., Kawarai T., RA Sato C., Morgan A., Werner J., Nussbaum R., Petit A., Okun M.S., RA McInerney A., Mandel R., Groen J.L., Fernandez H.H., Postuma R., RA Foote K.D., Salehi-Rad S., Liang Y., Reimsnider S., Tandon A., Hardy J., RA St George-Hyslop P., Singleton A.B.; RT "Analysis of the PINK1 gene in a large cohort of cases with Parkinson RT disease."; RL Arch. Neurol. 61:1898-1904(2004). RN [45] RP VARIANT PARK6 HIS-147. RX PubMed=15505171; DOI=10.1212/01.wnl.0000142089.38301.8e; RA Healy D.G., Abou-Sleiman P.M., Gibson J.M., Ross O.A., Jain S., Gandhi S., RA Gosal D., Muqit M.M.K., Wood N.W., Lynch T.; RT "PINK1 (PARK6) associated Parkinson disease in Ireland."; RL Neurology 63:1486-1488(2004). RN [46] RP VARIANT PARK6 ASP-309, CHARACTERIZATION OF VARIANT PARK6 ASP-309, FUNCTION, RP AND SUBCELLULAR LOCATION. RX PubMed=15087508; DOI=10.1126/science.1096284; RA Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M.K., Harvey K., RA Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., RA Albanese A., Nussbaum R., Gonzalez-Maldonado R., Deller T., Salvi S., RA Cortelli P., Gilks W.P., Latchman D.S., Harvey R.J., Dallapiccola B., RA Auburger G., Wood N.W.; RT "Hereditary early-onset Parkinson's disease caused by mutations in PINK1."; RL Science 304:1158-1160(2004). RN [47] RP VARIANT PARK6 VAL-268. RX PubMed=16207217; DOI=10.1111/j.1399-0004.2005.00500.x; RA Tan E.K., Yew K., Chua E., Shen H., Jamora R.D., Lee E., Puong K.Y., RA Zhao Y., Pavanni R., Wong M.C., Puvan K., Yih Y., Tan L.C.S.; RT "Analysis of PINK1 in Asian patients with familial parkinsonism."; RL Clin. Genet. 68:468-470(2005). RN [48] RP VARIANTS PARK6 HIS-279 AND GLN-534 INS, AND VARIANT LEU-115. RX PubMed=15970950; DOI=10.1038/sj.ejhg.5201455; RA Klein C., Djarmati A., Hedrich K., Schaefer N., Scaglione C., Marchese R., RA Kock N., Schuele B., Hiller A., Lohnau T., Winkler S., Wiegers K., RA Hering R., Bauer P., Riess O., Abbruzzese G., Martinelli P., RA Pramstaller P.P.; RT "PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset RT parkinsonism."; RL Eur. J. Hum. Genet. 13:1086-1093(2005). RN [49] RP CHARACTERIZATION OF VARIANTS PARK6 PRO-168 AND ASP-309. RX PubMed=16207731; DOI=10.1093/hmg/ddi377; RA Silvestri L., Caputo V., Bellacchio E., Atorino L., Dallapiccola B., RA Valente E.M., Casari G.; RT "Mitochondrial import and enzymatic activity of PINK1 mutants associated to RT recessive parkinsonism."; RL Hum. Mol. Genet. 14:3477-3492(2005). RN [50] RP VARIANT PARK6 ARG-388. RX PubMed=15955953; DOI=10.1212/01.wnl.0000164009.36740.4e; RA Li Y., Tomiyama H., Sato K., Hatano Y., Yoshino H., Atsumi M., RA Kitaguchi M., Sasaki S., Kawaguchi S., Miyajima H., Toda T., Mizuno Y., RA Hattori N.; RT "Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset RT parkinsonism."; RL Neurology 64:1955-1957(2005). RN [51] RP VARIANTS PARK6 PRO-168 AND LEU-196, AND VARIANTS LEU-115; THR-340; LYS-476 RP AND THR-521. RX PubMed=16009891; DOI=10.1212/01.wnl.0000167546.39375.82; RG The Italian Parkinson genetics network; RA Bonifati V., Rohe C.F., Breedveld G.J., Fabrizio E., De Mari M., RA Tassorelli C., Tavella A., Marconi R., Nicholl D.J., Chien H.F., RA Fincati E., Abbruzzese G., Marini P., De Gaetano A., Horstink M.W., RA Maat-Kievit J.A., Sampaio C., Antonini A., Stocchi F., Montagna P., RA Toni V., Guidi M., Dalla Libera A., Tinazzi M., De Pandis F., Fabbrini G., RA Goldwurm S., de Klein A., Barbosa E., Lopiano L., Martignoni E., RA Lamberti P., Vanacore N., Meco G., Oostra B.A.; RT "Early-onset parkinsonism associated with PINK1 mutations: frequency, RT genotypes, and phenotypes."; RL Neurology 65:87-95(2005). RN [52] RP VARIANTS ILE-317; THR-339; THR-383; SER-411; HIS-431; SER-451; SER-461; RP LYS-476; PRO-501 AND ARG-575, AND CHARACTERIZATION OF VARIANTS HIS-431; RP SER-451; LYS-476; PRO-501 AND ARG-575. RX PubMed=16969854; DOI=10.1002/ana.20960; RA Abou-Sleiman P.M., Muqit M.M.K., McDonald N.Q., Yang Y.X., Gandhi S., RA Healy D.G., Harvey K., Harvey R.J., Deas E., Bhatia K., Quinn N., Lees A., RA Latchman D.S., Wood N.W.; RT "A heterozygous effect for PINK1 mutations in Parkinson's disease?"; RL Ann. Neurol. 60:414-419(2006). RN [53] RP VARIANT PARK6 ASP-217. RX PubMed=16966503; DOI=10.1001/archneur.63.9.1257; RA Leutenegger A.-L., Salih M.A.M., Ibanez P., Mukhtar M.M., Lesage S., RA Arabi A., Lohmann E., Duerr A., Ahmed A.E.M., Brice A.; RT "Juvenile-onset Parkinsonism as a result of the first mutation in the RT adenosine triphosphate orientation domain of PINK1."; RL Arch. Neurol. 63:1257-1261(2006). RN [54] RP VARIANT PARK6 MET-313. RX PubMed=17030667; DOI=10.1001/archneur.63.10.1483; RA Chishti M.A., Bohlega S., Ahmed M., Loualich A., Carroll P., Sato C., RA St George-Hyslop P., Westaway D., Rogaeva E.; RT "T313M PINK1 mutation in an extended highly consanguineous Saudi family RT with early-onset Parkinson disease."; RL Arch. Neurol. 63:1483-1485(2006). RN [55] RP VARIANTS PARK6 GLY-125; LYS-240; PRO-369; ALA-386 AND VAL-409. RX PubMed=16401616; DOI=10.1093/brain/awl005; RG The French Parkinson's disease genetics study group; RA Ibanez P., Lesage S., Lohmann E., Thobois S., De Michele G., Borg M., RA Agid Y., Durr A., Brice A.; RT "Mutational analysis of the PINK1 gene in early-onset parkinsonism in RT Europe and North Africa."; RL Brain 129:686-694(2006). RN [56] RP VARIANT LEU-399. RX PubMed=16632486; DOI=10.1093/hmg/ddl104; RA Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q., RA Xia J.-H., Xia K., Zhang Z.; RT "Association of PINK1 and DJ-1 confers digenic inheritance of early-onset RT Parkinson's disease."; RL Hum. Mol. Genet. 15:1816-1825(2006). RN [57] RP VARIANT PARK6 THR-280, AND VARIANTS THR-340 AND THR-521. RX PubMed=16482571; DOI=10.1002/mds.20810; RA Tan E.-K., Yew K., Chua E., Puvan K., Shen H., Lee E., Puong K.-Y., RA Zhao Y., Pavanni R., Wong M.-C., Jamora D., de Silva D., Moe K.-T., RA Woon F.-P., Yuen Y., Tan L.; RT "PINK1 mutations in sporadic early-onset Parkinson's disease."; RL Mov. Disord. 21:789-793(2006). RN [58] RP VARIANT PARK6 GLN-407, AND VARIANTS THR-340 AND THR-521. RX PubMed=16257123; DOI=10.1016/j.neulet.2005.10.005; RA Fung H.-C., Chen C.-M., Hardy J., Singleton A.B., Lee-Chen G.-J., Wu Y.-R.; RT "Analysis of the PINK1 gene in a cohort of patients with sporadic early- RT onset parkinsonism in Taiwan."; RL Neurosci. Lett. 394:33-36(2006). RN [59] RP VARIANTS [LARGE SCALE ANALYSIS] TRP-148; SER-196; LEU-209; LEU-215; RP THR-339; THR-340; ILE-341; PHE-377; THR-477 AND THR-521. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [60] RP VARIANTS PHE-67; PRO-68; TRP-98; SER-111; VAL-124; MET-145; ASN-186; RP ILE-257; VAL-268; GLN-276; LEU-296; ILE-317; LEU-322; THR-339; THR-383; RP VAL-395; THR-442; LYS-476; ASN-525 AND THR-537. RX PubMed=18330912; DOI=10.1002/humu.20719; RG The Italian PD study group; RA Marongiu R., Ferraris A., Ialongo T., Michiorri S., Soleti F., Ferrari F., RA Elia A.E., Ghezzi D., Albanese A., Altavista M.C., Antonini A., Barone P., RA Brusa L., Cortelli P., Martinelli P., Pellecchia M.T., Pezzoli G., RA Scaglione C., Stanzione P., Tinazzi M., Zecchinelli A., Zeviani M., RA Cassetta E., Garavaglia B., Dallapiccola B., Bentivoglio A.R., RA Valente E.M.; RT "PINK1 heterozygous rare variants: prevalence, significance and phenotypic RT spectrum."; RL Hum. Mutat. 29:565-565(2008). RN [61] RP VARIANT PARK6 PRO-126. RX PubMed=18286320; DOI=10.1007/s00415-008-0763-4; RA Prestel J., Gempel K., Hauser T.K., Schweitzer K., Prokisch H., Ahting U., RA Freudenstein D., Bueltmann E., Naegele T., Berg D., Klopstock T., RA Gasser T.; RT "Clinical and molecular characterisation of a Parkinson family with a novel RT PINK1 mutation."; RL J. Neurol. 255:643-648(2008). RN [62] RP VARIANTS PARK6 MET-313 AND 492-ARG--LYS-581 DEL. RX PubMed=18785233; DOI=10.1002/mds.22156; RA Guo J.F., Xiao B., Liao B., Zhang X.W., Nie L.L., Zhang Y.H., Shen L., RA Jiang H., Xia K., Pan Q., Yan X.X., Tang B.S.; RT "Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese RT patients with autosomal recessive early-onset Parkinsonism."; RL Mov. Disord. 23:2074-2079(2008). RN [63] RP VARIANT PARK6 LEU-52. RX PubMed=19351622; DOI=10.1136/jmg.2008.063917; RA Brooks J., Ding J., Simon-Sanchez J., Paisan-Ruiz C., Singleton A.B., RA Scholz S.W.; RT "Parkin and PINK1 mutations in early-onset Parkinson's disease: RT comprehensive screening in publicly available cases and control."; RL J. Med. Genet. 46:375-381(2009). RN [64] RP VARIANT PARK6 PRO-347. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). CC -!- FUNCTION: Serine/threonine-protein kinase which acts as a sensor of CC mitochondrial damage and protects against mitochondrial dysfunction CC during cellular stress (PubMed:40080546). It phosphorylates CC mitochondrial proteins to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:14607334, PubMed:15087508, PubMed:18443288, CC PubMed:18957282, PubMed:19229105, PubMed:19966284, PubMed:20404107, CC PubMed:20547144, PubMed:20798600, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, CC PubMed:24784582, PubMed:24896179, PubMed:24898855, PubMed:25527291, CC PubMed:32484300). In healthy mitochondria, PINK1 is translocated across CC the mitochondrial outer membrane (MOM) via the translocase of the outer CC membrane (TOM) complex, and inserted into the mitochondrial inner CC membrane (MIM) via the translocase of the inner membrane (TIM23) CC complex where it is cleaved and released into the cytosol CC (PubMed:40080546). Depending on the severity of mitochondrial damage, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to eliminating severely damaged mitochondria via PINK1-PRKN- CC dependent mitophagy (PubMed:14607334, PubMed:15087508, PubMed:18443288, CC PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24898855, PubMed:32047033, CC PubMed:32484300). When cellular stress results in irreversible CC mitochondrial damage, PINK1 accumulates at the outer mitochondrial CC membrane (OMM) where it phosphorylates pre-existing polyubiquitin CC chains at 'Ser-65', recruits PRKN from the cytosol to the OMM and CC activates PRKN by phosphorylation at 'Ser-65'; activated PRKN then CC ubiquitinates VDAC1 and other OMM proteins to initiate mitophagy CC (PubMed:14607334, PubMed:15087508, PubMed:19966284, PubMed:20404107, CC PubMed:20798600, PubMed:23754282, PubMed:23933751, PubMed:24660806, CC PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291, CC PubMed:32047033, PubMed:40080546). The PINK1-PRKN pathway also promotes CC fission of damaged mitochondria through phosphorylation and PRKN- CC dependent degradation of mitochondrial proteins involved in fission CC such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855). This CC prevents the refusion of unhealthy mitochondria with the mitochondrial CC network or initiates mitochondrial fragmentation facilitating their CC later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051). CC Also promotes mitochondrial fission independently of PRKN and ATG7- CC mediated mitophagy, via the phosphorylation and activation of DNM1L CC (PubMed:18443288, PubMed:32484300). Regulates motility of damaged CC mitochondria by promoting the ubiquitination and subsequent degradation CC of MIRO1 and MIRO2; in motor neurons, this likely inhibits CC mitochondrial intracellular anterograde transport along the axons which CC probably increases the chance of the mitochondria undergoing mitophagy CC in the soma (PubMed:22396657). Required for ubiquinone reduction by CC mitochondrial complex I by mediating phosphorylation of complex I CC subunit NDUFA10 (By similarity). Phosphorylates LETM1, positively CC regulating its mitochondrial calcium transport activity CC (PubMed:29123128). {ECO:0000250|UniProtKB:Q99MQ3, CC ECO:0000269|PubMed:14607334, ECO:0000269|PubMed:15087508, CC ECO:0000269|PubMed:18443288, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20547144, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:24898855, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:32484300, ECO:0000269|PubMed:40080546}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:32484300}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32484300}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC -!- SUBUNIT: Upon mitochondrial depolarization, associates with the TOM CC complex and the VDAC2 homodimer; its import into the mitochondria is CC stalled at the TOM complex (PubMed:40080546). Upon mitochondrial CC depolarization, interacts with TIMM23 (PubMed:38416681). Forms a CC supercomplex with TOM and TIM23 complexes; PINK1-TOM-TIM23 supercomplex CC formation requires PINK1 interaction with TOMM20 and TOMM70 CC (PubMed:38416681). The interaction with TOM and TIM23 complexes is CC critical for PINK1 stabilization at the outer mitochondrial membrane, CC kinase activation and downstream mitophagy (PubMed:35391620, CC PubMed:38416681, PubMed:38848361, PubMed:40080546). Interacts with PRKN CC (PubMed:19966284, PubMed:20798600). Interacts with FBXO7 CC (PubMed:23933751). Forms a complex with PRKN and PARK7 CC (PubMed:19229105). Interacts with NENF (PubMed:31536960). CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:31536960, ECO:0000269|PubMed:35391620, CC ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681, CC ECO:0000269|PubMed:38848361, ECO:0000269|PubMed:40080546}. CC -!- INTERACTION: CC Q9BXM7; P63010-2: AP2B1; NbExp=3; IntAct=EBI-2846068, EBI-11529439; CC Q9BXM7; P05067: APP; NbExp=3; IntAct=EBI-2846068, EBI-77613; CC Q9BXM7; O15392: BIRC5; NbExp=3; IntAct=EBI-2846068, EBI-518823; CC Q9BXM7; Q9Y3I1: FBXO7; NbExp=8; IntAct=EBI-2846068, EBI-1161222; CC Q9BXM7; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-2846068, EBI-9102965; CC Q9BXM7; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-2846068, EBI-396453; CC Q9BXM7; P08238: HSP90AB1; NbExp=3; IntAct=EBI-2846068, EBI-352572; CC Q9BXM7; P42858: HTT; NbExp=9; IntAct=EBI-2846068, EBI-466029; CC Q9BXM7; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-2846068, EBI-21911304; CC Q9BXM7; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-2846068, EBI-1108377; CC Q9BXM7; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-2846068, EBI-373144; CC Q9BXM7; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-2846068, EBI-716063; CC Q9BXM7; P00491: PNP; NbExp=3; IntAct=EBI-2846068, EBI-712238; CC Q9BXM7; O60260: PRKN; NbExp=7; IntAct=EBI-2846068, EBI-716346; CC Q9BXM7; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-2846068, EBI-1396430; CC Q9BXM7; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-2846068, EBI-3942425; CC Q9BXM7; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-2846068, EBI-11959123; CC Q9BXM7; P28347-2: TEAD1; NbExp=3; IntAct=EBI-2846068, EBI-12151837; CC Q9BXM7; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-2846068, EBI-11141397; CC Q9BXM7; Q8N895: ZNF366; NbExp=3; IntAct=EBI-2846068, EBI-2813661; CC Q9BXM7-1; O60260: PRKN; NbExp=2; IntAct=EBI-15643376, EBI-716346; CC Q9BXM7-1; Q12931: TRAP1; NbExp=4; IntAct=EBI-15643376, EBI-1055869; CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:16672980, CC ECO:0000269|PubMed:18687899, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:31536960}. CC Mitochondrion inner membrane {ECO:0000250|UniProtKB:Q99MQ3}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22354088}. CC Note=Localizes mostly in mitochondrion and the two smaller proteolytic CC processed fragments localize mainly in cytosol (PubMed:19229105). In CC healthy mitochondria, PINK1 is translocated across the mitochondrial CC membranes (PubMed:40080546). Upon mitochondrial membrane depolarization CC following damage, PINK1 import is stalled, which induces its CC accumulation in the outer mitochondrial membrane and the activation of CC its kinase activity (PubMed:18957282, PubMed:40080546). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:40080546}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1 {ECO:0000269|PubMed:14607334}; CC IsoId=Q9BXM7-1; Sequence=Displayed; CC Name=2 {ECO:0000305}; CC IsoId=Q9BXM7-2; Sequence=VSP_050754, VSP_050755; CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle and CC testis, and at lower levels in brain, placenta, liver, kidney, CC pancreas, prostate, ovary and small intestine. Present in the embryonic CC testis from an early stage of development. CC {ECO:0000269|PubMed:11494141}. CC -!- PTM: Proteolytically cleaved (PubMed:19229105, PubMed:22354088, CC PubMed:30733118). In healthy cells, the precursor is continuously CC imported into the inner mitochondrial membrane (IMM), where it is CC proteolytically cleaved by mitochondrial-processing peptidase (MPP) and CC then undergoes further proteolytic cleavage by PARL or AFG3L2 to give CC rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088). The CC 52 kDa short form is then released into the cytosol where it rapidly CC undergoes proteasome-dependent degradation (PubMed:20404107). In CC unhealthy cells, when cellular stress conditions lead to the loss of CC mitochondrial membrane potential, mitochondrial import is impaired CC leading to the precursor accumulating on the outer mitochondrial CC membrane (OMM) (PubMed:20404107, PubMed:30733118). If accumulation at CC the OMM fails and it is imported into the depolarized mitochondria, it CC undergoes cleavage by the IMM protease OMA1, promoting its subsequent CC degradation by the proteasome (PubMed:30733118). CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:30733118}. CC -!- PTM: Autophosphorylated (PubMed:18957282, PubMed:20404107, CC PubMed:22910362). Loss of mitochondrial membrane potential results in CC the precursor accumulating on the outer mitochondrial membrane (OMM) CC where it is activated by autophosphorylation (PubMed:18957282, CC PubMed:20404107, PubMed:22910362). Autophosphorylation at Ser-228 and CC Ser-402 is sufficient and essential for selective recruitment of PRKN CC to depolarized mitochondria, via PINK1-dependent phosphorylation of CC ubiquitin and maybe PRKN (PubMed:18957282, PubMed:22910362). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:22910362}. CC -!- DISEASE: Parkinson disease 6 (PARK6) [MIM:605909]: An early-onset form CC of Parkinson disease, a neurodegenerative disorder characterized by CC parkinsonian signs such as rigidity, resting tremor and bradykinesia. A CC subset of patients manifest additional symptoms including CC hyperreflexia, autonomic instability, dementia and psychiatric CC disturbances. Symptoms show diurnal fluctuation and can improve after CC sleep. PARK6 pathogenesis involves respiratory complex I deficiency CC causing mitochondrial depolarization and dysfunction. Inheritance is CC autosomal recessive. {ECO:0000269|PubMed:15087508, CC ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15349870, CC ECO:0000269|PubMed:15505171, ECO:0000269|PubMed:15596610, CC ECO:0000269|PubMed:15955953, ECO:0000269|PubMed:15970950, CC ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207217, CC ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:16257123, CC ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:16482571, CC ECO:0000269|PubMed:16632486, ECO:0000269|PubMed:16966503, CC ECO:0000269|PubMed:17030667, ECO:0000269|PubMed:18286320, CC ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19351622, ECO:0000269|PubMed:20547144, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22043288, CC ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510, CC ECO:0000269|PubMed:24652937, ECO:0000269|PubMed:24784582}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB053323; BAB55647.1; -; mRNA. DR EMBL; AF316873; AAK28062.1; -; mRNA. DR EMBL; AK075225; BAC11484.1; -; mRNA. DR EMBL; AL391357; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC009534; AAH09534.1; -; mRNA. DR EMBL; BC028215; AAH28215.1; -; mRNA. DR CCDS; CCDS211.1; -. [Q9BXM7-1] DR RefSeq; NP_115785.1; NM_032409.3. [Q9BXM7-1] DR PDB; 9EIH; EM; 3.10 A; A/B=1-581. DR PDB; 9EII; EM; 2.75 A; B=1-581. DR PDB; 9EIJ; EM; 3.30 A; B=1-581. DR PDBsum; 9EIH; -. DR PDBsum; 9EII; -. DR PDBsum; 9EIJ; -. DR AlphaFoldDB; Q9BXM7; -. DR EMDB; EMD-48083; -. DR EMDB; EMD-48084; -. DR EMDB; EMD-48085; -. DR SMR; Q9BXM7; -. DR BioGRID; 122376; 696. DR CORUM; Q9BXM7; -. DR DIP; DIP-29427N; -. DR FunCoup; Q9BXM7; 1190. DR IntAct; Q9BXM7; 177. DR MINT; Q9BXM7; -. DR STRING; 9606.ENSP00000364204; -. DR ChEMBL; CHEMBL3337330; -. DR TCDB; 8.A.104.1.16; the 5'-amp-activated protein kinase (ampk) family. DR CarbonylDB; Q9BXM7; -. DR GlyGen; Q9BXM7; 3 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q9BXM7; -. DR PhosphoSitePlus; Q9BXM7; -. DR BioMuta; PINK1; -. DR DMDM; 48428484; -. DR MassIVE; Q9BXM7; -. DR PaxDb; 9606-ENSP00000364204; -. DR PeptideAtlas; Q9BXM7; -. DR ProteomicsDB; 79455; -. [Q9BXM7-1] DR ProteomicsDB; 79456; -. [Q9BXM7-2] DR ABCD; Q9BXM7; 4 sequenced antibodies. DR Antibodypedia; 1105; 806 antibodies from 48 providers. DR DNASU; 65018; -. DR Ensembl; ENST00000321556.5; ENSP00000364204.3; ENSG00000158828.9. [Q9BXM7-1] DR GeneID; 65018; -. DR KEGG; hsa:65018; -. DR MANE-Select; ENST00000321556.5; ENSP00000364204.3; NM_032409.3; NP_115785.1. DR UCSC; uc001bdm.3; human. [Q9BXM7-1] DR AGR; HGNC:14581; -. DR ClinPGx; PA33325; -. DR CTD; 65018; -. DR DisGeNET; 65018; -. DR GeneCards; PINK1; -. DR GeneReviews; PINK1; -. DR HGNC; HGNC:14581; PINK1. DR HPA; ENSG00000158828; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PINK1; -. DR MIM; 168600; phenotype. DR MIM; 605909; phenotype. DR MIM; 608309; gene. DR OpenTargets; ENSG00000158828; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000158828; -. DR eggNOG; KOG4158; Eukaryota. DR GeneTree; ENSGT00390000001206; -. DR HOGENOM; CLU_022208_1_0_1; -. DR InParanoid; Q9BXM7; -. DR OMA; TCCSLRN; -. DR OrthoDB; 1405469at2759; -. DR PAN-GO; Q9BXM7; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q9BXM7; -. DR PathwayCommons; Q9BXM7; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes. DR SignaLink; Q9BXM7; -. DR SIGNOR; Q9BXM7; -. DR Agora; ENSG00000158828; -. DR BioGRID-ORCS; 65018; 17 hits in 1195 CRISPR screens. DR ChiTaRS; PINK1; human. DR GeneWiki; PINK1; -. DR GenomeRNAi; 65018; -. DR Pharos; Q9BXM7; Tbio. DR PRO; PR:Q9BXM7; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9BXM7; protein. DR Bgee; ENSG00000158828; Expressed in tendon of biceps brachii and 210 other cell types or tissues. DR GO; GO:0097449; C:astrocyte projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0030424; C:axon; IDA:ParkinsonsUK-UCL. DR GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0055131; F:C3HC4-type RING finger domain binding; IPI:BHF-UCL. DR GO; GO:0016301; F:kinase activity; IDA:MGI. DR GO; GO:0019900; F:kinase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0016504; F:peptidase activator activity; TAS:ParkinsonsUK-UCL. DR GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB. DR GO; GO:0043422; F:protein kinase B binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0106310; F:protein serine kinase activity; IMP:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IMP:ParkinsonsUK-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:UniProtKB. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; TAS:ParkinsonsUK-UCL. DR GO; GO:0014046; P:dopamine secretion; IEA:Ensembl. DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; IMP:UniProtKB. DR GO; GO:0030097; P:hemopoiesis; IGI:ARUK-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0072656; P:maintenance of protein location in mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IMP:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProt. DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ParkinsonsUK-UCL. DR GO; GO:1903384; P:negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903298; P:negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:1903751; P:negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide; IDA:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; TAS:ParkinsonsUK-UCL. DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ParkinsonsUK-UCL. DR GO; GO:1901525; P:negative regulation of mitophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ParkinsonsUK-UCL. DR GO; GO:1903852; P:positive regulation of cristae formation; IMP:ParkinsonsUK-UCL. DR GO; GO:0033603; P:positive regulation of dopamine secretion; IEA:Ensembl. DR GO; GO:1904544; P:positive regulation of free ubiquitin chain polymerization; ISS:ParkinsonsUK-UCL. DR GO; GO:0016239; P:positive regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:1902958; P:positive regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IBA:GO_Central. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:ParkinsonsUK-UCL. DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:BHF-UCL. DR GO; GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; IEA:Ensembl. DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0002082; P:regulation of oxidative phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IDA:BHF-UCL. DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0022904; P:respiratory electron transport chain; IEA:Ensembl. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IGI:ParkinsonsUK-UCL. DR GO; GO:0038203; P:TORC2 signaling; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR CDD; cd14018; STKc_PINK1; 1. DR FunFam; 1.10.510.10:FF:000418; PTEN induced kinase 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR051511; MitoQC_Scaffold_Kinases. DR InterPro; IPR040110; PINK1_STKc. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR22972; SERINE/THREONINE PROTEIN KINASE; 1. DR PANTHER; PTHR22972:SF7; SERINE_THREONINE-PROTEIN KINASE PINK1, MITOCHONDRIAL; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Autophagy; Cytoplasm; KW Disease variant; Kinase; Magnesium; Membrane; Metal-binding; Mitochondrion; KW Mitochondrion inner membrane; Mitochondrion outer membrane; KW Neurodegeneration; Nucleotide-binding; Parkinson disease; Parkinsonism; KW Phosphoprotein; Primary mitochondrial disease; Proteomics identification; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Transit peptide. FT TRANSIT 1..77 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 78..581 FT /note="Serine/threonine-protein kinase PINK1, FT mitochondrial" FT /id="PRO_0000024369" FT DOMAIN 156..511 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000305" FT REGION 111..117 FT /note="Required for outer membrane localization; this FT region is trapped in the TOM complex upon mitochondrial FT depolarization" FT /evidence="ECO:0000269|PubMed:30733118, FT ECO:0000269|PubMed:40080546" FT REGION 189..208 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 362 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 162..170 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q02750, FT ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 186 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 228 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:22910362" FT MOD_RES 402 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:22910362" FT VAR_SEQ 1..307 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050754" FT VAR_SEQ 308..320 FT /note="LGHGRTLFLVMKN -> MCGSQRPSPLSTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050755" FT VARIANT 52 FT /note="P -> L (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs776293086)" FT /evidence="ECO:0000269|PubMed:19351622, FT ECO:0000269|PubMed:37160114" FT /id="VAR_089730" FT VARIANT 67 FT /note="L -> F (no effect on interaction with TIMM23; FT dbSNP:rs763142730)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046566" FT VARIANT 68 FT /note="R -> P (no effect on interaction with TIMM23; FT dbSNP:rs1385309950)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046567" FT VARIANT 78 FT /note="A -> V (severely decreased interaction with TIMM23; FT dbSNP:rs1409111496)" FT /evidence="ECO:0000269|PubMed:37160114" FT /id="VAR_089731" FT VARIANT 92 FT /note="C -> F (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs1553145550)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046568" FT VARIANT 98 FT /note="R -> W (severely decreased interaction with TIMM23; FT dbSNP:rs575668171)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046569" FT VARIANT 111 FT /note="I -> S (found in a patient with Parkinson disease; FT uncertain significance; under depolarizing conditions, it FT fails to support PINK1-TOM-TIM23 complex assembly and FT mitophagy activation; no effect on interaction with TIMM23; FT dbSNP:rs1553145560)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681" FT /id="VAR_046570" FT VARIANT 115 FT /note="Q -> L (under depolarizing conditions, does not FT affect PINK1-TOM-TIM23 complex assembly and mitophagy FT activation; no effect on interaction with TIMM23; FT dbSNP:rs148871409)" FT /evidence="ECO:0000269|PubMed:15970950, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38416681" FT /id="VAR_046571" FT VARIANT 124 FT /note="A -> V (no effect on interaction with TIMM23; FT dbSNP:rs1274588239)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046572" FT VARIANT 125 FT /note="C -> G (in PARK6; under depolarizing conditions, it FT fails to support PINK1-TOM-TIM23 complex assembly and FT mitophagy activation; no effect on interaction with FT TIMM23)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681" FT /id="VAR_062773" FT VARIANT 126 FT /note="Q -> P (in PARK6; strongly reduces interaction with FT PRKN; under depolarizing conditions, it fails to support FT PINK1-TOM-TIM23 complex assembly and mitophagy activation; FT loss of autophosphorylation on S-228 and kinase activation; FT no effect on interaction with TIMM23; dbSNP:rs775809722)" FT /evidence="ECO:0000269|PubMed:18286320, FT ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38416681, ECO:0000269|PubMed:38848361" FT /id="VAR_064344" FT VARIANT 145 FT /note="T -> M (no effect on interaction with TIMM23; FT dbSNP:rs45604240)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046573" FT VARIANT 147 FT /note="R -> H (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs138050841)" FT /evidence="ECO:0000269|PubMed:15505171, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046574" FT VARIANT 148 FT /note="L -> W (no effect on interaction with TIMM23; FT dbSNP:rs56297806)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:37160114" FT /id="VAR_041010" FT VARIANT 168 FT /note="A -> P (in PARK6; no effect on autophosphorylation; FT localizes to the mitochondria and immunogold experiments FT reveal that both wild-type and mutant proteins face the FT mitochondrial intermembrane space; no effect on interaction FT with TIMM23; dbSNP:rs768091663)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207731, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:37160114" FT /id="VAR_046575" FT VARIANT 170 FT /note="V -> G (in PARK6; dbSNP:rs1553145929)" FT /evidence="ECO:0000269|PubMed:24652937" FT /id="VAR_078934" FT VARIANT 186 FT /note="K -> N (in dbSNP:rs143204084)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046576" FT VARIANT 196 FT /note="P -> L (in PARK6; dbSNP:rs138302371)" FT /evidence="ECO:0000269|PubMed:16009891" FT /id="VAR_046577" FT VARIANT 196 FT /note="P -> S (in dbSNP:rs35802484)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041011" FT VARIANT 209 FT /note="P -> L (in dbSNP:rs34677717)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041012" FT VARIANT 215 FT /note="P -> L (in a glioblastoma multiforme sample; somatic FT mutation; dbSNP:rs371854396)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041013" FT VARIANT 217 FT /note="A -> D (in PARK6; dbSNP:rs74315360)" FT /evidence="ECO:0000269|PubMed:16966503" FT /id="VAR_046578" FT VARIANT 231 FT /note="E -> G (in dbSNP:rs1303935100)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046579" FT VARIANT 235 FT /note="N -> I (in dbSNP:rs1557562082)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046580" FT VARIANT 240 FT /note="E -> K (in PARK6; loss of autophosphorylation on S- FT 228 and kinase activation; no effect on interaction with FT TIMM23; dbSNP:rs573931674)" FT /evidence="ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38848361" FT /id="VAR_046581" FT VARIANT 257 FT /note="T -> I (in dbSNP:rs370906995)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046582" FT VARIANT 263 FT /note="R -> G (in dbSNP:rs1553146419)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046583" FT VARIANT 268 FT /note="L -> V (in PARK6; dbSNP:rs372280083)" FT /evidence="ECO:0000269|PubMed:16207217, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046584" FT VARIANT 271 FT /note="H -> Q (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs28940284)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046585" FT VARIANT 276 FT /note="R -> Q (in dbSNP:rs548506734)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046586" FT VARIANT 279 FT /note="R -> H (in PARK6; dbSNP:rs74315358)" FT /evidence="ECO:0000269|PubMed:15970950" FT /id="VAR_046587" FT VARIANT 280 FT /note="A -> T (in PARK6; dbSNP:rs772510148)" FT /evidence="ECO:0000269|PubMed:16482571" FT /id="VAR_062774" FT VARIANT 296 FT /note="P -> L (in dbSNP:rs779060308)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046588" FT VARIANT 305 FT /note="P -> L (in dbSNP:rs7349186)" FT /id="VAR_018993" FT VARIANT 309 FT /note="G -> D (in PARK6; affects cellular response to FT stress resulting in increased mitochondrial depolarization FT under stress conditions compared to wild type; has no FT effect on autophosphorylation; strongly reduces interaction FT with PRKN; decreases PRKN and SNCAIP ubiquitination and FT degradation; decreases Drp1 phosphorylation; loss of FT ubiquitin phosphorylation; no effect on interaction with FT TIMM23; dbSNP:rs74315355)" FT /evidence="ECO:0000269|PubMed:15087508, FT ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:32484300, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38848361" FT /id="VAR_018994" FT VARIANT 313 FT /note="T -> M (in PARK6; decreases PRKN and SNCAIP FT ubiquitination and degradation; slightly decreases Drp1 FT phosphorylation; dbSNP:rs74315359)" FT /evidence="ECO:0000269|PubMed:17030667, FT ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:32484300" FT /id="VAR_046589" FT VARIANT 317 FT /note="V -> I (in dbSNP:rs200949139)" FT /evidence="ECO:0000269|PubMed:16969854, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046590" FT VARIANT 318 FT /note="M -> L (in dbSNP:rs139226733)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046591" FT VARIANT 322 FT /note="P -> L (in dbSNP:rs768019187)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046592" FT VARIANT 339 FT /note="A -> T (in dbSNP:rs55831733)" FT /evidence="ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:18330912" FT /id="VAR_041014" FT VARIANT 340 FT /note="A -> T (in dbSNP:rs3738136)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123, FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846" FT /id="VAR_018995" FT VARIANT 341 FT /note="M -> I (in dbSNP:rs35813094)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041015" FT VARIANT 347 FT /note="L -> P (in PARK6; strongly reduces interaction with FT PRKN; reduced ubiquitination of MIRO1; severely decreased FT interaction with TIMM23; dbSNP:rs28940285)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:20798600, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046593" FT VARIANT 362 FT /note="D -> H" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046594" FT VARIANT 369 FT /note="L -> P (in PARK6; dbSNP:rs1195888869)" FT /evidence="ECO:0000269|PubMed:16401616" FT /id="VAR_062775" FT VARIANT 377 FT /note="C -> F (in dbSNP:rs34203620)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041016" FT VARIANT 383 FT /note="A -> T (in dbSNP:rs45515602)" FT /evidence="ECO:0000269|PubMed:16969854, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046595" FT VARIANT 386 FT /note="G -> A (in PARK6; abolishes kinase activity; no FT effect on interaction with TIMM23)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:37160114" FT /id="VAR_062776" FT VARIANT 388 FT /note="C -> R (in PARK6; dbSNP:rs1553146806)" FT /evidence="ECO:0000269|PubMed:15955953" FT /id="VAR_046596" FT VARIANT 395 FT /note="G -> V (in dbSNP:rs1035071310)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046597" FT VARIANT 399 FT /note="P -> L (found in early-onset Parkinson disease with FT digenic inheritance; likely pathogenic; the patient also FT has mutation S-39 in PARK7; decreases PRKN and SNCAIP FT ubiquitination and degradation; dbSNP:rs119451946)" FT /evidence="ECO:0000269|PubMed:16632486, FT ECO:0000269|PubMed:19229105" FT /id="VAR_062777" FT VARIANT 407 FT /note="R -> Q (in PARK6; early-onset; dbSNP:rs556540177)" FT /evidence="ECO:0000269|PubMed:16257123" FT /id="VAR_062778" FT VARIANT 409 FT /note="G -> V (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs1553146818)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:37160114" FT /id="VAR_062779" FT VARIANT 411 FT /note="G -> S (in dbSNP:rs45478900)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046598" FT VARIANT 417 FT /note="E -> G (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs1553146822)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046599" FT VARIANT 425 FT /note="P -> S (in dbSNP:rs554114655)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046600" FT VARIANT 431 FT /note="Y -> H (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs74315361)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046601" FT VARIANT 442 FT /note="I -> T (in dbSNP:rs1553146877)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046602" FT VARIANT 451 FT /note="N -> S (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs747400197)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046603" FT VARIANT 456..581 FT /note="Missing (in PARK6)" FT /evidence="ECO:0000269|PubMed:24652937" FT /id="VAR_078935" FT VARIANT 461 FT /note="L -> S" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046604" FT VARIANT 464 FT /note="R -> H (in PARK6; dbSNP:rs764328076)" FT /evidence="ECO:0000269|PubMed:15349860" FT /id="VAR_046605" FT VARIANT 476 FT /note="E -> K (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs115477764)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:16009891, FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:18330912" FT /id="VAR_046606" FT VARIANT 477 FT /note="S -> T (in dbSNP:rs34416410)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041017" FT VARIANT 489 FT /note="L -> P (in PARK6; dbSNP:rs1553146903)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046607" FT VARIANT 492..581 FT /note="Missing (in PARK6; mitochondria are deformed and FT dysfunctional with decreased mitochondrial membrane FT potential; shows increased apoptosis; increased oxidative FT stress; decreased phosphorylation of DNM1L and Drp1; FT dbSNP:rs34208370)" FT /evidence="ECO:0000269|PubMed:18785233, FT ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:32484300" FT /id="VAR_084338" FT VARIANT 501 FT /note="R -> P (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs61744200)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046608" FT VARIANT 521 FT /note="N -> T (in dbSNP:rs1043424)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123, FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846" FT /id="VAR_018996" FT VARIANT 525 FT /note="D -> N (in dbSNP:rs531477772)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046609" FT VARIANT 534 FT /note="Q -> QQ (in PARK6; loss of autophosphorylation on S- FT 228 and kinase activation; no effect on interaction with FT TIMM23)" FT /evidence="ECO:0000269|PubMed:15970950, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38848361" FT /id="VAR_046610" FT VARIANT 537 FT /note="A -> T (in dbSNP:rs771032673)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046611" FT VARIANT 575 FT /note="C -> R (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs1553147052)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046612" FT MUTAGEN 112..117 FT /note="EEKQAE->AAKQAA: In 3EA; impaired ability to localize FT to the outer mitochondrial membrane." FT /evidence="ECO:0000269|PubMed:30733118" FT MUTAGEN 131 FT /note="I->E: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 219 FT /note="K->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with Ala-362 and Ala-384." FT /evidence="ECO:0000269|PubMed:23620051" FT MUTAGEN 219 FT /note="K->M: Loss of enzyme activity and impaired FT localization of PRKN to mitochondria; when associated with FT A-362 and A-384." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:32047033" FT MUTAGEN 362 FT /note="D->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with A-219 and A-384. Loss of FT enzyme activity and impaired localization of PRKN to FT mitochondria; when associated with M-219 and A-384." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033" FT MUTAGEN 384 FT /note="D->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with A-219 and A-362. Loss of FT enzyme activity and impaired localization of PRKN to FT mitochondria; when associated with M-219 and A-362." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033" FT MUTAGEN 384 FT /note="D->N: Loss of activity. Abolishes Drp1 FT phosphorylation. No effect on localization to FT mitochondria." FT /evidence="ECO:0000269|PubMed:32484300" FT MUTAGEN 532 FT /note="L->A: Under depolarizing conditions, it results in FT severely reduced autophosphorylation on S-228 and loss of FT kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 536 FT /note="A->E: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 536 FT /note="A->S: Under depolarizing conditions, it fails to FT support PINK1-TOM-TIM23 complex assembly and mitophagy FT activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 539 FT /note="L->A: Under depolarizing conditions, it results in FT severely reduced autophosphorylation on S-228 and loss of FT kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 540 FT /note="L->A: Under depolarizing conditions, does not affect FT autophosphorylation on S-228 and kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 540 FT /note="L->K: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 543 FT /note="R->D: No effect on interaction with TOMM20 and FT mitophagy activation under depolarizing conditions." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 543 FT /note="R->G: Under depolarizing conditions, it fails to FT support PINK1-TOM-TIM23 complex assembly and mitophagy FT activation." FT /evidence="ECO:0000269|PubMed:38416681" FT CONFLICT 209 FT /note="P -> A (in Ref. 5; AAH28215)" FT /evidence="ECO:0000305" FT CONFLICT 419 FT /note="S -> P (in Ref. 3; BAC11484)" FT /evidence="ECO:0000305" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 67..69 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 71..73 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 77..90 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 108..135 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 153..155 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 157..164 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 166..174 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 216..222 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 230..236 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 237..243 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 277..283 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 313..319 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 322..324 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 325..331 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 336..356 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 367..372 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 378..382 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 385..387 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 392..396 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 397..399 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 408..412 FT /evidence="ECO:0007829|PDB:9EIJ" FT HELIX 416..419 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 428..430 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 434..446 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 454..456 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 457..459 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 463..465 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 480..489 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 494..496 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 500..512 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 514..517 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:9EIH" FT HELIX 524..544 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 545..547 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 550..560 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 564..578 FT /evidence="ECO:0007829|PDB:9EII" SQ SEQUENCE 581 AA; 62769 MW; 721FE01F63263A64 CRC64; MAVRQALGRG LQLGRALLLR FTGKPGRAYG LGRPGPAAGC VRGERPGWAA GPGAEPRRVG LGLPNRLRFF RQSVAGLAAR LQRQFVVRAW GCAGPCGRAV FLAFGLGLGL IEEKQAESRR AVSACQEIQA IFTQKSKPGP DPLDTRRLQG FRLEEYLIGQ SIGKGCSAAV YEATMPTLPQ NLEVTKSTGL LPGRGPGTSA PGEGQERAPG APAFPLAIKM MWNISAGSSS EAILNTMSQE LVPASRVALA GEYGAVTYRK SKRGPKQLAP HPNIIRVLRA FTSSVPLLPG ALVDYPDVLP SRLHPEGLGH GRTLFLVMKN YPCTLRQYLC VNTPSPRLAA MMLLQLLEGV DHLVQQGIAH RDLKSDNILV ELDPDGCPWL VIADFGCCLA DESIGLQLPF SSWYVDRGGN GCLMAPEVST ARPGPRAVID YSKADAWAVG AIAYEIFGLV NPFYGQGKAH LESRSYQEAQ LPALPESVPP DVRQLVRALL QREASKRPSA RVAANVLHLS LWGEHILALK NLKLDKMVGW LLQQSAATLL ANRLTEKCCV ETKMKMLFLA NLECETLCQA ALLLCSWRAA L // ID PRIO_HUMAN Reviewed; 253 AA. AC P04156; O60489; P78446; Q15216; Q15221; Q27H91; Q5QPB4; Q8TBG0; Q96E70; AC Q9UP19; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 28-JAN-2026, entry version 280. DE RecName: Full=Major prion protein; DE Short=PrP; DE AltName: Full=ASCR; DE AltName: Full=PrP27-30; DE AltName: Full=PrP33-35C; DE AltName: CD_antigen=CD230; DE Flags: Precursor; GN Name=PRNP; Synonyms=ALTPRP, PRIP, PRP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3755672; DOI=10.1089/dna.1986.5.315; RA Kretzschmar H.A., Stowring L.E., Westaway D., Stubblebine W.H., RA Prusiner S.B., Dearmond S.J.; RT "Molecular cloning of a human prion protein cDNA."; RL DNA 5:315-324(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1678248; RA Puckett C., Concannon P., Casey C., Hood L.E.; RT "Genomic structure of the human prion protein gene."; RL Am. J. Hum. Genet. 49:320-329(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9799790; DOI=10.1101/gr.8.10.1022; RA Lee I.Y., Westaway D., Smit A.F.A., Wang K., Seto J., Chen L., Acharya C., RA Ankener M., Baskin D., Cooper C., Yao H., Prusiner S.B., Hood L.E.; RT "Complete genomic sequence and analysis of the prion protein gene region RT from three mammalian species."; RL Genome Res. 8:1022-1037(1998). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GSD ARG-187. RC TISSUE=Blood; RX PubMed=10581485; RX DOI=10.1002/(sici)1096-8628(19991215)88:6<653::aid-ajmg14>3.0.co;2-e; RA Cervenakova L., Buetefisch C., Lee H.S., Taller I., Stone G., RA Gibbs C.J. Jr., Brown P., Hallett M., Goldfarb L.G.; RT "Novel PRNP sequence variant associated with familial encephalopathy."; RL Am. J. Med. Genet. 88:653-656(1999). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Prostate; RA Hryb D.J., Reynolds T.A., Nakhla A.M., Kahn S.M., Khan S.M., Romas N.A., RA Rosner W.; RT "Cloning of human prostate prion protein cDNA."; RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Zhang J., Liu Y., Chen H., Jiang H., Lu W., Zhu X., Xie Q., Cai X., Liu X.; RT "Analysis and comparison of several mammalian prion protein genes Prnp."; RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-253. RX PubMed=3014653; DOI=10.1126/science.3014653; RA Liao Y.-C.J., Lebo R.V., Clawson G.A., Smuckler E.A.; RT "Human prion protein cDNA: molecular cloning, chromosomal mapping, and RT biological implications."; RL Science 233:364-367(1986). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-232, AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1363802; DOI=10.1093/hmg/1.6.443; RA Diedrich J.F., Knopman D.S., List J.F., Olson K., Frey W.H., Emory C.R., RA Sung J.H., Haase A.T.; RT "Deletion in the prion protein gene in a demented patient."; RL Hum. Mol. Genet. 1:443-444(1992). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 8-253, AND VARIANT SCHIZOAFFECTIVE RP DISORDER SER-171. RX PubMed=9384372; DOI=10.1038/36757; RA Samaia H.B., Mari J.J., Vallada H.P., Moura R.P., Simpson A.J.G., RA Brentani R.R.; RT "A prion-linked psychiatric disorder."; RL Nature 390:241-241(1997). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 41-85, AND VARIANT 56-GLY--GLY-63 DEL. RX PubMed=7485229; DOI=10.1002/ajmg.1320600104; RA Perry R.T., Go R.C., Harrell L.E., Acton R.T.; RT "SSCP analysis and sequencing of the human prion protein gene (PRNP) RT detects two different 24 bp deletions in an atypical Alzheimer's disease RT family."; RL Am. J. Med. Genet. 60:12-18(1995). RN [13] RP PROTEIN SEQUENCE OF 58-85 AND 111-150. RX PubMed=1672107; DOI=10.1002/j.1460-2075.1991.tb07977.x; RA Tagliavini F., Prelli F., Ghiso J., Bugiani O., Serban D., Prusiner S.B., RA Farlow M.R., Ghetti B., Frangione B.; RT "Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana RT kindred) is an 11 kd fragment of prion protein with an N-terminal glycine RT at codon 58."; RL EMBO J. 10:513-519(1991). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 84-91. RX PubMed=1683708; DOI=10.1073/pnas.88.23.10926; RA Goldfarb L.G., Brown P., McCombie W.R., Goldgaber D., Swergold G.D., RA Wills P.R., Cervenakova L., Baron H., Gibbs C.J. Jr., Gajdusek D.C.; RT "Transmissible familial Creutzfeldt-Jakob disease associated with five, RT seven, and eight extra octapeptide coding repeats in the PRNP gene."; RL Proc. Natl. Acad. Sci. U.S.A. 88:10926-10930(1991). RN [15] RP INVOLVEMENT IN HDL1. RX PubMed=9792871; DOI=10.1086/302093; RA Xiang F., Almqvist E.W., Huq M., Lundin A., Hayden M.R., Edstroem L., RA Anvret M., Zhang Z.; RT "A Huntington disease-like neurodegenerative disorder maps to chromosome RT 20p."; RL Am. J. Hum. Genet. 63:1431-1438(1998). RN [16] RP COPPER-BINDING, AND FUNCTION. RX PubMed=12732622; DOI=10.1074/jbc.m300394200; RA Mani K., Cheng F., Havsmark B., Jonsson M., Belting M., Fransson L.A.; RT "Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S- RT nitroso-dependent autocleavage of glypican-1 heparan sulfate."; RL J. Biol. Chem. 278:38956-38965(2003). RN [17] RP GLYCOSYLATION AT ASN-181, VARIANT SENF ALA-183, AND CHARACTERIZATION OF RP VARIANT SENF ALA-183. RX PubMed=12214108; DOI=10.3233/jad-2000-2104; RA Capellari S., Zaidi S.I., Long A.C., Kwon E.E., Petersen R.B.; RT "The Thr183Ala mutation, not the loss of the first glycosylation site, RT alters the physical properties of the prion protein."; RL J. Alzheimers Dis. 2:27-35(2000). RN [18] RP COPPER-BINDING. RX PubMed=16144413; DOI=10.1021/ja053254z; RA Chattopadhyay M., Walter E.D., Newell D.J., Jackson P.J., RA Aronoff-Spencer E., Peisach J., Gerfen G.J., Bennett B., Antholine W.E., RA Millhauser G.L.; RT "The octarepeat domain of the prion protein binds Cu(II) with three RT distinct coordination modes at pH 7.4."; RL J. Am. Chem. Soc. 127:12647-12656(2005). RN [19] RP COPPER-BINDING, AND ZINC-BINDING. RX PubMed=18034490; DOI=10.1021/ja077146j; RA Walter E.D., Stevens D.J., Visconte M.P., Millhauser G.L.; RT "The prion protein is a combined zinc and copper binding protein: Zn2+ RT alters the distribution of Cu2+ coordination modes."; RL J. Am. Chem. Soc. 129:15440-15441(2007). RN [20] RP RETRACTED PAPER. RX PubMed=19059915; DOI=10.1074/jbc.m804051200; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 284:2787-2794(2009). RN [21] RP RETRACTION NOTICE OF PUBMED:19059915. RX PubMed=29222195; DOI=10.1074/jbc.w117.000658; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 292:20044-20044(2017). RN [22] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-197. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, AND DISEASE ASSOCIATION. RX PubMed=19936054; DOI=10.1371/journal.ppat.1000666; RA Taylor D.R., Whitehouse I.J., Hooper N.M.; RT "Glypican-1 mediates both prion protein lipid raft association and disease RT isoform formation."; RL PLoS Pathog. 5:E1000666-E1000666(2009). RN [24] RP COPPER-BINDING. RX PubMed=19381258; DOI=10.1371/journal.ppat.1000390; RA Stevens D.J., Walter E.D., Rodriguez A., Draper D., Davies P., Brown D.R., RA Millhauser G.L.; RT "Early onset prion disease from octarepeat expansion correlates with copper RT or zinc binding properties."; RL PLoS Pathog. 5:E1000390-E1000390(2009). RN [25] RP SUBUNIT, AND DOMAIN. RX PubMed=20375014; DOI=10.1074/jbc.m110.111815; RA Adrover M., Pauwels K., Prigent S., de Chiara C., Xu Z., Chapuis C., RA Pastore A., Rezaei H.; RT "Prion fibrillization is mediated by a native structural element that RT comprises helices H2 and H3."; RL J. Biol. Chem. 285:21004-21012(2010). RN [26] RP COPPER-BINDING, CIRCULAR DICHROISM, DOMAIN, FUNCTION, AND SUBUNIT. RX PubMed=20564047; DOI=10.1002/jcb.22743; RA Wu D., Zhang W., Luo Q., Luo K., Huang L., Wang W., Huang T., Chen R., RA Lin Y., Pang D., Xiao G.; RT "Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in RT acidic environment."; RL J. Cell. Biochem. 111:627-633(2010). RN [27] RP BICISTRONIC GENE. RX PubMed=21478263; DOI=10.1096/fj.10-173815; RA Vanderperre B., Staskevicius A.B., Tremblay G., McCoy M., O'Neill M.A., RA Cashman N.R., Roucou X.; RT "An overlapping reading frame in the PRNP gene encodes a novel polypeptide RT distinct from the prion protein."; RL FASEB J. 25:2373-2386(2011). RN [28] RP INTERACTION WITH KIAA1191. RX PubMed=21153684; DOI=10.1007/s11010-010-0690-4; RA Mishra M., Inoue N., Heese K.; RT "Characterizing the novel protein p33MONOX."; RL Mol. Cell. Biochem. 350:127-134(2011). RN [29] RP STRUCTURE BY NMR OF 90-231 OF MUTANT LYS-200. RX PubMed=10954699; DOI=10.1074/jbc.c000483200; RA Zhang Y., Swietnicki W., Zagorski M.G., Surewicz W.K., Soennichsen F.D.; RT "Solution structure of the E200K variant of human prion protein. RT Implications for the mechanism of pathogenesis in familial prion RT diseases."; RL J. Biol. Chem. 275:33650-33654(2000). RN [30] RP STRUCTURE BY NMR OF 23-230. RX PubMed=10618385; DOI=10.1073/pnas.97.1.145; RA Zahn R., Liu A., Luhrs T., Riek R., von Schroetter C., Lopez Garcia F., RA Billeter M., Calzolai L., Wider G., Wuethrich K.; RT "NMR solution structure of the human prion protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:145-150(2000). RN [31] RP STRUCTURE BY NMR OF 118-221. RX PubMed=10900000; DOI=10.1073/pnas.97.15.8340; RA Calzolai L., Lysek D.A., Guntert P., von Schroetter C., Riek R., Zahn R., RA Wuethrich K.; RT "NMR structures of three single-residue variants of the human prion RT protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:8340-8345(2000). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 119-226, DOMAIN, AND SUBUNIT. RX PubMed=11524679; DOI=10.1038/nsb0901-770; RA Knaus K.J., Morillas M., Swietnicki W., Malone M., Surewicz W.K., Yee V.C.; RT "Crystal structure of the human prion protein reveals a mechanism for RT oligomerization."; RL Nat. Struct. Biol. 8:770-774(2001). RN [33] RP X-RAY CRYSTALLOGRAPHY (0.75 ANGSTROMS) OF 61-65 IN COMPLEX WITH COPPER ION, RP DOMAIN, AND SUBUNIT. RX PubMed=11900542; DOI=10.1021/bi011922x; RA Burns C.S., Aronoff-Spencer E., Dunham C.M., Lario P., Avdievich N.I., RA Antholine W.E., Olmstead M.M., Vrielink A., Gerfen G.J., Peisach J., RA Scott W.G., Millhauser G.L.; RT "Molecular features of the copper binding sites in the octarepeat domain of RT the prion protein."; RL Biochemistry 41:3991-4001(2002). RN [34] RP STRUCTURE BY NMR OF 61-68, DISULFIDE BOND, AND SUBUNIT. RX PubMed=14623188; DOI=10.1016/j.jmb.2003.09.048; RA Zahn R.; RT "The octapeptide repeats in mammalian prion protein constitute a pH- RT dependent folding and aggregation site."; RL J. Mol. Biol. 334:477-488(2003). RN [35] RP REVIEW ON VARIANTS. RX PubMed=8364585; DOI=10.1002/humu.1380020303; RA Palmer M.S., Collinge J.; RT "Mutations and polymorphisms in the prion protein gene."; RL Hum. Mutat. 2:168-173(1993). RN [36] RP REVIEW ON VARIANTS, AND INVOLVEMENT IN PRION DISEASES. RX PubMed=8105771; DOI=10.1001/archneur.1993.00540110011002; RA Prusiner S.B.; RT "Genetic and infectious prion diseases."; RL Arch. Neurol. 50:1129-1153(1993). RN [37] RP X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 170-175, SUBUNIT, AND DOMAIN. RX PubMed=17468747; DOI=10.1038/nature05695; RA Sawaya M.R., Sambashivan S., Nelson R., Ivanova M.I., Sievers S.A., RA Apostol M.I., Thompson M.J., Balbirnie M., Wiltzius J.J., McFarlane H.T., RA Madsen A.O., Riekel C., Eisenberg D.; RT "Atomic structures of amyloid cross-beta spines reveal varied steric RT zippers."; RL Nature 447:453-457(2007). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 119-231 IN COMPLEX WITH FAB RP FRAGMENT OF MONOCLONAL ANTIBODY ICSM 18, AND SUBUNIT. RX PubMed=19204296; DOI=10.1073/pnas.0809170106; RA Antonyuk S.V., Trevitt C.R., Strange R.W., Jackson G.S., Sangar D., RA Batchelor M., Cooper S., Fraser C., Jones S., Georgiou T., RA Khalili-Shirazi A., Clarke A.R., Hasnain S.S., Collinge J.; RT "Crystal structure of human prion protein bound to a therapeutic RT antibody."; RL Proc. Natl. Acad. Sci. U.S.A. 106:2554-2558(2009). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 125-227 OF VARIANT VAL-129, RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, VARIANT GSD RP SER-198, SUBUNIT, AND DOMAIN. RX PubMed=19927125; DOI=10.1038/emboj.2009.333; RA Lee S., Antony L., Hartmann R., Knaus K.J., Surewicz K., Surewicz W.K., RA Yee V.C.; RT "Conformational diversity in prion protein variants influences RT intermolecular beta-sheet formation."; RL EMBO J. 29:251-262(2010). RN [40] RP VARIANT GSD LEU-102. RX PubMed=2564168; DOI=10.1038/338342a0; RA Hsiao K., Baker H.F., Crow T.J., Poulter M., Owen F., Terwilliger J.D., RA Westaway D., Ott J., Pursiner S.B.; RT "Linkage of a prion protein missense variant to Gerstmann-Straussler RT syndrome."; RL Nature 338:342-345(1989). RN [41] RP VARIANTS LEU-102; VAL-117 AND VAL-129. RX PubMed=2783132; DOI=10.1016/0006-291x(89)92317-6; RA Doh-Ura K., Tateishi J., Sasaki H., Kitamoto T., Sakaki Y.; RT "Pro-->Leu change at position 102 of prion protein is the most common but RT not the sole mutation related to Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 163:974-979(1989). RN [42] RP VARIANT FFI ASN-178. RX PubMed=1347910; DOI=10.1212/wnl.42.3.669; RA Medori R., Montagna P., Tritschler H.J., Leblanc A., Cortelli P., RA Tinuper P., Lugaresi E., Gambetti P.; RT "Fatal familial insomnia: a second kindred with mutation of prion protein RT gene at codon 178."; RL Neurology 42:669-670(1992). RN [43] RP VARIANT CJD ASN-178. RX PubMed=1671440; DOI=10.1016/0140-6736(91)91198-4; RA Goldfarb L.G., Haltia M., Brown P., Nieto A., Kovanen J., McCombie W.R., RA Trapp S., Gajdusek D.C.; RT "New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish RT Creutzfeldt-Jakob kindred."; RL Lancet 337:425-425(1991). RN [44] RP VARIANT CJD LYS-200. RX PubMed=1975028; DOI=10.1016/0140-6736(90)92073-q; RA Goldfarb L., Mitrova E., Brown P., Toh B.K., Gajdusek D.C.; RT "Mutation in codon 200 of scrapie amyloid protein gene in two clusters of RT Creutzfeldt-Jakob disease in Slovakia."; RL Lancet 336:514-515(1990). RN [45] RP VARIANT GSD ARG-217. RX PubMed=1363810; DOI=10.1038/ng0492-68; RA Hsiao K., Dlouhy S.R., Farlow M.R., Cass C., da Costa M., Conneally P.M., RA Hodes M.E., Ghetti B., Prusiner S.B.; RT "Mutant prion proteins in Gerstmann-Straussler-Scheinker disease with RT neurofibrillary tangles."; RL Nat. Genet. 1:68-71(1992). RN [46] RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, CHARACTERIZATION RP OF VARIANT VAL-129, CHARACTERIZATION OF VARIANT CJD ASN-178, RP CHARACTERIZATION OF VARIANT FFI ASN-178, AND POLYMORPHISM. RX PubMed=1439789; DOI=10.1126/science.1439789; RA Goldfarb L.G., Petersen R.B., Tabaton M., Brown P., LeBlanc A.C., RA Montagna P., Cortelli P., Julien J., Vital C., Pendelbury W.W.; RT "Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease RT phenotype determined by a DNA polymorphism."; RL Science 258:806-808(1992). RN [47] RP VARIANTS CJD ILE-180 AND ARG-232. RX PubMed=8461023; DOI=10.1006/bbrc.1993.1275; RA Kitamoto T., Ohta M., Doh-Ura K., Hitoshi S., Terao Y., Tateishi J.; RT "Novel missense variants of prion protein in Creutzfeldt-Jakob disease or RT Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 191:709-714(1993). RN [48] RP VARIANT CJD ILE-210. RX PubMed=7902693; DOI=10.1002/ana.410340608; RA Pocchiari M., Salvatore M., Cutruzzola F., Genuardi M., Allcatelli C.T., RA Masullo C., Macchi G., Alema G., Galgani S., Xi Y.G., Petraroli R., RA Silvestrini M.C., Brunori M.; RT "A new point mutation of the prion protein gene in Creutzfeldt-Jakob RT disease."; RL Ann. Neurol. 34:802-807(1993). RN [49] RP VARIANT GSD LEU-105. RX PubMed=7902972; DOI=10.1212/wnl.43.12.2723-a; RA Yamada M., Itoh Y., Fujigasaki H., Naruse S., Kaneko K., Kitamoto T., RA Tateishi J., Otomo E., Hayakawa M., Tanaka J., Matsushita M., Miyatake T.; RT "A missense mutation at codon 105 with codon 129 polymorphism of the prion RT protein gene in a new variant of Gerstmann-Straussler-Scheinker disease."; RL Neurology 43:2723-2724(1993). RN [50] RP VARIANT GSD LEU-105. RX PubMed=7699395; DOI=10.1016/0022-510x(94)90138-4; RA Itoh Y., Yamada M., Hayakawa M., Shozawa T., Tanaka J., Matsushita M., RA Kitamoto T., Tateishi J., Otomo E.; RT "A variant of Gerstmann-Straussler-Scheinker disease carrying codon 105 RT mutation with codon 129 polymorphism of the prion protein gene: a RT clinicopathological study."; RL J. Neurol. Sci. 127:77-86(1994). RN [51] RP VARIANT CJD LYS-200. RX PubMed=7906019; DOI=10.1212/wnl.44.2.299; RA Inoue I., Kitamoto T., Doh-Ura K., Shii H., Goto I., Tateishi J.; RT "Japanese family with Creutzfeldt-Jakob disease with codon 200 point RT mutation of the prion protein gene."; RL Neurology 44:299-301(1994). RN [52] RP VARIANT CJD LYS-200. RX PubMed=7913755; DOI=10.1098/rstb.1994.0033; RA Gabizon R., Rosenman H., Meiner Z., Kahana I., Kahana E., Shugart Y., RA Ott J., Prusiner S.B.; RT "Mutation in codon 200 and polymorphism in codon 129 of the prion protein RT gene in Libyan Jews with Creutzfeldt-Jakob disease."; RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 343:385-390(1994). RN [53] RP VARIANT GSD LEU-102. RX PubMed=7783876; DOI=10.1212/wnl.45.6.1127; RA Young K., Jones C.K., Piccardo P., Lazzarini A., Golbe L.I., RA Zimmerman T.R., Dickson D.W., McLachlan D.C., St George-Hyslop P.H., RA Lennox A.; RT "Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and RT methionine at codon 129 of PRNP in previously unreported patients."; RL Neurology 45:1127-1134(1995). RN [54] RP VARIANT GSD LEU-102, AND VARIANT LYS-219. RX PubMed=8797472; DOI=10.1212/wnl.47.3.734; RA Barbanti P., Fabbrini G., Salvatore M., Petraroli R., Cardone F., Maras B., RA Equestre M., Macchi G., Lenzi G.L., Pocchiari M.; RT "Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity RT in a previously unreported family with Gerstmann-Straussler-Scheinker RT disease (PrP-P102L mutation)."; RL Neurology 47:734-741(1996). RN [55] RP VARIANT CJD HIS-208. RX PubMed=8909447; DOI=10.1212/wnl.47.5.1305; RA Mastrianni J.A., Iannicola C., Myers R.M., Dearmond S., Prusiner S.B.; RT "Mutation of the prion protein gene at codon 208 in familial Creutzfeldt- RT Jakob disease."; RL Neurology 47:1305-1312(1996). RN [56] RP VARIANT SENF ALA-183. RX PubMed=9266722; DOI=10.1002/ana.410420203; RA Nitrini R., Rosemberg S., Passos-Bueno M.R., da Silva L.S., Iughetti P., RA Papadopoulos M., Carrilho P.M., Caramelli P., Albrecht S., Zatz M., RA Leblanc A.; RT "Familial spongiform encephalopathy associated with a novel prion protein RT gene mutation."; RL Ann. Neurol. 42:138-146(1997). RN [57] RP VARIANTS GSD ASN-202 AND PRO-212. RX PubMed=9786248; DOI=10.1097/00005072-199810000-00010; RA Piccardo P., Dlouhy S.R., Lievens P.M., Young K., Bird T.D., Nochlin D., RA Dickson D.W., Vinters H.V., Zimmerman T.R., Mackenzie I.R., Kish S.J., RA Ang L.C., De Carli C., Pocchiari M., Brown P., Gibbs C.J. Jr., RA Gajdusek D.C., Bugiani O., Ironside J., Tagliavini F., Ghetti B.; RT "Phenotypic variability of Gerstmann-Straussler-Scheinker disease is RT associated with prion protein heterogeneity."; RL J. Neuropathol. Exp. Neurol. 57:979-988(1998). RN [58] RP VARIANT LYS-219, CHARACTERIZATION OF VARIANT LYS-219, AND POLYMORPHISM. RX PubMed=9482303; DOI=10.1016/s0140-6736(05)78358-6; RA Shibuya S., Higuchi J., Shin R.W., Tateishi J., Kitamoto T.; RT "Protective prion protein polymorphisms against sporadic Creutzfeldt-Jakob RT disease."; RL Lancet 351:419-419(1998). RN [59] RP VARIANTS ARG-188 AND SER-238. RX PubMed=10987652; DOI=10.1007/s004399900124; RA Windl O., Giese A., Schulz-Schaeffer W., Zerr I., Skworc K., Arendt S., RA Oberdieck C., Bodemer M., Poser S., Kretzschmar H.A.; RT "Molecular genetics of human prion diseases in Germany."; RL Hum. Genet. 105:244-252(1999). RN [60] RP VARIANTS EARLY-ONSET DEMENTIA LEU-102; ALA-183 AND LYS-188. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [61] RP VARIANTS CJD LYS-196; ILE-203 AND GLN-211. RX PubMed=10790216; RX DOI=10.1002/(sici)1098-1004(200005)15:5<482::aid-humu16>3.0.co;2-1; RA Peoc'h K., Manivet P., Beaudry P., Attane F., Besson G., Didier H., RA Delasnerie-Laupretre N., Laplanche J.-L.; RT "Identification of three novel mutations (E196K, V203I, E211Q) in the prion RT protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob RT disease phenotype."; RL Hum. Mutat. 15:482-482(2000). RN [62] RP VARIANT GSD VAL-131. RX PubMed=11709001; DOI=10.1001/archneur.58.11.1899; RA Panegyres P.K., Toufexis K., Kakulas B.A., Cernevakova L., Brown P., RA Ghetti B., Piccardo P., Dlouhy S.R.; RT "A new PRNP mutation (G131V) associated with Gerstmann-Straussler-Scheinker RT disease."; RL Arch. Neurol. 58:1899-1902(2001). RN [63] RP VARIANT VAL-129, AND CHARACTERIZATION OF VARIANT VAL-129. RX PubMed=12690204; DOI=10.1126/science.1083320; RA Mead S., Stumpf M.P., Whitfield J., Beck J.A., Poulter M., Campbell T., RA Uphill J.B., Goldstein D., Alpers M., Fisher E.M., Collinge J.; RT "Balancing selection at the prion protein gene consistent with prehistoric RT kurulike epidemics."; RL Science 300:640-643(2003). RN [64] RP VARIANT VAL-127, AND INVOLVEMENT IN KURU. RX PubMed=19923577; DOI=10.1056/nejmoa0809716; RA Mead S., Whitfield J., Poulter M., Shah P., Uphill J., Campbell T., RA Al-Dujaily H., Hummerich H., Beck J., Mein C.A., Verzilli C., Whittaker J., RA Alpers M.P., Collinge J.; RT "A novel protective prion protein variant that colocalizes with kuru RT exposure."; RL N. Engl. J. Med. 361:2056-2065(2009). RN [65] RP VARIANT VAL-127, CHARACTERIZATION OF VARIANT VAL-127, INVOLVEMENT IN KURU, RP AND POLYMORPHISM. RX PubMed=26061765; DOI=10.1038/nature14510; RA Asante E.A., Smidak M., Grimshaw A., Houghton R., Tomlinson A., Jeelani A., RA Jakubcova T., Hamdan S., Richard-Londt A., Linehan J.M., Brandner S., RA Alpers M., Whitfield J., Mead S., Wadsworth J.D., Collinge J.; RT "A naturally occurring variant of the human prion protein completely RT prevents prion disease."; RL Nature 522:478-481(2015). CC -!- FUNCTION: Its primary physiological function is unclear. May play a CC role in neuronal development and synaptic plasticity. May be required CC for neuronal myelin sheath maintenance. May promote myelin homeostasis CC through acting as an agonist for ADGRG6 receptor. May play a role in CC iron uptake and iron homeostasis. Soluble oligomers are toxic to CC cultured neuroblastoma cells and induce apoptosis (in vitro) (By CC similarity). Association with GPC1 (via its heparan sulfate chains) CC targets PRNP to lipid rafts. Also provides Cu(2+) or Zn(2+) for the CC ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate CC side chains (By similarity). {ECO:0000250|UniProtKB:P04925, CC ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:19936054, CC ECO:0000269|PubMed:20564047, ECO:0000305}. CC -!- SUBUNIT: Monomer and homodimer. Has a tendency to aggregate into CC amyloid fibrils containing a cross-beta spine, formed by a steric CC zipper of superposed beta-strands. Soluble oligomers may represent an CC intermediate stage on the path to fibril formation. Copper binding may CC promote oligomerization (PubMed:11524679, PubMed:11900542, CC PubMed:14623188, PubMed:17468747, PubMed:19204296, PubMed:19927125, CC PubMed:20375014, PubMed:20564047). Interacts with GRB2, APP, CC ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts CC with MGRN1; this interaction alters MGRN1 subcellular location and CC causes lysosomal enlargement (By similarity). Interacts with KIAA1191 CC (PubMed:21153684). Interacts with ADGRG6 (By similarity). CC {ECO:0000250|UniProtKB:P04925, ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:14623188, CC ECO:0000269|PubMed:17468747, ECO:0000269|PubMed:19204296, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20375014, CC ECO:0000269|PubMed:20564047, ECO:0000269|PubMed:21153684}. CC -!- INTERACTION: CC P04156; Q9UL18: AGO1; NbExp=2; IntAct=EBI-977302, EBI-527363; CC P04156; Q9UKV8: AGO2; NbExp=4; IntAct=EBI-977302, EBI-528269; CC P04156; P05067: APP; NbExp=6; IntAct=EBI-977302, EBI-77613; CC P04156; P05067-4: APP; NbExp=2; IntAct=EBI-977302, EBI-302641; CC P04156; PRO_0000000092 [P05067]: APP; NbExp=3; IntAct=EBI-977302, EBI-821758; CC P04156; Q8WXF7: ATL1; NbExp=3; IntAct=EBI-977302, EBI-2410266; CC P04156; P25311: AZGP1; NbExp=4; IntAct=EBI-977302, EBI-2513837; CC P04156; P55085: F2RL1; NbExp=3; IntAct=EBI-977302, EBI-4303189; CC P04156; Q13642: FHL1; NbExp=3; IntAct=EBI-977302, EBI-912547; CC P04156; O75084: FZD7; NbExp=3; IntAct=EBI-977302, EBI-746917; CC P04156; P49639: HOXA1; NbExp=4; IntAct=EBI-977302, EBI-740785; CC P04156; P42858: HTT; NbExp=13; IntAct=EBI-977302, EBI-466029; CC P04156; P10636: MAPT; NbExp=2; IntAct=EBI-977302, EBI-366182; CC P04156; P29372: MPG; NbExp=4; IntAct=EBI-977302, EBI-1043398; CC P04156; Q9BSJ6: PIMREG; NbExp=5; IntAct=EBI-977302, EBI-2568609; CC P04156; Q9H4B4: PLK3; NbExp=4; IntAct=EBI-977302, EBI-751877; CC P04156; Q06830: PRDX1; NbExp=4; IntAct=EBI-977302, EBI-353193; CC P04156; P04156: PRNP; NbExp=33; IntAct=EBI-977302, EBI-977302; CC P04156; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-977302, EBI-11528848; CC P04156; Q8CJG0: Ago2; Xeno; NbExp=2; IntAct=EBI-977302, EBI-528299; CC P04156; P04925: Prnp; Xeno; NbExp=3; IntAct=EBI-977302, EBI-768613; CC P04156; P10279: PRNP; Xeno; NbExp=5; IntAct=EBI-977302, EBI-7430632; CC P04156; P23907: PRNP; Xeno; NbExp=3; IntAct=EBI-977302, EBI-7670302; CC PRO_0000025675; P31424-2: Grm5; Xeno; NbExp=4; IntAct=EBI-8830282, EBI-8830305; CC PRO_0000025675; P52480: Pkm; Xeno; NbExp=5; IntAct=EBI-8830282, EBI-647785; CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor CC {ECO:0000269|PubMed:19936054}. Golgi apparatus CC {ECO:0000250|UniProtKB:P04925}. Note=Targeted to lipid rafts via CC association with the heparan sulfate chains of GPC1. Colocates, in the CC presence of Cu(2+), to vesicles in para- and perinuclear regions, where CC both proteins undergo internalization. Heparin displaces PRNP from CC lipid rafts and promotes endocytosis. {ECO:0000269|PubMed:19936054}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=1; Synonyms=PrP; CC IsoId=P04156-1; Sequence=Displayed; CC Name=3; Synonyms=AltPrP; CC IsoId=F7VJQ1-1; Sequence=External; CC -!- DOMAIN: The normal, monomeric form, PRPN(C), has a mainly alpha-helical CC structure. Misfolding of this form produces a disease-associated, CC protease-resistant form, PRPN (Sc), accompanied by a large increase of CC the beta-sheet content and formation of amyloid fibrils. These fibrils CC consist of a cross-beta spine, formed by a steric zipper of superposed CC beta-strands. Disease mutations may favor intermolecular contacts via CC short beta strands, and may thereby trigger oligomerization. In CC addition, the heparan-sulfate proteoglycan, GPC1, promotes the CC association of PRPN (C) to lipid rafts and appears to facilitate the CC conversion to PRPN (Sc). {ECO:0000269|PubMed:17468747, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20564047}. CC -!- DOMAIN: Contains an N-terminal region composed of octamer repeats. At CC low copper concentrations, the sidechains of His residues from three or CC four repeats contribute to the binding of a single copper ion. CC Alternatively, a copper ion can be bound by interaction with the CC sidechain and backbone amide nitrogen of a single His residue. The CC observed copper binding stoichiometry suggests that two repeat regions CC cooperate to stabilize the binding of a single copper ion. At higher CC copper concentrations, each octamer can bind one copper ion by CC interactions with the His sidechain and Gly backbone atoms. A mixture CC of binding types may occur, especially in the case of octamer repeat CC expansion. Copper binding may stabilize the conformation of this region CC and may promote oligomerization. {ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:20375014}. CC -!- PTM: The glycosylation pattern (the amount of mono-, di- and non- CC glycosylated forms or glycoforms) seems to differ in normal and CJD CC prion. {ECO:0000269|PubMed:12214108}. CC -!- POLYMORPHISM: The five tandem octapeptide repeats region is highly CC unstable. Insertions or deletions of octapeptide repeat units are CC associated to prion disease. {ECO:0000269|PubMed:1683708}. CC -!- POLYMORPHISM: A number of polymorphisms confer resistance to prion CC diseases (PubMed:1439789, PubMed:19923577, PubMed:26061765, CC PubMed:9482303). Val-127 has been selected for in response to the Kuru CC epidemic and confers resistance to prion disease by acting as a CC 'dominant negative' inhibitor of prion conversion (PubMed:26061765). CC Val-127 is not only itself resistant to conformational conversion, but CC also inhibits conversion of wild-type proteins. Confers protection CC against classical Creutzfeldt-Jakob disease (CJD) and Kuru in the CC heterozygous state, but can be infected with variant CJD prions, CC resulting from exposure to bovine spongiform encephalopathy prions. CC Confers complete resistance to all prion strains when homozygous CC (PubMed:26061765). Always associated with M-129 variant CC (PubMed:26061765). Val-129 confers relative protection against CC acquired, sporadic and some inherited prion diseases in the CC heterozygous state, possibly by preventing homodimerization CC (PubMed:1439789). Lys-219 confers relative protection against sporadic CC Creutzfeldt-Jakob disease (CJD) in the heterozygous state CC (PubMed:9482303). {ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:26061765, ECO:0000269|PubMed:9482303}. CC -!- DISEASE: Note=PrP is found in high quantity in the brain of humans and CC animals infected with neurodegenerative diseases known as transmissible CC spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob CC disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler CC disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in CC humans; scrapie in sheep and goat; bovine spongiform encephalopathy CC (BSE) in cattle; transmissible mink encephalopathy (TME); chronic CC wasting disease (CWD) of mule deer and elk; feline spongiform CC encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) CC in nyala and greater kudu. The prion diseases illustrate three CC manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) CC dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to CC occur after consumption of prion-infected foodstuffs. CC {ECO:0000269|PubMed:8105771}. CC -!- DISEASE: Creutzfeldt-Jakob disease (CJD) [MIM:123400]: Occurs primarily CC as a sporadic disorder (1 per million), while 10-15% are familial. CC Accidental transmission of CJD to humans appears to be iatrogenic CC (contaminated human growth hormone (HGH), corneal transplantation, CC electroencephalographic electrode implantation, etc.). Epidemiologic CC studies have failed to implicate the ingestion of infected animal meat CC in the pathogenesis of CJD in human. The triad of microscopic features CC that characterize the prion diseases consists of (1) spongiform CC degeneration of neurons, (2) severe astrocytic gliosis that often CC appears to be out of proportion to the degree of nerve cell loss, and CC (3) amyloid plaque formation. CJD is characterized by progressive CC dementia and myoclonic seizures, affecting adults in mid-life. Some CC patients present sleep disorders, abnormalities of high cortical CC function, cerebellar and corticospinal disturbances. The disease ends CC in death after a 3-12 months illness. {ECO:0000269|PubMed:10790216, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, CC ECO:0000269|PubMed:1975028, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:7902693, ECO:0000269|PubMed:7906019, CC ECO:0000269|PubMed:7913755, ECO:0000269|PubMed:8461023, CC ECO:0000269|PubMed:8909447}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Fatal familial insomnia (FFI) [MIM:600072]: Autosomal dominant CC disorder and is characterized by neuronal degeneration limited to CC selected thalamic nuclei and progressive insomnia. CC {ECO:0000269|PubMed:1347910, ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:19927125}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gerstmann-Straussler disease (GSD) [MIM:137440]: A rare CC inherited prion disease characterized by adult onset of memory loss, CC dementia, ataxia, and pathologic deposition of amyloid-like plaques in CC the brain. GSD presents with progressive limb and truncal ataxia, CC dysarthria, and cognitive decline in the thirties and forties, and the CC average disease duration is 7 years. {ECO:0000269|PubMed:10581485, CC ECO:0000269|PubMed:11709001, ECO:0000269|PubMed:1363810, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:7699395, CC ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:7902972, CC ECO:0000269|PubMed:8797472, ECO:0000269|PubMed:9786248}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Huntington disease-like 1 (HDL1) [MIM:603218]: Autosomal CC dominant, early-onset neurodegenerative disorder with prominent CC psychiatric features. {ECO:0000269|PubMed:9792871}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Kuru (KURU) [MIM:245300]: Kuru is transmitted during CC ritualistic cannibalism, among natives of the New Guinea highlands. CC Patients exhibit various movement disorders like cerebellar CC abnormalities, rigidity of the limbs, and clonus. Emotional lability is CC present, and dementia is conspicuously absent. Death usually occurs CC from 3 to 12 month after onset. {ECO:0000269|PubMed:19923577, CC ECO:0000269|PubMed:26061765}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spongiform encephalopathy with neuropsychiatric features CC (SENF) [MIM:606688]: Autosomal dominant presenile dementia with a CC rapidly progressive and protracted clinical course. The dementia was CC characterized clinically by frontotemporal features, including early CC personality changes. Some patients had memory loss, several showed CC aggressiveness, hyperorality and verbal stereotypy, others had CC parkinsonian symptoms. {ECO:0000269|PubMed:12214108, CC ECO:0000269|PubMed:9266722}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which CC also produces the alternative prion protein/AltPrP (AC F7VJQ1) from an CC overlapping reading frame. {ECO:0000305|PubMed:21478263}. CC -!- MISCELLANEOUS: The alternative prion protein/AltPrP (AC F7VJQ1) and CC PRNP have no apparent direct functional relation since a mutation that CC removes the start codon of the AltPrP has no apparent effect on the CC biology of PRNP. In mouse and hamster, the alternative initiation AUG CC codon is absent and is replaced by a GUG codon. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the prion family. {ECO:0000305}. CC -!- CAUTION: An isoform was shown to be localized to both the cytoplasm and CC the nucleus and to be sumoylated with SUMO1 (PubMed:19059915). The CC article has later been withdrawn by the authors. CC {ECO:0000269|PubMed:19059915, ECO:0000305|PubMed:29222195}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=PRNP entry; CC URL="https://en.wikipedia.org/wiki/PRNP"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The shape of harm - Issue CC 179 of May 2016; CC URL="https://www.proteinspotlight.org/back_issues/179/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M13899; AAA60182.1; -; mRNA. DR EMBL; X83416; CAA58442.1; -; Genomic_DNA. DR EMBL; U29185; AAC78725.1; -; Genomic_DNA. DR EMBL; AF076976; AAD46098.1; -; Genomic_DNA. DR EMBL; AY008282; AAG21693.1; -; mRNA. DR EMBL; DQ408531; ABD63004.1; -; Genomic_DNA. DR EMBL; AL133396; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC012844; AAH12844.1; -; mRNA. DR EMBL; BC022532; AAH22532.1; -; mRNA. DR EMBL; D00015; BAA00011.1; -; mRNA. DR EMBL; M13667; AAA19664.1; -; mRNA. DR EMBL; M81929; AAB59442.1; -; Genomic_DNA. DR EMBL; M81930; AAB59443.1; -; Genomic_DNA. DR EMBL; AF030575; AAC05365.1; -; Genomic_DNA. DR EMBL; S80732; AAB50648.2; -; Genomic_DNA. DR EMBL; S80743; AAB50649.2; -; Genomic_DNA. DR EMBL; S71208; AAB20521.1; -; Genomic_DNA. DR EMBL; S71210; AAB20522.1; -; Genomic_DNA. DR EMBL; S71212; AAB20523.1; -; Genomic_DNA. DR CCDS; CCDS13080.1; -. [P04156-1] DR PIR; A24173; UJHU. DR RefSeq; NP_000302.1; NM_000311.5. [P04156-1] DR RefSeq; NP_001073590.1; NM_001080121.3. [P04156-1] DR RefSeq; NP_001073591.1; NM_001080122.3. [P04156-1] DR RefSeq; NP_001073592.1; NM_001080123.3. [P04156-1] DR RefSeq; NP_001258490.1; NM_001271561.2. DR RefSeq; NP_898902.1; NM_183079.4. [P04156-1] DR PDB; 1E1G; NMR; -; A=125-228. DR PDB; 1E1J; NMR; -; A=125-228. DR PDB; 1E1P; NMR; -; A=125-228. DR PDB; 1E1S; NMR; -; A=125-228. DR PDB; 1E1U; NMR; -; A=125-228. DR PDB; 1E1W; NMR; -; A=125-228. DR PDB; 1FKC; NMR; -; A=90-231. DR PDB; 1FO7; NMR; -; A=90-231. DR PDB; 1H0L; NMR; -; A=121-230. DR PDB; 1HJM; NMR; -; A=125-228. DR PDB; 1HJN; NMR; -; A=125-228. DR PDB; 1I4M; X-ray; 2.00 A; A=119-226. DR PDB; 1OEH; NMR; -; A=77-84. DR PDB; 1OEI; NMR; -; A=61-84. DR PDB; 1QLX; NMR; -; A=23-230. DR PDB; 1QLZ; NMR; -; A=23-230. DR PDB; 1QM0; NMR; -; A=90-230. DR PDB; 1QM1; NMR; -; A=90-230. DR PDB; 1QM2; NMR; -; A=121-230. DR PDB; 1QM3; NMR; -; A=121-230. DR PDB; 2IV4; NMR; -; A=180-195. DR PDB; 2IV5; NMR; -; A=173-195. DR PDB; 2IV6; NMR; -; A=173-195. DR PDB; 2K1D; NMR; -; A=90-231. DR PDB; 2KUN; NMR; -; A=90-231. DR PDB; 2LBG; NMR; -; A=110-136. DR PDB; 2LEJ; NMR; -; A=90-231. DR PDB; 2LFT; NMR; -; A=90-231. DR PDB; 2LSB; NMR; -; A=90-231. DR PDB; 2LV1; NMR; -; A=90-231. DR PDB; 2M8T; NMR; -; A=90-231. DR PDB; 2OL9; X-ray; 0.85 A; A=170-175. DR PDB; 2W9E; X-ray; 2.90 A; A=119-231. DR PDB; 3HAF; X-ray; 2.26 A; A=90-231. DR PDB; 3HAK; X-ray; 1.80 A; A=125-227. DR PDB; 3HEQ; X-ray; 1.80 A; A/B=90-231. DR PDB; 3HER; X-ray; 1.85 A; A/B=90-231. DR PDB; 3HES; X-ray; 2.00 A; A/B=90-231. DR PDB; 3HJ5; X-ray; 3.10 A; A/B=90-231. DR PDB; 3HJX; X-ray; 2.00 A; A=126-231. DR PDB; 3MD4; X-ray; 1.15 A; A/B=127-132. DR PDB; 3MD5; X-ray; 1.40 A; A/B=127-132. DR PDB; 3NHC; X-ray; 1.57 A; A/B=127-132. DR PDB; 3NHD; X-ray; 1.92 A; A/B=127-132. DR PDB; 3NVF; X-ray; 1.80 A; A=138-143. DR PDB; 4DGI; X-ray; 2.40 A; A=120-230. DR PDB; 4E1H; X-ray; 1.40 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4E1I; X-ray; 2.03 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4KML; X-ray; 1.50 A; A=24-231. DR PDB; 4N9O; X-ray; 1.50 A; A=90-231. DR PDB; 5L6R; NMR; -; A=90-226. DR PDB; 5YJ4; NMR; -; A=91-231. DR PDB; 5YJ5; NMR; -; A=91-231. DR PDB; 6DU9; X-ray; 2.33 A; A=90-230. DR PDB; 6LNI; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=23-231. DR PDB; 6PQ5; X-ray; 1.50 A; A/B=113-118. DR PDB; 6PQA; X-ray; 1.46 A; A=119-124. DR PDB; 6SUZ; X-ray; 2.50 A; A=125-223. DR PDB; 6SV2; X-ray; 2.30 A; A=119-231. DR PDB; 6UUR; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=94-178. DR PDB; 7DWV; EM; 3.07 A; A/B/C/D/E/F=23-231. DR PDB; 7FHQ; NMR; -; A=91-231. DR PDB; 7RL4; EM; 2.86 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=23-144. DR PDB; 7RVC; EM; 1.00 A; A=168-176. DR PDB; 7RVE; EM; 0.85 A; A=168-176. DR PDB; 7RVJ; EM; 1.00 A; A/B=169-175. DR PDB; 7RVK; EM; 1.00 A; A=169-175. DR PDB; 7RVL; EM; 1.00 A; A=168-176. DR PDB; 7UMQ; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDB; 7UN5; EM; 3.13 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDBsum; 1E1G; -. DR PDBsum; 1E1J; -. DR PDBsum; 1E1P; -. DR PDBsum; 1E1S; -. DR PDBsum; 1E1U; -. DR PDBsum; 1E1W; -. DR PDBsum; 1FKC; -. DR PDBsum; 1FO7; -. DR PDBsum; 1H0L; -. DR PDBsum; 1HJM; -. DR PDBsum; 1HJN; -. DR PDBsum; 1I4M; -. DR PDBsum; 1OEH; -. DR PDBsum; 1OEI; -. DR PDBsum; 1QLX; -. DR PDBsum; 1QLZ; -. DR PDBsum; 1QM0; -. DR PDBsum; 1QM1; -. DR PDBsum; 1QM2; -. DR PDBsum; 1QM3; -. DR PDBsum; 2IV4; -. DR PDBsum; 2IV5; -. DR PDBsum; 2IV6; -. DR PDBsum; 2K1D; -. DR PDBsum; 2KUN; -. DR PDBsum; 2LBG; -. DR PDBsum; 2LEJ; -. DR PDBsum; 2LFT; -. DR PDBsum; 2LSB; -. DR PDBsum; 2LV1; -. DR PDBsum; 2M8T; -. DR PDBsum; 2OL9; -. DR PDBsum; 2W9E; -. DR PDBsum; 3HAF; -. DR PDBsum; 3HAK; -. DR PDBsum; 3HEQ; -. DR PDBsum; 3HER; -. DR PDBsum; 3HES; -. DR PDBsum; 3HJ5; -. DR PDBsum; 3HJX; -. DR PDBsum; 3MD4; -. DR PDBsum; 3MD5; -. DR PDBsum; 3NHC; -. DR PDBsum; 3NHD; -. DR PDBsum; 3NVF; -. DR PDBsum; 4DGI; -. DR PDBsum; 4E1H; -. DR PDBsum; 4E1I; -. DR PDBsum; 4KML; -. DR PDBsum; 4N9O; -. DR PDBsum; 5L6R; -. DR PDBsum; 5YJ4; -. DR PDBsum; 5YJ5; -. DR PDBsum; 6DU9; -. DR PDBsum; 6LNI; -. DR PDBsum; 6PQ5; -. DR PDBsum; 6PQA; -. DR PDBsum; 6SUZ; -. DR PDBsum; 6SV2; -. DR PDBsum; 6UUR; -. DR PDBsum; 7DWV; -. DR PDBsum; 7FHQ; -. DR PDBsum; 7RL4; -. DR PDBsum; 7RVC; -. DR PDBsum; 7RVE; -. DR PDBsum; 7RVJ; -. DR PDBsum; 7RVK; -. DR PDBsum; 7RVL; -. DR PDBsum; 7UMQ; -. DR PDBsum; 7UN5; -. DR AlphaFoldDB; P04156; -. DR BMRB; P04156; -. DR EMDB; EMD-0931; -. DR EMDB; EMD-20900; -. DR EMDB; EMD-24514; -. DR EMDB; EMD-26607; -. DR EMDB; EMD-26613; -. DR EMDB; EMD-30887; -. DR SASBDB; P04156; -. DR SMR; P04156; -. DR BioGRID; 111606; 2255. DR CORUM; P04156; -. DR DIP; DIP-29933N; -. DR ELM; P04156; -. DR FunCoup; P04156; 501. DR IntAct; P04156; 454. DR MINT; P04156; -. DR STRING; 9606.ENSP00000399376; -. DR BindingDB; P04156; -. DR ChEMBL; CHEMBL4869; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB00759; Tetracycline. DR DrugCentral; P04156; -. DR MoonDB; P04156; Predicted. DR TCDB; 1.C.48.1.2; the prion peptide (prp) family. DR GlyConnect; 2056; 3 N-Linked glycans (1 site). DR GlyCosmos; P04156; 2 sites, 6 glycans. DR GlyGen; P04156; 4 sites, 12 N-linked glycans (2 sites), 2 O-linked glycans (2 sites). DR iPTMnet; P04156; -. DR MetOSite; P04156; -. DR PhosphoSitePlus; P04156; -. DR SwissPalm; P04156; -. DR BioMuta; PRNP; -. DR DMDM; 130912; -. DR jPOST; P04156; -. DR MassIVE; P04156; -. DR PaxDb; 9606-ENSP00000368752; -. DR PeptideAtlas; P04156; -. DR ProteomicsDB; 51667; -. [P04156-1] DR Pumba; P04156; -. DR ABCD; P04156; 3 sequenced antibodies. DR Antibodypedia; 3351; 881 antibodies from 47 providers. DR DNASU; 5621; -. DR Ensembl; ENST00000379440.9; ENSP00000368752.4; ENSG00000171867.19. DR Ensembl; ENST00000424424.2; ENSP00000411599.2; ENSG00000171867.19. DR Ensembl; ENST00000430350.2; ENSP00000399376.2; ENSG00000171867.19. DR Ensembl; ENST00000457586.2; ENSP00000415284.2; ENSG00000171867.19. DR GeneID; 5621; -. DR KEGG; hsa:5621; -. DR MANE-Select; ENST00000379440.9; ENSP00000368752.4; NM_000311.5; NP_000302.1. DR AGR; HGNC:9449; -. DR ClinPGx; PA33796; -. DR CTD; 5621; -. DR DisGeNET; 5621; -. DR GeneCards; PRNP; -. DR GeneReviews; PRNP; -. DR HGNC; HGNC:9449; PRNP. DR HPA; ENSG00000171867; Tissue enhanced (choroid). DR MalaCards; PRNP; -. DR MIM; 123400; phenotype. DR MIM; 137440; phenotype. DR MIM; 176640; gene. DR MIM; 245300; phenotype. DR MIM; 600072; phenotype. DR MIM; 603218; phenotype. DR MIM; 606688; phenotype. DR OpenTargets; ENSG00000171867; -. DR Orphanet; 280397; Familial Alzheimer-like prion disease. DR Orphanet; 466; Fatal familial insomnia. DR Orphanet; 356; Gerstmann-Straussler-Scheinker syndrome. DR Orphanet; 157941; Huntington disease-like 1. DR Orphanet; 282166; Inherited Creutzfeldt-Jakob disease. DR Orphanet; 454745; Kuru. DR Orphanet; 397606; PrP systemic amyloidosis. DR VEuPathDB; HostDB:ENSG00000171867; -. DR eggNOG; ENOG502S2A8; Eukaryota. DR GeneTree; ENSGT00510000049083; -. DR InParanoid; P04156; -. DR OMA; QMCTTQY; -. DR OrthoDB; 9048788at2759; -. DR PAN-GO; P04156; 3 GO annotations based on evolutionary models. DR PhylomeDB; P04156; -. DR PathwayCommons; P04156; -. DR Reactome; R-HSA-419037; NCAM1 interactions. DR Reactome; R-HSA-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane. DR SignaLink; P04156; -. DR Agora; ENSG00000171867; -. DR BioGRID-ORCS; 5621; 10 hits in 1169 CRISPR screens. DR CD-CODE; 7A2E2A6F; Synthetic Condensate 000125. DR CD-CODE; 8188F968; Tau-Prion Multiphasic condensate. DR CD-CODE; 9F779CC8; Nuclear body. DR ChiTaRS; PRNP; human. DR EvolutionaryTrace; P04156; -. DR GenomeRNAi; 5621; -. DR Pharos; P04156; Tchem. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P04156; protein. DR Bgee; ENSG00000171867; Expressed in Brodmann (1909) area 23 and 209 other cell types or tissues. DR ExpressionAtlas; P04156; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; TAS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0009897; C:external side of plasma membrane; NAS:ARUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0019898; C:extrinsic component of membrane; TAS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0016234; C:inclusion body; IMP:CAFA. DR GO; GO:0045121; C:membrane raft; IDA:MGI. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; TAS:ARUK-UCL. DR GO; GO:0014069; C:postsynaptic density; ISS:ARUK-UCL. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0001540; F:amyloid-beta binding; IDA:ARUK-UCL. DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; ISS:ARUK-UCL. DR GO; GO:0043008; F:ATP-dependent protein binding; IEA:Ensembl. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903135; F:cupric ion binding; IEA:Ensembl. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0005539; F:glycosaminoglycan binding; ISS:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005521; F:lamin binding; IEA:Ensembl. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0060090; F:molecular adaptor activity; IDA:DisProt. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:DisProt. DR GO; GO:0140677; F:molecular function activator activity; IEA:Ensembl. DR GO; GO:0002020; F:protease binding; ISS:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; ISS:ARUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl. DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB. DR GO; GO:0031802; F:type 5 metabotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0071280; P:cellular response to copper ion; IDA:MGI. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0097062; P:dendritic spine maintenance; TAS:ARUK-UCL. DR GO; GO:0006878; P:intracellular copper ion homeostasis; NAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:0007611; P:learning or memory; ISS:ARUK-UCL. DR GO; GO:0007616; P:long-term memory; TAS:ARUK-UCL. DR GO; GO:0046007; P:negative regulation of activated T cell proliferation; ISS:BHF-UCL. DR GO; GO:1902992; P:negative regulation of amyloid precursor protein catabolic process; ISS:ARUK-UCL. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; ISS:ARUK-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; ISS:BHF-UCL. DR GO; GO:1902951; P:negative regulation of dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; ISS:BHF-UCL. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:BHF-UCL. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0010955; P:negative regulation of protein processing; TAS:ARUK-UCL. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0032689; P:negative regulation of type II interferon production; ISS:BHF-UCL. DR GO; GO:1990535; P:neuron projection maintenance; ISS:ARUK-UCL. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IGI:ARUK-UCL. DR GO; GO:1900451; P:positive regulation of glutamate receptor signaling pathway; IGI:ARUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:CAFA. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:ARUK-UCL. DR GO; GO:0031648; P:protein destabilization; IMP:CAFA. DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro. DR GO; GO:1905664; P:regulation of calcium ion import across plasma membrane; ISS:ARUK-UCL. DR GO; GO:0051726; P:regulation of cell cycle; IEA:UniProtKB-KW. DR GO; GO:1900449; P:regulation of glutamate receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:1901379; P:regulation of potassium ion transmembrane transport; IEA:Ensembl. DR GO; GO:1904645; P:response to amyloid-beta; ISS:ARUK-UCL. DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB. DR DisProt; DP00466; -. DR FunFam; 1.10.790.10:FF:000001; Major prion protein; 1. DR Gene3D; 1.10.790.10; Prion/Doppel protein, beta-ribbon domain; 1. DR InterPro; IPR000817; Prion. DR InterPro; IPR036924; Prion/Doppel_b-ribbon_dom_sf. DR InterPro; IPR022416; Prion/Doppel_prot_b-ribbon_dom. DR InterPro; IPR020949; Prion_copper_b_octapeptide. DR InterPro; IPR025860; Prion_N. DR PANTHER; PTHR15506; DOPPEL PRION; 1. DR PANTHER; PTHR15506:SF2; MAJOR PRION PROTEIN; 1. DR Pfam; PF00377; Prion; 1. DR Pfam; PF11587; Prion_bPrPp; 1. DR Pfam; PF03991; Prion_octapep; 1. DR PRINTS; PR00341; PRION. DR SMART; SM00157; PRP; 1. DR SUPFAM; SSF54098; Prion-like; 1. DR PROSITE; PS00291; PRION_1; 1. DR PROSITE; PS00706; PRION_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Amyloid; Amyloidosis; Cell cycle; KW Cell membrane; Copper; Direct protein sequencing; Disease variant; KW Disulfide bond; Glycoprotein; Golgi apparatus; GPI-anchor; Growth arrest; KW Lipoprotein; Membrane; Metal-binding; Prion; Proteomics identification; KW Reference proteome; Repeat; Signal; Zinc. FT SIGNAL 1..22 FT /evidence="ECO:0000250|UniProtKB:P04925" FT CHAIN 23..230 FT /note="Major prion protein" FT /id="PRO_0000025675" FT PROPEP 231..253 FT /note="Removed in mature form" FT /evidence="ECO:0000250|UniProtKB:P04273" FT /id="PRO_0000025676" FT REPEAT 51..59 FT /note="1" FT REPEAT 60..67 FT /note="2" FT REPEAT 68..75 FT /note="3" FT REPEAT 76..83 FT /note="4" FT REPEAT 84..91 FT /note="5" FT REGION 23..230 FT /note="Interaction with GRB2, ERI3 and SYN1" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 23..38 FT /note="Interaction with ADGRG6" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 26..108 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 51..91 FT /note="5 X 8 AA tandem repeats of P-H-G-G-G-W-G-Q" FT COMPBIAS 52..95 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 61 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 62 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 63 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 69 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 70 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 71 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 77 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 78 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 79 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 85 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 86 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 87 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT LIPID 230 FT /note="GPI-anchor amidated serine" FT /evidence="ECO:0000250|UniProtKB:P04273" FT CARBOHYD 181 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12214108" FT CARBOHYD 197 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 179..214 FT /evidence="ECO:0000269|PubMed:14623188" FT VARIANT 56..63 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:1363802, FT ECO:0000269|PubMed:1678248, ECO:0000269|PubMed:7485229" FT /id="VAR_013763" FT VARIANT 102 FT /note="P -> L (in GSD and early-onset dementia; FT dbSNP:rs74315401)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:2783132, FT ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:8797472" FT /id="VAR_006464" FT VARIANT 105 FT /note="P -> L (in GSD; dbSNP:rs11538758)" FT /evidence="ECO:0000269|PubMed:7699395, FT ECO:0000269|PubMed:7902972" FT /id="VAR_006465" FT VARIANT 117 FT /note="A -> V (linked to development of dementing FT Gerstmann-Straussler disease; dbSNP:rs74315402)" FT /evidence="ECO:0000269|PubMed:2783132" FT /id="VAR_006466" FT VARIANT 127 FT /note="G -> V (protective factor against Kuru; protective FT factor against prion disease; confers protection against FT classical Creutzfeldt-Jakob disease (CJD) and Kuru in the FT heterozygous state but can be infected with variant CJD FT prions resulting from exposure to bovine spongiform FT encephalopathy prions; confers complete resistance to all FT prion strains when homozygous; acts as a 'dominant FT negative' inhibitor of prion conversion; is not only itself FT resistant to conformational conversion, but also inhibits FT conversion of wild-type proteins; dbSNP:rs267606980)" FT /evidence="ECO:0000269|PubMed:19923577, FT ECO:0000269|PubMed:26061765" FT /id="VAR_073722" FT VARIANT 129 FT /note="M -> V (protective factor against acquired, sporadic FT and some inherited prion diseases in the heterozygous FT state, possibly by preventing homodimerization; determines FT the disease phenotype in patients who have a PrP mutation FT at position 178; patients with M-129 develop FFI, those FT with V-129 develop CJD; dbSNP:rs1799990)" FT /evidence="ECO:0000269|PubMed:12690204, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, FT ECO:0000269|PubMed:2783132" FT /id="VAR_006467" FT VARIANT 131 FT /note="G -> V (in GSD; dbSNP:rs74315410)" FT /evidence="ECO:0000269|PubMed:11709001" FT /id="VAR_014264" FT VARIANT 171 FT /note="N -> S (in schizoaffective disorder; FT dbSNP:rs16990018)" FT /evidence="ECO:0000269|PubMed:9384372" FT /id="VAR_006468" FT VARIANT 178 FT /note="D -> N (in FFI and CJD; dbSNP:rs74315403)" FT /evidence="ECO:0000269|PubMed:1347910, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, FT ECO:0000269|PubMed:19927125" FT /id="VAR_006469" FT VARIANT 180 FT /note="V -> I (in CJD; dbSNP:rs74315408)" FT /evidence="ECO:0000269|PubMed:1439789, FT ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:8461023" FT /id="VAR_006470" FT VARIANT 183 FT /note="T -> A (in SENF and early-onset dementia; induces FT loss of glycosylation at N-181; dbSNP:rs74315411)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:12214108, ECO:0000269|PubMed:9266722" FT /id="VAR_006471" FT VARIANT 187 FT /note="H -> R (in GSD; dbSNP:rs74315413)" FT /evidence="ECO:0000269|PubMed:10581485" FT /id="VAR_008746" FT VARIANT 188 FT /note="T -> K (in early-onset dementia and dementia due to FT prion diseases)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_008748" FT VARIANT 188 FT /note="T -> R (in dbSNP:rs372878791)" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008747" FT VARIANT 196 FT /note="E -> K (in CJD)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008749" FT VARIANT 198 FT /note="F -> S (in GSD; atypical form with neurofibrillary FT tangles; dbSNP:rs74315405)" FT /evidence="ECO:0000269|PubMed:19927125" FT /id="VAR_006472" FT VARIANT 200 FT /note="E -> K (in CJD; dbSNP:rs28933385)" FT /evidence="ECO:0000269|PubMed:1975028, FT ECO:0000269|PubMed:7906019, ECO:0000269|PubMed:7913755" FT /id="VAR_006473" FT VARIANT 202 FT /note="D -> N (in GSD; dbSNP:rs761807915)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008750" FT VARIANT 203 FT /note="V -> I (in CJD; uncertain significance; FT dbSNP:rs776593792)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008751" FT VARIANT 208 FT /note="R -> H (in CJD; dbSNP:rs74315412)" FT /evidence="ECO:0000269|PubMed:8909447" FT /id="VAR_006474" FT VARIANT 210 FT /note="V -> I (in CJD; dbSNP:rs74315407)" FT /evidence="ECO:0000269|PubMed:7902693" FT /id="VAR_006475" FT VARIANT 211 FT /note="E -> Q (in CJD; dbSNP:rs398122370)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008752" FT VARIANT 212 FT /note="Q -> P (in GSD; dbSNP:rs751882709)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008753" FT VARIANT 217 FT /note="Q -> R (in GSD; with neurofibrillary tangles; FT dbSNP:rs74315406)" FT /evidence="ECO:0000269|PubMed:1363810" FT /id="VAR_006476" FT VARIANT 219 FT /note="E -> K (confers relative protection against sporadic FT Creutzfeldt-Jakob disease (CJD) in the heterozygous state; FT dbSNP:rs1800014)" FT /evidence="ECO:0000269|PubMed:8797472, FT ECO:0000269|PubMed:9482303" FT /id="VAR_006477" FT VARIANT 232 FT /note="M -> R (in CJD; dbSNP:rs74315409)" FT /evidence="ECO:0000269|PubMed:8461023" FT /id="VAR_006478" FT VARIANT 238 FT /note="P -> S" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008754" FT CONFLICT 118 FT /note="Missing (in Ref. 9; AAA19664/BAA00011)" FT /evidence="ECO:0000305" FT CONFLICT 169 FT /note="Y -> H (in Ref. 6; ABD63004)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="Q -> K (in Ref. 8; AAH22532)" FT /evidence="ECO:0000305" FT STRAND 63..67 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 70..73 FT /evidence="ECO:0007829|PDB:1OEI" FT TURN 74..76 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 79..82 FT /evidence="ECO:0007829|PDB:1OEH" FT STRAND 92..95 FT /evidence="ECO:0007829|PDB:5YJ4" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:5L6R" FT STRAND 109..112 FT /evidence="ECO:0007829|PDB:7RL4" FT TURN 114..117 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 118..122 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:1H0L" FT STRAND 128..131 FT /evidence="ECO:0007829|PDB:3MD4" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 138..140 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 141..143 FT /evidence="ECO:0007829|PDB:1E1S" FT HELIX 144..153 FT /evidence="ECO:0007829|PDB:4KML" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 159..163 FT /evidence="ECO:0007829|PDB:1E1U" FT HELIX 166..168 FT /evidence="ECO:0007829|PDB:4KML" FT TURN 171..173 FT /evidence="ECO:0007829|PDB:1QM0" FT STRAND 178..181 FT /evidence="ECO:0007829|PDB:4E1H" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 189..192 FT /evidence="ECO:0007829|PDB:6LNI" FT TURN 193..195 FT /evidence="ECO:0007829|PDB:3HAK" FT STRAND 196..202 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 205..210 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 212..215 FT /evidence="ECO:0007829|PDB:4E1H" FT TURN 223..225 FT /evidence="ECO:0007829|PDB:3HER" FT TURN 228..230 FT /evidence="ECO:0007829|PDB:2LFT" SQ SEQUENCE 253 AA; 27661 MW; 43DB596BAAA66484 CRC64; MANLGCWMLV LFVATWSDLG LCKKRPKPGG WNTGGSRYPG QGSPGGNRYP PQGGGGWGQP HGGGWGQPHG GGWGQPHGGG WGQPHGGGWG QGGGTHSQWN KPSKPKTNMK HMAGAAAAGA VVGGLGGYML GSAMSRPIIH FGSDYEDRYY RENMHRYPNQ VYYRPMDEYS NQNNFVHDCV NITIKQHTVT TTTKGENFTE TDVKMMERVV EQMCITQYER ESQAYYQRGS SMVLFSSPPV ILLISFLIFL IVG // ID PRKN_HUMAN Reviewed; 465 AA. AC O60260; A3FG77; A8K975; D3JZW7; D3K2X0; Q5TFV8; Q5VVX4; Q6Q2I6; Q8NI41; AC Q8NI43; Q8NI44; Q8WW07; DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 28-JAN-2026, entry version 236. DE RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000305}; DE Short=Parkin; DE EC=2.3.2.31 {ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:32047033}; DE AltName: Full=Parkin RBR E3 ubiquitin-protein ligase {ECO:0000312|HGNC:HGNC:8607}; DE AltName: Full=Parkinson juvenile disease protein 2; DE Short=Parkinson disease protein 2; GN Name=PRKN {ECO:0000312|HGNC:HGNC:8607}; Synonyms=PARK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INVOLVEMENT IN PARK2, AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain, and Skeletal muscle; RX PubMed=9560156; DOI=10.1038/33416; RA Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., RA Yokochi M., Mizuno Y., Shimizu N.; RT "Mutations in the parkin gene cause autosomal recessive juvenile RT parkinsonism."; RL Nature 392:605-608(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP VARIANTS ARG-311 AND THR-371, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19501131; DOI=10.1016/j.neulet.2009.05.079; RA Kasap M., Akpinar G., Sazci A., Idrisoglu H.A., Vahaboglu H.; RT "Evidence for the presence of full-length PARK2 mRNA and Parkin protein in RT human blood."; RL Neurosci. Lett. 460:196-200(2009). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4). RA D'Agata V., Scapagnini G., Cavallaro S.; RT "Functional and molecular diversity of parkin."; RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 7 AND 8). RC TISSUE=Retina; RA Campello L., Esteve-Rudd J., Cuenca N., Martin-Nieto J.; RT "Homo sapiens PARK2 transcript variants."; RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 312-361. RA Zou H.Q., Chan P.; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP SUBCELLULAR LOCATION. RX PubMed=10319893; RX DOI=10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z; RA Shimura H., Hattori N., Kubo S., Yoshikawa M., Kitada T., Matsumine H., RA Asakawa S., Minoshima S., Yamamura Y., Shimizu N., Mizuno Y.; RT "Immunohistochemical and subcellular localization of Parkin protein: RT absence of protein in autosomal recessive juvenile parkinsonism patients."; RL Ann. Neurol. 45:668-672(1999). RN [11] RP FUNCTION IN UBIQUITINATION. RX PubMed=10973942; DOI=10.1074/jbc.c000447200; RA Imai Y., Soda M., Takahashi R.; RT "Parkin suppresses unfolded protein stress-induced cell death through its RT E3 ubiquitin-protein ligase activity."; RL J. Biol. Chem. 275:35661-35664(2000). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240. RX PubMed=10888878; DOI=10.1038/77060; RA Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., RA Shimizu N., Iwai K., Chiba T., Tanaka K., Suzuki T.; RT "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein RT ligase."; RL Nat. Genet. 25:302-305(2000). RN [13] RP INTERACTION WITH UBE2L6 AND SEPTIN5, AND UBIQUITINATION OF SEPTIN5. RX PubMed=11078524; DOI=10.1073/pnas.240347797; RA Zhang Y., Gao J., Chung K.K.K., Huang H., Dawson V.L., Dawson T.M.; RT "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes RT the degradation of the synaptic vesicle-associated protein, CDCrel-1."; RL Proc. Natl. Acad. Sci. U.S.A. 97:13354-13359(2000). RN [14] RP UBIQUITINATION OF GPR37. RX PubMed=11439185; DOI=10.1016/s0092-8674(01)00407-x; RA Imai Y., Soda M., Inoue H., Hattori N., Mizuno Y., Takahashi R.; RT "An unfolded putative transmembrane polypeptide, which can lead to RT endoplasmic reticulum stress, is a substrate of Parkin."; RL Cell 105:891-902(2001). RN [15] RP FUNCTION, INTERACTION WITH SNCAIP, CHARACTERIZATION OF VARIANTS PARK2 RP ARG-240; CYS-256; TRP-275 AND ASN-415, AND MUTAGENESIS OF CYS-337; CYS-421 RP AND CYS-431. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK2 RP PRO-42 AND ARG-240. RX PubMed=11431533; DOI=10.1126/science.1060627; RA Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P., Trockenbacher A., RA Schneider R., Mizuno Y., Kosik K.S., Selkoe D.J.; RT "Ubiquitination of a new form of alpha-synuclein by parkin from human RT brain: implications for Parkinson's disease."; RL Science 293:263-269(2001). RN [17] RP PRESENCE OF ATYPICAL RING FINGER DOMAINS. RX PubMed=12446796; DOI=10.1093/oxfordjournals.molbev.a004029; RA Marin I., Ferrus A.; RT "Comparative genomics of the RBR family, including the Parkinson's disease- RT related gene parkin and the genes of the ariadne subfamily."; RL Mol. Biol. Evol. 19:2039-2050(2002). RN [18] RP FUNCTION, INTERACTION WITH STUB1; HSP70 AND GPR37, AND UBIQUITINATION OF RP STUB1. RX PubMed=12150907; DOI=10.1016/s1097-2765(02)00583-x; RA Imai Y., Soda M., Hatakeyama S., Akagi T., Hashikawa T., Nakayama K., RA Takahashi R.; RT "CHIP is associated with Parkin, a gene responsible for familial RT Parkinson's disease, and enhances its ubiquitin ligase activity."; RL Mol. Cell 10:55-67(2002). RN [19] RP INTERACTION WITH SYT11, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF RP VARIANTS PARK2 GLY-289 AND ARG-418. RX PubMed=12925569; DOI=10.1093/hmg/ddg269; RA Huynh D.P., Scoles D.R., Nguyen D., Pulst S.M.; RT "The autosomal recessive juvenile Parkinson disease gene product, parkin, RT interacts with and ubiquitinates synaptotagmin XI."; RL Hum. Mol. Genet. 12:2587-2597(2003). RN [20] RP INTERACTION WITH PACRG. RX PubMed=14532270; DOI=10.1074/jbc.m309655200; RA Imai Y., Soda M., Murakami T., Shoji M., Abe K., Takahashi R.; RT "A product of the human gene adjacent to parkin is a component of Lewy RT bodies and suppresses Pael receptor-induced cell death."; RL J. Biol. Chem. 278:51901-51910(2003). RN [21] RP FUNCTION, INTERACTION WITH FBXW7 AND CUL1, TISSUE SPECIFICITY, AND RP UBIQUITINATION OF CYCLIN E. RX PubMed=12628165; DOI=10.1016/s0896-6273(03)00084-9; RA Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E., RA Abeliovich A.; RT "Parkin is a component of an SCF-like ubiquitin ligase complex and protects RT postmitotic neurons from kainate excitotoxicity."; RL Neuron 37:735-749(2003). RN [22] RP INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=14614460; DOI=10.1038/sj.onc.1207072; RA Denison S.R., Wang F., Becker N.A., Schuele B., Kock N., Phillips L.A., RA Klein C., Smith D.I.; RT "Alterations in the common fragile site gene Parkin in ovarian and other RT cancers."; RL Oncogene 22:8370-8378(2003). RN [23] RP FUNCTION, INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=12719539; DOI=10.1073/pnas.0931262100; RA Cesari R., Martin E.S., Calin G.A., Pentimalli F., Bichi R., McAdams H., RA Trapasso F., Drusco A., Shimizu M., Masciullo V., D'Andrilli G., RA Scambia G., Picchio M.C., Alder H., Godwin A.K., Croce C.M.; RT "Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is RT a candidate tumor suppressor gene on chromosome 6q25-q27."; RL Proc. Natl. Acad. Sci. U.S.A. 100:5956-5961(2003). RN [24] RP REVIEW. RX PubMed=15229644; DOI=10.1038/sj.embor.7400188; RA Kahle P.J., Haass C.; RT "How does parkin ligate ubiquitin to Parkinson's disease?"; RL EMBO Rep. 5:681-685(2004). RN [25] RP FUNCTION, UBIQUITINATION, AND S-NITROSYLATION. RX PubMed=15105460; DOI=10.1126/science.1093891; RA Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., RA Dawson V.L., Dawson T.M.; RT "S-nitrosylation of parkin regulates ubiquitination and compromises RT parkin's protective function."; RL Science 304:1328-1331(2004). RN [26] RP INTERACTION WITH PSMA7. RX PubMed=15987638; DOI=10.1016/j.febslet.2005.06.003; RA Dachsel J.C., Lucking C.B., Deeg S., Schultz E., Lalowski M., RA Casademunt E., Corti O., Hampe C., Patenge N., Vaupel K., Yamamoto A., RA Dichgans M., Brice A., Wanker E.E., Kahle P.J., Gasser T.; RT "Parkin interacts with the proteasome subunit alpha4."; RL FEBS Lett. 579:3913-3919(2005). RN [27] RP FUNCTION, AND INTERACTION WITH SNCAIP. RX PubMed=15728840; DOI=10.1523/jneurosci.4474-04.2005; RA Lim K.L., Chew K.C., Tan J.M., Wang C., Chung K.K., Zhang Y., Tanaka Y., RA Smith W., Engelender S., Ross C.A., Dawson V.L., Dawson T.M.; RT "Parkin mediates nonclassical, proteasomal-independent ubiquitination of RT synphilin-1: implications for Lewy body formation."; RL J. Neurosci. 25:2002-2009(2005). RN [28] RP FUNCTION, AND INTERACTION WITH AIMP2. RX PubMed=16135753; DOI=10.1523/jneurosci.2172-05.2005; RA Ko H.S., von Coelln R., Sriram S.R., Kim S.W., Chung K.K.K., Pletnikova O., RA Troncoso J., Johnson B., Saffary R., Goh E.L., Song H., Park B.-J., RA Kim M.J., Kim S., Dawson V.L., Dawson T.M.; RT "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase RT cofactor, p38/JTV-1, leads to catecholaminergic cell death."; RL J. Neurosci. 25:7968-7978(2005). RN [29] RP INTERACTION WITH LRRK2. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., RA Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [30] RP INTERACTION WITH RANBP2. RX PubMed=16332688; DOI=10.1074/jbc.m504994200; RA Um J.W., Min D.S., Rhim H., Kim J., Paik S.R., Chung K.C.; RT "Parkin ubiquitinates and promotes the degradation of RanBP2."; RL J. Biol. Chem. 281:3595-3603(2006). RN [31] RP INTERACTION WITH SUMO1, AND SUBCELLULAR LOCATION. RX PubMed=16955485; DOI=10.1002/jnr.21041; RA Um J.W., Chung K.C.; RT "Functional modulation of parkin through physical interaction with SUMO- RT 1."; RL J. Neurosci. Res. 84:1543-1554(2006). RN [32] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17846173; DOI=10.1083/jcb.200611128; RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D., RA Chin L.S.; RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to RT aggresomes via binding to HDAC6."; RL J. Cell Biol. 178:1025-1038(2007). RN [33] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-175 AND THR-217, AND RP MUTAGENESIS OF THR-175; THR-217 AND CYS-238. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [34] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND SUBCELLULAR LOCATION. RX PubMed=19029340; DOI=10.1083/jcb.200809125; RA Narendra D., Tanaka A., Suen D.F., Youle R.J.; RT "Parkin is recruited selectively to impaired mitochondria and promotes RT their autophagy."; RL J. Cell Biol. 183:795-803(2008). RN [35] RP INTERACTION WITH RNF41, UBIQUITINATION, MUTAGENESIS OF CYS-421, AND RP FUNCTION. RX PubMed=18541373; DOI=10.1016/j.neulet.2008.05.052; RA Yu F., Zhou J.; RT "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative RT stress."; RL Neurosci. Lett. 440:4-8(2008). RN [36] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PARK2 RP PRO-42. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [37] RP FUNCTION IN PROTECTION OF APOPTOSIS, CHARACTERIZATION OF VARIANTS PARK2 RP ASN-161; CYS-256; TRP-275; ARG-418 AND ARG-441, AND DOMAIN. RX PubMed=19801972; DOI=10.1038/ncb1981; RA da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A., Safe S., RA Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S., Shen J., RA Checler F.; RT "Transcriptional repression of p53 by parkin and impairment by mutations RT associated with autosomal recessive juvenile Parkinson's disease."; RL Nat. Cell Biol. 11:1370-1375(2009). RN [38] RP INTERACTION WITH PINK1. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [39] RP FUNCTION, INTERACTION WITH BCL2, SUBCELLULAR LOCATION, AND CHARACTERIZATION RP OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND LEU-437. RX PubMed=20889974; DOI=10.1074/jbc.m110.101469; RA Chen D., Gao F., Li B., Wang H., Xu Y., Zhu C., Wang G.; RT "Parkin mono-ubiquitinates Bcl-2 and regulates autophagy."; RL J. Biol. Chem. 285:38214-38223(2010). RN [40] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PINK1, AND CHARACTERIZATION OF VARIANTS PARK ASN-415 AND ASP-430. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [41] RP FUNCTION, INTERACTION WITH ZNF746, AND CHARACTERIZATION OF VARIANTS PARK2 RP TRP-275; ASP-430 AND PHE-431. RX PubMed=21376232; DOI=10.1016/j.cell.2011.02.010; RA Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., RA Troconso J.C., Dawson V.L., Dawson T.M.; RT "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration RT in Parkinson's disease."; RL Cell 144:689-702(2011). RN [42] RP CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289. RX PubMed=20889486; DOI=10.1093/hmg/ddq428; RA Rose J.M., Novoselov S.S., Robinson P.A., Cheetham M.E.; RT "Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain RT mutant."; RL Hum. Mol. Genet. 20:16-27(2011). RN [43] RP FUNCTION. RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011; RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K., RA De Strooper B., Vandenberghe W.; RT "Parkin interacts with Ambra1 to induce mitophagy."; RL J. Neurosci. 31:10249-10261(2011). RN [44] RP FUNCTION, REACTION MECHANISM, AND INTERACTION WITH UBE2L3. RX PubMed=21532592; DOI=10.1038/nature09966; RA Wenzel D.M., Lissounov A., Brzovic P.S., Klevit R.E.; RT "UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT RT hybrids."; RL Nature 474:105-108(2011). RN [45] RP FUNCTION, INTERACTION WITH CHPF, AND SUBCELLULAR LOCATION. RX PubMed=22082830; DOI=10.1093/hmg/ddr530; RA Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y., Takahashi T., RA Kagawa N., Matsumoto M., Matsumoto M., Takahashi R., Kaji R., Mitsui T.; RT "Parkin interacts with Klokin1 for mitochondrial import and maintenance of RT membrane potential."; RL Hum. Mol. Genet. 21:991-1003(2012). RN [46] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 ASN-211 AND ASN-415. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [47] RP PHOSPHORYLATION AT SER-65, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [48] RP FUNCTION. RX PubMed=23685073; DOI=10.1016/j.molcel.2013.04.012; RA Haddad D.M., Vilain S., Vos M., Esposito G., Matta S., Kalscheuer V.M., RA Craessaerts K., Leyssen M., Nascimento R.M., Vianna-Morgante A.M., RA De Strooper B., Van Esch H., Morais V.A., Verstreken P.; RT "Mutations in the intellectual disability gene Ube2a cause neuronal RT dysfunction and impair parkin-dependent mitophagy."; RL Mol. Cell 50:831-843(2013). RN [49] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [50] RP INTERACTION WITH BAG4; BAG5; HSPA1L; HSPA1A AND HSPA8. RX PubMed=24270810; DOI=10.1038/nature12748; RA Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A., Buehler E., RA Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E., Youle R.J.; RT "High-content genome-wide RNAi screens identify regulators of parkin RT upstream of mitophagy."; RL Nature 504:291-295(2013). RN [51] RP UBIQUITINATION, MUTAGENESIS OF GLY-429, AND CHARACTERIZATION OF VARIANTS RP PARK2 ASN-415 AND ASP-430. RX PubMed=23770917; DOI=10.1038/ncomms2983; RA Spratt D.E., Martinez-Torres R.J., Noh Y.J., Mercier P., Manczyk N., RA Barber K.R., Aguirre J.D., Burchell L., Purkiss A., Walden H., Shaw G.S.; RT "A molecular explanation for the recessive nature of parkin-linked RT Parkinson's disease."; RL Nat. Commun. 4:1983-1983(2013). RN [52] RP FUNCTION IN MITOPHAGY, INTERACTION WITH MFN2, AND SUBCELLULAR LOCATION. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [53] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [54] RP SUBCELLULAR LOCATION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [55] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND CYS-431. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [56] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [57] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND TRP-403. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [58] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [59] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [60] RP FUNCTION. RX PubMed=25621951; DOI=10.1038/ncb3097; RA Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M., RA Kirkpatrick D.S., Bingol B., Corn J.E.; RT "USP30 and parkin homeostatically regulate atypical ubiquitin chains on RT mitochondria."; RL Nat. Cell Biol. 17:160-169(2015). RN [61] RP FUNCTION, ISGYLATION OF LYS-349 AND LYS-369, AND ACTIVITY REGULATION. RX PubMed=27534820; DOI=10.1098/rsob.160193; RA Im E., Yoo L., Hyun M., Shin W.H., Chung K.C.; RT "Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase RT activity of parkin."; RL Open Biol. 6:0-0(2016). RN [62] RP FUNCTION, MUTAGENESIS OF CYS-431, AND CHARACTERIZATION OF VARIANT PARK2 RP ASN-415. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [63] RP FUNCTION. RX PubMed=33499712; DOI=10.1080/15548627.2021.1874133; RA Kojima W., Yamano K., Kosako H., Imai K., Kikuchi R., Tanaka K., RA Matsuda N.; RT "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site RT in response to selective and non-selective autophagy."; RL Autophagy 1:1-26(2021). RN [64] RP STRUCTURE BY NMR OF 1-76, AND INTERACTION WITH PSMD4. RX PubMed=12634850; DOI=10.1038/sj.embor.embor764; RA Sakata E., Yamaguchi Y., Kurimoto E., Kikuchi J., Yokoyama S., Yamada S., RA Kawahara H., Yokosawa H., Hattori N., Mizuno Y., Tanaka K., Kato K.; RT "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin- RT like domain."; RL EMBO Rep. 4:301-306(2003). RN [65] RP STRUCTURE BY NMR OF 307-384 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF RP VARIANT PARK2 PRO-351, MUTAGENESIS OF CYS-332 AND CYS-365, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17360614; DOI=10.1073/pnas.0610548104; RA Beasley S.A., Hristova V.A., Shaw G.S.; RT "Structure of the Parkin in-between-ring domain provides insights for E3- RT ligase dysfunction in autosomal recessive Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 104:3095-3100(2007). RN [66] RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 137-465, ACTIVITY REGULATION, AND RP MUTAGENESIS OF CYS-431; HIS-433 AND GLU-444. RX PubMed=23727886; DOI=10.1038/emboj.2013.125; RA Wauer T., Komander D.; RT "Structure of the human Parkin ligase domain in an autoinhibited state."; RL EMBO J. 32:2099-2112(2013). RN [67] RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 137-465, ACTIVE SITE, CATALYTIC RP ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-431; HIS-433 AND RP GLU-444. RX PubMed=23770887; DOI=10.1038/ncomms2982; RA Riley B.E., Lougheed J.C., Callaway K., Velasquez M., Brecht E., Nguyen L., RA Shaler T., Walker D., Yang Y., Regnstrom K., Diep L., Zhang Z., Chiou S., RA Bova M., Artis D.R., Yao N., Baker J., Yednock T., Johnston J.A.; RT "Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RT RING and HECT ligases."; RL Nat. Commun. 4:1982-1982(2013). RN [68] RP REVIEW ON VARIANTS. RX PubMed=14976155; DOI=10.1093/hmg/ddh089; RA Mata I.F., Lockhart P.J., Farrer M.J.; RT "Parkin genetics: one model for Parkinson's disease."; RL Hum. Mol. Genet. 13:R127-R133(2004). RN [69] RP VARIANT PARK2 ARG-240. RX PubMed=9731209; DOI=10.1006/bbrc.1998.9134; RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RT "Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene."; RL Biochem. Biophys. Res. Commun. 249:754-758(1998). RN [70] RP ERRATUM OF PUBMED:9731209. RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RL Biochem. Biophys. Res. Commun. 251:666-666(1998). RN [71] RP VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415, AND VARIANTS ASN-167; RP LEU-380 AND ASN-394. RX PubMed=10072423; DOI=10.1093/hmg/8.4.567; RA Abbas N., Luecking C.B., Ricard S., Duerr A., Bonifati V., De Michele G., RA Bouley S., Vaughan J.R., Gasser T., Marconi R., Broussolle E., RA Brefel-Courbon C., Harhangi B.S., Oostra B.A., Fabrizio E., Bohme G.A., RA Pradier L., Wood N.W., Filla A., Meco G., Denefle P., Agid Y., Brice A.; RT "A wide variety of mutations in the parkin gene are responsible for RT autosomal recessive parkinsonism in Europe."; RL Hum. Mol. Genet. 8:567-574(1999). RN [72] RP VARIANT ASN-167. RX PubMed=10511432; DOI=10.1097/00001756-199909090-00008; RA Satoh J., Kuroda Y.; RT "Association of codon 167 Ser/Asn heterozygosity in the parkin gene with RT sporadic Parkinson's disease."; RL NeuroReport 10:2735-2739(1999). RN [73] RP VARIANT PARK2 PHE-431. RX PubMed=10939576; RX DOI=10.1002/1531-8249(200008)48:2<245::aid-ana15>3.3.co;2-u; RA Maruyama M., Ikeuchi T., Saito M., Ishikawa A., Yuasa T., Tanaka H., RA Hayashi S., Wakabayashi K., Takahashi H., Tsuji S.; RT "Novel mutations, pseudo-dominant inheritance, and possible familial RT affects in patients with autosomal recessive juvenile parkinsonism."; RL Ann. Neurol. 48:245-250(2000). RN [74] RP VARIANTS ASN-167; TRP-366 AND LEU-380. RX PubMed=10965160; DOI=10.1159/000008203; RA Hu C.-J., Sung S.-M., Liu H.-C., Lee C.-C., Tsai C.-H., Chang J.-G.; RT "Polymorphisms of the parkin gene in sporadic Parkinson's disease among RT Chinese in Taiwan."; RL Eur. Neurol. 44:90-93(2000). RN [75] RP VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; RP GLU-328; ASN-415 AND ASP-430, AND VARIANT CYS-334. RX PubMed=10824074; DOI=10.1056/nejm200005253422103; RA Luecking C.B., Duerr A., Bonifati V., Vaughan J.R., De Michele G., RA Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y., RA Brice A.; RT "Association between early-onset Parkinson's disease and mutations in the RT parkin gene."; RL N. Engl. J. Med. 342:1560-1567(2000). RN [76] RP VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430. RX PubMed=11179010; DOI=10.1086/318791; RA Periquet M., Luecking C.B., Vaughan J.R., Bonifati V., Duerr A., RA De Michele G., Horstink M., Farrer M., Illarioshkin S.N., Pollak P., RA Borg M., Brefel-Courbon C., Denefle P., Meco G., Gasser T., Breteler M.M., RA Wood N.W., Agid Y., Brice A.; RT "Origin of the mutations in the parkin gene in Europe: exon rearrangements RT are independent recurrent events, whereas point mutations may result from RT founder effects."; RL Am. J. Hum. Genet. 68:617-626(2001). RN [77] RP VARIANT PARK2 GLU-82. RX PubMed=11487568; DOI=10.1093/hmg/10.16.1649; RA Hedrich K., Kann M., Lanthaler A.J., Dalski A., Eskelson C., Landt O., RA Schwinger E., Vieregge P., Lang A.E., Breakefield X.O., Ozelius L.J., RA Pramstaller P.P., Klein C.; RT "The importance of gene dosage studies: mutational analysis of the parkin RT gene in early-onset parkinsonism."; RL Hum. Mol. Genet. 10:1649-1656(2001). RN [78] RP VARIANT PARK2 TYR-212. RX PubMed=11163284; DOI=10.1016/s0304-3940(00)01733-x; RA Pineda-Trujillo N., Carvajal-Carmona L.G., Buritica O., Moreno S., RA Uribe C., Pineda D., Toro M., Garcia F., Arias W., Bedoya G., Lopera F., RA Ruiz-Linares A.; RT "A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of RT juvenile parkinsonism in a population from North West Colombia."; RL Neurosci. Lett. 298:87-90(2001). RN [79] RP VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441. RX PubMed=12116199; DOI=10.1002/ajmg.10525; RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.; RT "Complex relationship between parkin mutations and Parkinson disease."; RL Am. J. Med. Genet. 114:584-591(2002). RN [80] RP ERRATUM OF PUBMED:12116199. RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.J.; RL Am. J. Med. Genet. 114:992-992(2002). RN [81] RP VARIANTS PARK2 LEU-37 AND PRO-351. RX PubMed=12112109; DOI=10.1002/ana.10179; RA Kann M., Jacobs H., Mohrmann K., Schumacher K., Hedrich K., Garrels J., RA Wiegers K., Schwinger E., Pramstaller P.P., Breakefield X.O., Ozelius L.J., RA Vieregge P., Klein C.; RT "Role of parkin mutations in 111 community-based patients with early-onset RT parkinsonism."; RL Ann. Neurol. 51:621-625(2002). RN [82] RP VARIANTS PARK2 GLU-56 AND TYR-212. RX PubMed=12056932; DOI=10.1001/archneur.59.6.966; RA Hoenicka J., Vidal L., Morales B., Ampuero I., Jimenez-Jimenez F.J., RA Berciano J., del Ser T., Jimenez A., Ruiz P.G., de Yebenes J.G.; RT "Molecular findings in familial Parkinson disease in Spain."; RL Arch. Neurol. 59:966-970(2002). RN [83] RP VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437. RX PubMed=12114481; DOI=10.1136/jmg.39.7.489; RA Nichols W.C., Pankratz N., Uniacke S.K., Pauciulo M.W., Halter C., RA Rudolph A., Conneally P.M., Foroud T.; RT "Linkage stratification and mutation analysis at the parkin locus RT identifies mutation positive Parkinson's disease families."; RL J. Med. Genet. 39:489-492(2002). RN [84] RP VARIANT PARK2 MET-15, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12397156; DOI=10.1136/jnnp.73.5.582; RA Munoz E., Tolosa E., Pastor P., Marti M.J., Valldeoriola F., RA Campdelacreu J., Oliva R.; RT "Relative high frequency of the c.255delA parkin gene mutation in Spanish RT patients with autosomal recessive parkinsonism."; RL J. Neurol. Neurosurg. Psych. 73:582-584(2002). RN [85] RP VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437. RX PubMed=11971093; DOI=10.1212/wnl.58.8.1239; RA Hedrich K., Marder K., Harris J., Kann M., Lynch T., Meija-Santana H., RA Pramstaller P.P., Schwinger E., Bressman S.B., Fahn S., Klein C.; RT "Evaluation of 50 probands with early-onset Parkinson's disease for parkin RT mutations."; RL Neurology 58:1239-1246(2002). RN [86] RP VARIANT PARK2 PRO-46. RX PubMed=12362318; RA Xu Y., Liu Z., Wang Y., Tao E., Chen G., Chen B.; RT "A new point mutation on exon 2 of parkin gene in Parkinson's disease."; RL Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:409-411(2002). RN [87] RP VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437, VARIANTS PARK TYR-253; RP CYS-256; TRP-275 AND ASN-280, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12730996; DOI=10.1002/ana.10524; RA Oliveira S.A., Scott W.K., Martin E.R., Nance M.A., Watts R.L., RA Hubble J.P., Koller W.C., Pahwa R., Stern M.B., Hiner B.C., Ondo W.G., RA Allen F.H. Jr., Scott B.L., Goetz C.G., Small G.W., Mastaglia F., RA Stajich J.M., Zhang F., Booze M.W., Winn M.P., Middleton L.T., Haines J.L., RA Pericak-Vance M.A., Vance J.M.; RT "Parkin mutations and susceptibility alleles in late-onset Parkinson's RT disease."; RL Ann. Neurol. 53:624-629(2003). RN [88] RP VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437, VARIANT ASN-167, AND RP INVOLVEMENT IN LATE-ONSET PARK. RX PubMed=12629236; DOI=10.1212/01.wnl.0000049470.00180.07; RA Foroud T., Uniacke S.K., Liu L., Pankratz N., Rudolph A., Halter C., RA Shults C., Marder K., Conneally P.M., Nichols W.C.; RT "Heterozygosity for a mutation in the parkin gene leads to later onset RT Parkinson disease."; RL Neurology 60:796-801(2003). RN [89] RP VARIANTS HIS-100; SER-271 AND SER-339. RX PubMed=12781599; DOI=10.1016/s1353-8020(03)00018-x; RA Chen R., Gosavi N.S., Langston J.W., Chan P.; RT "Parkin mutations are rare in patients with young-onset parkinsonism in a RT US population."; RL Parkinsonism Relat. Disord. 9:309-312(2003). RN [90] RP VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418. RX PubMed=15584030; DOI=10.1002/mds.20343; RG Italian Parkinson Genetics Network; RA Bertoli-Avella A.M., Giroud-Benitez J.L., Akyol A., Barbosa E., Schaap O., RA van der Linde H.C., Martignoni E., Lopiano L., Lamberti P., Fincati E., RA Antonini A., Stocchi F., Montagna P., Squitieri F., Marini P., RA Abbruzzese G., Fabbrini G., Marconi R., Dalla Libera A., Trianni G., RA Guidi M., De Gaetano A., Boff Maegawa G., De Leo A., Gallai V., de Rosa G., RA Vanacore N., Meco G., van Duijn C.M., Oostra B.A., Heutink P., Bonifati V.; RT "Novel parkin mutations detected in patients with early-onset Parkinson's RT disease."; RL Mov. Disord. 20:424-431(2005). RN [91] RP CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ASN-211; ARG-240; ASN-280 AND RP GLU-328. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [92] RP VARIANT PARK2 TRP-275. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). RN [93] RP VARIANT CYS-334. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [94] RP CHARACTERIZATION OF VARIANTS PARK PRO-42 AND TRP-275, AND FUNCTION. RX PubMed=29311685; DOI=10.1038/s41467-017-02593-y; RA Wang C., Kang X., Zhou L., Chai Z., Wu Q., Huang R., Xu H., Hu M., Sun X., RA Sun S., Li J., Jiao R., Zuo P., Zheng L., Yue Z., Zhou Z.; RT "Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and RT Parkinson's disease-like pathology."; RL Nat. Commun. 9:81-81(2018). CC -!- FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, CC catalyzing the covalent attachment of ubiquitin moieties onto substrate CC proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:29311685, CC PubMed:32047033). Substrates include SYT11 and VDAC1 (PubMed:29311685, CC PubMed:32047033). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, CC MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and CC AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536). Mediates CC monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and CC 'Lys-63'-linked polyubiquitination of substrates depending on the CC context (PubMed:19229105, PubMed:20889974, PubMed:25474007, CC PubMed:25621951, PubMed:32047033). Participates in the removal and/or CC detoxification of abnormally folded or damaged protein by mediating CC 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: CC 'Lys-63'-linked polyubiquitinated misfolded proteins are then CC recognized by HDAC6, leading to their recruitment to aggresomes, CC followed by degradation (PubMed:17846173, PubMed:19229105). Mediates CC 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated CC isoform of SNCAIP, possibly playing a role in Lewy-body formation CC (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:15728840, CC PubMed:19229105). Mediates monoubiquitination of BCL2, thereby acting CC as a positive regulator of autophagy (PubMed:20889974). Protects CC against mitochondrial dysfunction during cellular stress, by acting CC downstream of PINK1 to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:11439185, PubMed:18957282, PubMed:19029340, CC PubMed:19966284, PubMed:21376232, PubMed:22082830, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24660806, PubMed:24784582, CC PubMed:24896179, PubMed:25474007, PubMed:25527291, PubMed:32047033). CC Depending on the severity of mitochondrial damage and/or dysfunction, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to regulating mitochondrial dynamics and eliminating CC severely damaged mitochondria via mitophagy (PubMed:11439185, CC PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:21376232, CC PubMed:22082830, PubMed:22396657, PubMed:23620051, PubMed:23685073, CC PubMed:23933751, PubMed:24896179, PubMed:25527291, PubMed:32047033, CC PubMed:33499712). Activation and recruitment onto the outer membrane of CC damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated CC phosphorylation of both PRKN and ubiquitin (PubMed:24660806, CC PubMed:24784582, PubMed:25474007, PubMed:25527291). After mitochondrial CC damage, functions with PINK1 to mediate the decision between mitophagy CC or preventing apoptosis by inducing either the poly- or CC monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 CC promotes mitophagy, while monoubiquitination of VDAC1 decreases CC mitochondrial calcium influx which ultimately inhibits apoptosis CC (PubMed:27534820, PubMed:32047033). When cellular stress results in CC irreversible mitochondrial damage, promotes the autophagic degradation CC of dysfunctional depolarized mitochondria (mitophagy) by promoting the CC ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, CC MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, CC PubMed:22396657, PubMed:23620051, PubMed:23685073, PubMed:23933751, CC PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, CC 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to CC mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway CC also promotes fission of damaged mitochondria by PINK1-mediated CC phosphorylation which promotes the PRKN-dependent degradation of CC mitochondrial proteins involved in fission such as MFN2 CC (PubMed:23620051). This prevents the refusion of unhealthy mitochondria CC with the mitochondrial network or initiates mitochondrial fragmentation CC facilitating their later engulfment by autophagosomes CC (PubMed:23620051). Regulates motility of damaged mitochondria via the CC ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor CC neurons, this likely inhibits mitochondrial intracellular anterograde CC transport along the axons which probably increases the chance of the CC mitochondria undergoing mitophagy in the soma (PubMed:22396657). CC Involved in mitochondrial biogenesis via the 'Lys-48'-linked CC polyubiquitination of transcriptional repressor ZNF746/PARIS which CC leads to its subsequent proteasomal degradation and allows activation CC of the transcription factor PPARGC1A (PubMed:21376232). Limits the CC production of reactive oxygen species (ROS) (PubMed:18541373). CC Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In CC collaboration with CHPF isoform 2, may enhance cell viability and CC protect cells from oxidative stress (PubMed:22082830). Independently of CC its ubiquitin ligase activity, protects from apoptosis by the CC transcriptional repression of p53/TP53 (PubMed:19801972). May protect CC neurons against alpha synuclein toxicity, proteasomal dysfunction, CC GPR37 accumulation, and kainate-induced excitotoxicity CC (PubMed:11439185). May play a role in controlling neurotransmitter CC trafficking at the presynaptic terminal and in calcium-dependent CC exocytosis. May represent a tumor suppressor gene (PubMed:12719539). CC {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11439185, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12150907, CC ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:21753002, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23685073, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:25621951, ECO:0000269|PubMed:27534820, CC ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:33499712}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; CC EC=2.3.2.31; Evidence={ECO:0000269|PubMed:23770887}; CC -!- ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe- CC 463 inserts into a hydrophobic groove in RING-0, occluding the CC ubiquitin acceptor site Cys-431, whereas the REP repressor element CC binds RING-1 and blocks its E2-binding site (PubMed:23727886, CC PubMed:23770887). Activation of PRKN requires 2 steps: (1) CC phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated CC ubiquitin, leading to unlock repression of the catalytic Cys-431 by the CC RING-0 region via an allosteric mechanism and converting PRKN to its CC fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25474007, CC PubMed:25527291). According to another report, phosphorylation at Ser- CC 65 by PINK1 is not essential for activation and only binding to CC phosphorylated ubiquitin is essential to unlock repression CC (PubMed:24751536). In addition, ISG15 conjugation positively regulates CC its ubiquitin E3 ligase activity by suppressing the intramolecular CC interaction that maintains its autoinhibited conformation CC (PubMed:27534820). {ECO:0000269|PubMed:23727886, CC ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:27534820}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 CC (PubMed:11078524, PubMed:21532592). Mediates 'Lys-63'-linked CC polyubiquitination by associating with UBE2V1. Part of a SCF-like CC complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). CC Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the CC C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates CC the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including CC STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the CC complex increases during ER stress (PubMed:12150907). STUB1 promotes CC the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN- CC mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently CC associates with unfolded GPR37 and inhibits the E3 activity of PRKN, CC whereas, STUB1 enhances the E3 activity of PRKN through promotion of CC dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). CC Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). CC Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 CC (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes CC nuclear localization and autoubiquitination (PubMed:16955485). CC Interacts (via first RING-type domain) with AIMP2 (via N-terminus) CC (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, CC PubMed:18541373). Interacts with PINK1 (PubMed:19966284, CC PubMed:20798600). Forms a complex with PINK1 and PARK7 CC (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 CC may facilitate PRKN transport into the mitochondria (PubMed:22082830). CC Interacts with MFN2 (phosphorylated), promotes PRKN localization in CC dysfunctional depolarized mitochondria (PubMed:23620051). Interacts CC with FBXO7; this promotes translocation to dysfunctional depolarized CC mitochondria (PubMed:23933751). Interacts with ZNF746 CC (PubMed:21376232). Interacts with heat shock protein 70 family members, CC including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes CC translocation to damaged mitochondria (PubMed:24270810). Interacts with CC BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits CC translocation to damaged mitochondria (PubMed:24270810). Forms a CC complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 CC (By similarity). {ECO:0000250|UniProtKB:Q9WVS6, CC ECO:0000269|PubMed:11078524, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165, CC ECO:0000269|PubMed:12634850, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:14532270, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:15987638, ECO:0000269|PubMed:16135753, CC ECO:0000269|PubMed:16332688, ECO:0000269|PubMed:16352719, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:18541373, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24270810}. CC -!- INTERACTION: CC O60260; P54252-2: ATXN3; NbExp=5; IntAct=EBI-716346, EBI-9684323; CC O60260; Q8IZ52-2: CHPF; NbExp=5; IntAct=EBI-716346, EBI-9029620; CC O60260; Q9Y3I1: FBXO7; NbExp=10; IntAct=EBI-716346, EBI-1161222; CC O60260; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-716346, EBI-9102965; CC O60260; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-716346, EBI-301697; CC O60260; P08238: HSP90AB1; NbExp=2; IntAct=EBI-716346, EBI-352572; CC O60260; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-716346, EBI-739832; CC O60260; Q5S007: LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863; CC O60260; Q86UL8: MAGI2; NbExp=2; IntAct=EBI-716346, EBI-311035; CC O60260; O95140: MFN2; NbExp=4; IntAct=EBI-716346, EBI-3324756; CC O60260; Q16342: PDCD2; NbExp=5; IntAct=EBI-716346, EBI-359462; CC O60260; Q9BXM7: PINK1; NbExp=7; IntAct=EBI-716346, EBI-2846068; CC O60260; Q9BXM7-1: PINK1; NbExp=2; IntAct=EBI-716346, EBI-15643376; CC O60260; O60260: PRKN; NbExp=5; IntAct=EBI-716346, EBI-716346; CC O60260; O14818-1: PSMA7; NbExp=5; IntAct=EBI-716346, EBI-7679034; CC O60260; P49792: RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138; CC O60260; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430; CC O60260; Q15645: TRIP13; NbExp=4; IntAct=EBI-716346, EBI-358993; CC O60260; Q6NUN9: ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525; CC O60260; Q9Z2Q6: Septin5; Xeno; NbExp=2; IntAct=EBI-716346, EBI-772125; CC O60260; P68510: Ywhah; Xeno; NbExp=6; IntAct=EBI-716346, EBI-444641; CC O60260; PRO_0000045592 [Q99IB8]; Xeno; NbExp=3; IntAct=EBI-716346, EBI-6858513; CC O60260-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-21251460, EBI-25840993; CC O60260-5; Q86WR3: ANUBL1; NbExp=3; IntAct=EBI-21251460, EBI-25880850; CC O60260-5; P63010-2: AP2B1; NbExp=6; IntAct=EBI-21251460, EBI-11529439; CC O60260-5; P05067: APP; NbExp=5; IntAct=EBI-21251460, EBI-77613; CC O60260-5; Q0P5N6: ARL16; NbExp=6; IntAct=EBI-21251460, EBI-10186132; CC O60260-5; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-21251460, EBI-25844820; CC O60260-5; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-707573; CC O60260-5; Q8WXK3-2: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-12015080; CC O60260-5; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-21251460, EBI-14199987; CC O60260-5; Q9H672-2: ASB7; NbExp=3; IntAct=EBI-21251460, EBI-12104328; CC O60260-5; Q96DX5: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-745641; CC O60260-5; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-25843552; CC O60260-5; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-21251460, EBI-1048913; CC O60260-5; P54253: ATXN1; NbExp=6; IntAct=EBI-21251460, EBI-930964; CC O60260-5; O14867: BACH1; NbExp=3; IntAct=EBI-21251460, EBI-1263541; CC O60260-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-21251460, EBI-10988864; CC O60260-5; A8KA13: BCL6B; NbExp=3; IntAct=EBI-21251460, EBI-10174813; CC O60260-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-21251460, EBI-2837444; CC O60260-5; P29466-3: CASP1; NbExp=6; IntAct=EBI-21251460, EBI-12248206; CC O60260-5; Q13939: CCIN; NbExp=3; IntAct=EBI-21251460, EBI-25879469; CC O60260-5; P78396-2: CCNA1; NbExp=3; IntAct=EBI-21251460, EBI-21770675; CC O60260-5; Q00535: CDK5; NbExp=3; IntAct=EBI-21251460, EBI-1041567; CC O60260-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-21251460, EBI-350590; CC O60260-5; Q9UBU7: DBF4; NbExp=3; IntAct=EBI-21251460, EBI-372690; CC O60260-5; Q5QP82-2: DCAF10; NbExp=3; IntAct=EBI-21251460, EBI-10983996; CC O60260-5; P61962: DCAF7; NbExp=3; IntAct=EBI-21251460, EBI-359808; CC O60260-5; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-21251460, EBI-25842815; CC O60260-5; Q9BW61: DDA1; NbExp=3; IntAct=EBI-21251460, EBI-2510241; CC O60260-5; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-21251460, EBI-25842538; CC O60260-5; P78352-2: DLG4; NbExp=6; IntAct=EBI-21251460, EBI-631152; CC O60260-5; P31689: DNAJA1; NbExp=6; IntAct=EBI-21251460, EBI-347834; CC O60260-5; O77932: DXO; NbExp=3; IntAct=EBI-21251460, EBI-372173; CC O60260-5; O75530-2: EED; NbExp=3; IntAct=EBI-21251460, EBI-11132357; CC O60260-5; Q8TC29: ENKUR; NbExp=6; IntAct=EBI-21251460, EBI-9246952; CC O60260-5; Q6P1L5: FAM117B; NbExp=3; IntAct=EBI-21251460, EBI-3893327; CC O60260-5; O00757: FBP2; NbExp=3; IntAct=EBI-21251460, EBI-719781; CC O60260-5; P57775: FBXW4; NbExp=3; IntAct=EBI-21251460, EBI-2372268; CC O60260-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-21251460, EBI-396453; CC O60260-5; P22607: FGFR3; NbExp=3; IntAct=EBI-21251460, EBI-348399; CC O60260-5; Q9H2C0: GAN; NbExp=3; IntAct=EBI-21251460, EBI-764342; CC O60260-5; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-21251460, EBI-8799578; CC O60260-5; Q96IK5: GMCL1; NbExp=3; IntAct=EBI-21251460, EBI-2548508; CC O60260-5; P62879: GNB2; NbExp=3; IntAct=EBI-21251460, EBI-356942; CC O60260-5; Q7Z602: GPR141; NbExp=3; IntAct=EBI-21251460, EBI-21649723; CC O60260-5; P06396: GSN; NbExp=3; IntAct=EBI-21251460, EBI-351506; CC O60260-5; P68431: H3C12; NbExp=3; IntAct=EBI-21251460, EBI-79722; CC O60260-5; Q86YM7: HOMER1; NbExp=6; IntAct=EBI-21251460, EBI-746815; CC O60260-5; P0DMV8: HSPA1A; NbExp=6; IntAct=EBI-21251460, EBI-11052499; CC O60260-5; P11142: HSPA8; NbExp=9; IntAct=EBI-21251460, EBI-351896; CC O60260-5; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-21251460, EBI-21911304; CC O60260-5; Q8NA54: IQUB; NbExp=3; IntAct=EBI-21251460, EBI-10220600; CC O60260-5; P05161: ISG15; NbExp=3; IntAct=EBI-21251460, EBI-746466; CC O60260-5; Q9UKP3-2: ITGB1BP2; NbExp=3; IntAct=EBI-21251460, EBI-25856470; CC O60260-5; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-21251460, EBI-25871195; CC O60260-5; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-21251460, EBI-2796400; CC O60260-5; Q6TDP4: KLHL17; NbExp=3; IntAct=EBI-21251460, EBI-21328926; CC O60260-5; O94889: KLHL18; NbExp=3; IntAct=EBI-21251460, EBI-2510096; CC O60260-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-21251460, EBI-714379; CC O60260-5; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-21251460, EBI-6426464; CC O60260-5; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-21251460, EBI-10241252; CC O60260-5; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-21251460, EBI-1044640; CC O60260-5; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-21251460, EBI-1108377; CC O60260-5; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-21251460, EBI-739832; CC O60260-5; O95777: LSM8; NbExp=6; IntAct=EBI-21251460, EBI-347779; CC O60260-5; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-21251460, EBI-373144; CC O60260-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-21251460, EBI-7796455; CC O60260-5; P61244-4: MAX; NbExp=3; IntAct=EBI-21251460, EBI-25848049; CC O60260-5; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-21251460, EBI-4397720; CC O60260-5; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-21251460, EBI-21250407; CC O60260-5; P51948: MNAT1; NbExp=3; IntAct=EBI-21251460, EBI-716139; CC O60260-5; Q8N594: MPND; NbExp=3; IntAct=EBI-21251460, EBI-2512452; CC O60260-5; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-21251460, EBI-10698053; CC O60260-5; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-21251460, EBI-3446748; CC O60260-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-21251460, EBI-1058491; CC O60260-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-21251460, EBI-25830200; CC O60260-5; P68402: PAFAH1B2; NbExp=3; IntAct=EBI-21251460, EBI-713724; CC O60260-5; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-21251460, EBI-17159452; CC O60260-5; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-21251460, EBI-11022007; CC O60260-5; Q96MG8: PCMTD1; NbExp=3; IntAct=EBI-21251460, EBI-2561395; CC O60260-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-21251460, EBI-6309018; CC O60260-5; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-21251460, EBI-716063; CC O60260-5; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-21251460, EBI-12339509; CC O60260-5; Q6ZR37: PLEKHG7; NbExp=6; IntAct=EBI-21251460, EBI-12891828; CC O60260-5; P25786: PSMA1; NbExp=6; IntAct=EBI-21251460, EBI-359352; CC O60260-5; P40306: PSMB10; NbExp=3; IntAct=EBI-21251460, EBI-603329; CC O60260-5; P28070: PSMB4; NbExp=3; IntAct=EBI-21251460, EBI-603350; CC O60260-5; O60671: RAD1; NbExp=6; IntAct=EBI-21251460, EBI-721835; CC O60260-5; Q8NDN9-2: RCBTB1; NbExp=3; IntAct=EBI-21251460, EBI-25880533; CC O60260-5; P41220: RGS2; NbExp=6; IntAct=EBI-21251460, EBI-712388; CC O60260-5; A0A087WUY2: RGS3; NbExp=6; IntAct=EBI-21251460, EBI-25879714; CC O60260-5; O94844: RHOBTB1; NbExp=3; IntAct=EBI-21251460, EBI-6426999; CC O60260-5; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-21251460, EBI-714023; CC O60260-5; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-21251460, EBI-396669; CC O60260-5; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-21251460, EBI-21535400; CC O60260-5; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-21251460, EBI-25829984; CC O60260-5; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-21251460, EBI-749039; CC O60260-5; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-21251460, EBI-2130308; CC O60260-5; Q96A37: RNF166; NbExp=3; IntAct=EBI-21251460, EBI-2130320; CC O60260-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-21251460, EBI-743938; CC O60260-5; Q96BH1: RNF25; NbExp=3; IntAct=EBI-21251460, EBI-2129220; CC O60260-5; P08865: RPSA; NbExp=3; IntAct=EBI-21251460, EBI-354112; CC O60260-5; Q8N488: RYBP; NbExp=6; IntAct=EBI-21251460, EBI-752324; CC O60260-5; Q15393: SF3B3; NbExp=3; IntAct=EBI-21251460, EBI-346977; CC O60260-5; Q2NKQ1-4: SGSM1; NbExp=6; IntAct=EBI-21251460, EBI-10182463; CC O60260-5; Q14190-2: SIM2; NbExp=3; IntAct=EBI-21251460, EBI-21623725; CC O60260-5; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-21251460, EBI-358545; CC O60260-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-21251460, EBI-9845742; CC O60260-5; P37840: SNCA; NbExp=8; IntAct=EBI-21251460, EBI-985879; CC O60260-5; Q9Y6H5-5: SNCAIP; NbExp=6; IntAct=EBI-21251460, EBI-25880040; CC O60260-5; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-21251460, EBI-538492; CC O60260-5; O14544: SOCS6; NbExp=3; IntAct=EBI-21251460, EBI-3929549; CC O60260-5; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-21251460, EBI-11959123; CC O60260-5; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-21251460, EBI-2510414; CC O60260-5; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-21251460, EBI-8345366; CC O60260-5; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-21251460, EBI-5235340; CC O60260-5; Q9C004: SPRY4; NbExp=3; IntAct=EBI-21251460, EBI-354861; CC O60260-5; Q96BD6: SPSB1; NbExp=3; IntAct=EBI-21251460, EBI-2659201; CC O60260-5; Q99619: SPSB2; NbExp=3; IntAct=EBI-21251460, EBI-2323209; CC O60260-5; O75886: STAM2; NbExp=3; IntAct=EBI-21251460, EBI-373258; CC O60260-5; O95630: STAMBP; NbExp=3; IntAct=EBI-21251460, EBI-396676; CC O60260-5; Q9UNE7: STUB1; NbExp=6; IntAct=EBI-21251460, EBI-357085; CC O60260-5; Q9BT88: SYT11; NbExp=6; IntAct=EBI-21251460, EBI-751770; CC O60260-5; Q13148: TARDBP; NbExp=3; IntAct=EBI-21251460, EBI-372899; CC O60260-5; Q16650: TBR1; NbExp=6; IntAct=EBI-21251460, EBI-1047158; CC O60260-5; Q15554-4: TERF2; NbExp=6; IntAct=EBI-21251460, EBI-25840535; CC O60260-5; Q04724: TLE1; NbExp=3; IntAct=EBI-21251460, EBI-711424; CC O60260-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-21251460, EBI-25831574; CC O60260-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-21251460, EBI-74615; CC O60260-5; P19474: TRIM21; NbExp=3; IntAct=EBI-21251460, EBI-81290; CC O60260-5; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-21251460, EBI-17716262; CC O60260-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-21251460, EBI-25840976; CC O60260-5; P57075-2: UBASH3A; NbExp=6; IntAct=EBI-21251460, EBI-7353612; CC O60260-5; P0CG47: UBB; NbExp=6; IntAct=EBI-21251460, EBI-413034; CC O60260-5; O15205: UBD; NbExp=3; IntAct=EBI-21251460, EBI-6657186; CC O60260-5; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-21251460, EBI-988826; CC O60260-5; P68036: UBE2L3; NbExp=3; IntAct=EBI-21251460, EBI-711173; CC O60260-5; P61081: UBE2M; NbExp=3; IntAct=EBI-21251460, EBI-1041660; CC O60260-5; Q9C0C9: UBE2O; NbExp=3; IntAct=EBI-21251460, EBI-2339946; CC O60260-5; Q13404: UBE2V1; NbExp=3; IntAct=EBI-21251460, EBI-1050671; CC O60260-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-21251460, EBI-11530712; CC O60260-5; Q9Y3C8: UFC1; NbExp=3; IntAct=EBI-21251460, EBI-1045733; CC O60260-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-21251460, EBI-17761788; CC O60260-5; O75604-3: USP2; NbExp=3; IntAct=EBI-21251460, EBI-10696113; CC O60260-5; P18206-2: VCL; NbExp=6; IntAct=EBI-21251460, EBI-11027067; CC O60260-5; P45880: VDAC2; NbExp=6; IntAct=EBI-21251460, EBI-354022; CC O60260-5; P40337-2: VHL; NbExp=3; IntAct=EBI-21251460, EBI-12157263; CC O60260-5; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-21251460, EBI-11141397; CC O60260-5; O00308: WWP2; NbExp=3; IntAct=EBI-21251460, EBI-743923; CC O60260-5; Q04917: YWHAH; NbExp=6; IntAct=EBI-21251460, EBI-306940; CC O60260-5; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-21251460, EBI-25842419; CC O60260-5; Q15916: ZBTB6; NbExp=3; IntAct=EBI-21251460, EBI-7227791; CC O60260-5; Q9Y649; NbExp=3; IntAct=EBI-21251460, EBI-25900580; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24898855}. Nucleus CC {ECO:0000269|PubMed:16955485}. Endoplasmic reticulum CC {ECO:0000269|PubMed:19501131}. Mitochondrion CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24898855}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:Q9WVS6}. Cell projection, neuron projection CC {ECO:0000269|PubMed:12925569}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9WVS6}. Presynapse CC {ECO:0000250|UniProtKB:Q9WVS6}. Note=Mainly localizes in the cytosol CC (PubMed:19029340, PubMed:19229105). Co-localizes with SYT11 in CC neutrites (PubMed:12925569). Co-localizes with SNCAIP in brainstem Lewy CC bodies (PubMed:10319893, PubMed:11431533). Translocates to CC dysfunctional mitochondria that have lost the mitochondrial membrane CC potential; recruitment to mitochondria is PINK1-dependent CC (PubMed:18957282, PubMed:19966284, PubMed:23620051, PubMed:24898855). CC Mitochondrial localization also gradually increases with cellular CC growth (PubMed:22082830). {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:24898855}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=1; CC IsoId=O60260-1; Sequence=Displayed; CC Name=2; Synonyms=SV5DEL; CC IsoId=O60260-2; Sequence=VSP_011707; CC Name=3; CC IsoId=O60260-3; Sequence=VSP_011706, VSP_011709, VSP_011710; CC Name=4; CC IsoId=O60260-4; Sequence=VSP_011705; CC Name=5; CC IsoId=O60260-5; Sequence=VSP_011708, VSP_011711, VSP_011712; CC Name=6; CC IsoId=O60260-6; Sequence=VSP_041563; CC Name=7; Synonyms=SV5,9DEL; CC IsoId=O60260-7; Sequence=VSP_011707, VSP_053651; CC Name=8; Synonyms=SV9DEL; CC IsoId=O60260-8; Sequence=VSP_053651; CC -!- TISSUE SPECIFICITY: Highly expressed in the brain including the CC substantia nigra (PubMed:19501131, PubMed:9560156). Expressed in heart, CC testis and skeletal muscle (PubMed:9560156). Expression is down- CC regulated or absent in tumor biopsies, and absent in the brain of PARK2 CC patients (PubMed:12719539, PubMed:14614460). Overexpression protects CC dopamine neurons from kainate-mediated apoptosis (PubMed:12628165). CC Found in serum (at protein level) (PubMed:19501131). CC {ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:14614460, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:9560156}. CC -!- DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S CC proteasomes. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: The RING-type 1 zinc finger domain is required to repress CC p53/TP53 transcription. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: Members of the RBR family are atypical E3 ligases. They CC interact with the E2 conjugating enzyme UBE2L3 and function like HECT- CC type E3 enzymes: they bind E2s via the first RING domain, but require CC an obligate trans-thiolation step during the ubiquitin transfer, CC requiring a conserved cysteine residue in the second RING domain. CC {ECO:0000269|PubMed:23770917, ECO:0000305|PubMed:21532592}. CC -!- PTM: ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN- CC beta stimulation. ISGylation positively regulates its E3 ligase CC activity. {ECO:0000269|PubMed:27534820}. CC -!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own CC degradation (PubMed:19229105, PubMed:23770917, PubMed:25474007). Also CC polyubiquitinated by RNF41 for proteasomal degradation CC (PubMed:19229105). {ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:25474007}. CC -!- PTM: S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase CC activity by S-nitrosylation could contribute to the degenerative CC process in PD by impairing the ubiquitination of PRKN substrates. CC {ECO:0000269|PubMed:15105460}. CC -!- PTM: Phosphorylated (PubMed:18957282, PubMed:23754282, PubMed:24660806, CC PubMed:24784582, PubMed:25474007). Activation requires phosphorylation CC at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin CC (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, CC PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is CC important for mitochondrial localization (PubMed:18957282). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12629236, CC ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:29311685}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC Heterozygous mutations act as susceptibility alleles for late-onset CC Parkinson disease (PubMed:12629236, PubMed:12730996). CC -!- DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: An autosomal CC recessive form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability. PARK2 differs from classic forms of CC Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation CC of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia CC is absent. Pathologically, patients show loss of dopaminergic neurons CC in the substantia nigra, similar to that seen in classic Parkinson CC disease; however, Lewy bodies (intraneuronal accumulations of CC aggregated proteins) are absent. Disease onset is usually before age 40 CC years. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, CC ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, CC ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, CC ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, CC ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, CC ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, CC ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, CC ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, CC ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:9560156, CC ECO:0000269|PubMed:9731209}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PRKN may be involved in the development and/or CC progression of ovarian cancer. CC -!- MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q telomere is CC hyper-recombinable and lies within FRA6E, the third most common fragile CC site in tumor tissue. CC -!- SIMILARITY: Belongs to the RBR family. Parkin subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue 131 CC of September 2011; CC URL="https://www.proteinspotlight.org/back_issues/131"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB009973; BAA25751.1; -; mRNA. DR EMBL; EF375726; ABN46990.1; -; mRNA. DR EMBL; AF381282; AAM21457.1; -; mRNA. DR EMBL; AF381283; AAM21458.1; -; mRNA. DR EMBL; AF381286; AAM21461.1; -; mRNA. DR EMBL; GU345839; ADB90270.1; -; mRNA. DR EMBL; GU345840; ADB90271.1; -; mRNA. DR EMBL; GU361467; ADB91979.1; -; mRNA. DR EMBL; AK292590; BAF85279.1; -; mRNA. DR EMBL; AL035697; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL132982; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000886; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001576; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001577; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001578; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP003699; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47573.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47574.1; -; Genomic_DNA. DR EMBL; BC022014; AAH22014.1; -; mRNA. DR EMBL; AY564225; AAS88422.1; -; Genomic_DNA. DR CCDS; CCDS5281.1; -. [O60260-1] DR CCDS; CCDS5282.1; -. [O60260-2] DR CCDS; CCDS5283.1; -. [O60260-6] DR RefSeq; NP_004553.2; NM_004562.3. [O60260-1] DR RefSeq; NP_054642.2; NM_013987.3. [O60260-2] DR RefSeq; NP_054643.2; NM_013988.3. [O60260-6] DR PDB; 1IYF; NMR; -; A=1-76. DR PDB; 2JMO; NMR; -; A=308-384. DR PDB; 4BM9; X-ray; 2.25 A; A=137-465. DR PDB; 4I1F; X-ray; 1.58 A; A=141-465. DR PDB; 4I1H; X-ray; 2.00 A; A=141-465. DR PDB; 5C1Z; X-ray; 1.79 A; A/B=1-465. DR PDB; 5C23; X-ray; 2.37 A; A/B=1-465. DR PDB; 5C9V; X-ray; 2.35 A; A=137-465. DR PDB; 5N2W; X-ray; 2.68 A; A=1-465. DR PDB; 5N38; X-ray; 2.60 A; A=1-465. DR PDB; 5TR5; NMR; -; A=1-76. DR PDB; 6GLC; X-ray; 1.80 A; A=1-382. DR PDB; 6HUE; X-ray; 2.85 A; A/B=1-465. DR PDB; 6N13; NMR; -; B=144-465. DR PDB; 8IK6; X-ray; 3.30 A; A/C=139-465. DR PDB; 8IKM; X-ray; 1.92 A; A=141-382, C=1-140. DR PDB; 8IKT; X-ray; 2.60 A; A=77-382, C=1-76. DR PDB; 8IKV; X-ray; 2.35 A; A/C=139-465. DR PDB; 8JWV; X-ray; 2.90 A; A=141-465. DR PDB; 8WZN; X-ray; 1.80 A; A=141-465. DR PDB; 8WZO; X-ray; 2.25 A; A=141-465. DR PDBsum; 1IYF; -. DR PDBsum; 2JMO; -. DR PDBsum; 4BM9; -. DR PDBsum; 4I1F; -. DR PDBsum; 4I1H; -. DR PDBsum; 5C1Z; -. DR PDBsum; 5C23; -. DR PDBsum; 5C9V; -. DR PDBsum; 5N2W; -. DR PDBsum; 5N38; -. DR PDBsum; 5TR5; -. DR PDBsum; 6GLC; -. DR PDBsum; 6HUE; -. DR PDBsum; 6N13; -. DR PDBsum; 8IK6; -. DR PDBsum; 8IKM; -. DR PDBsum; 8IKT; -. DR PDBsum; 8IKV; -. DR PDBsum; 8JWV; -. DR PDBsum; 8WZN; -. DR PDBsum; 8WZO; -. DR AlphaFoldDB; O60260; -. DR BMRB; O60260; -. DR SMR; O60260; -. DR BioGRID; 111105; 3437. DR CORUM; O60260; -. DR DIP; DIP-37655N; -. DR FunCoup; O60260; 952. DR IntAct; O60260; 311. DR MINT; O60260; -. DR STRING; 9606.ENSP00000355865; -. DR BindingDB; O60260; -. DR TCDB; 8.A.52.2.1; the ubiquitin-related protein degradation (upd) family. DR GlyGen; O60260; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O60260; -. DR PhosphoSitePlus; O60260; -. DR BioMuta; PRKN; -. DR MassIVE; O60260; -. DR PaxDb; 9606-ENSP00000355865; -. DR PeptideAtlas; O60260; -. DR ProteomicsDB; 49290; -. [O60260-1] DR ProteomicsDB; 49291; -. [O60260-2] DR ProteomicsDB; 49292; -. [O60260-3] DR ProteomicsDB; 49293; -. [O60260-4] DR ProteomicsDB; 49294; -. [O60260-5] DR ProteomicsDB; 49295; -. [O60260-6] DR Antibodypedia; 4264; 797 antibodies from 52 providers. DR DNASU; 5071; -. DR Ensembl; ENST00000366896.5; ENSP00000355862.1; ENSG00000185345.25. [O60260-6] DR Ensembl; ENST00000366897.5; ENSP00000355863.1; ENSG00000185345.25. [O60260-2] DR Ensembl; ENST00000366898.6; ENSP00000355865.1; ENSG00000185345.25. [O60260-1] DR Ensembl; ENST00000479615.5; ENSP00000434414.1; ENSG00000185345.25. [O60260-3] DR GeneID; 5071; -. DR KEGG; hsa:5071; -. DR MANE-Select; ENST00000366898.6; ENSP00000355865.1; NM_004562.3; NP_004553.2. DR UCSC; uc003qty.5; human. [O60260-1] DR AGR; HGNC:8607; -. DR CIViC; 5071; 2 evidence items across 2 molecular profiles. DR ClinPGx; PA32942; -. DR CTD; 5071; -. DR DisGeNET; 5071; -. DR GeneCards; PRKN; -. DR GeneReviews; PRKN; -. DR HGNC; HGNC:8607; PRKN. DR HPA; ENSG00000185345; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PRKN; -. DR MIM; 168600; phenotype. DR MIM; 600116; phenotype. DR MIM; 602544; gene. DR OpenTargets; ENSG00000185345; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000185345; -. DR eggNOG; KOG0006; Eukaryota. DR GeneTree; ENSGT00390000011034; -. DR HOGENOM; CLU_050804_0_0_1; -. DR InParanoid; O60260; -. DR OMA; DPKWDIK; -. DR OrthoDB; 1431934at2759; -. DR PAN-GO; O60260; 15 GO annotations based on evolutionary models. DR PhylomeDB; O60260; -. DR BRENDA; 2.3.2.27; 2681. DR BRENDA; 2.3.2.31; 2681. DR PathwayCommons; O60260; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; O60260; -. DR SIGNOR; O60260; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000185345; -. DR BioGRID-ORCS; 5071; 13 hits in 1187 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PARK2; human. DR EvolutionaryTrace; O60260; -. DR GeneWiki; Parkin_(ligase); -. DR GenomeRNAi; 5071; -. DR Pharos; O60260; Tbio. DR PRO; PR:O60260; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O60260; protein. DR Bgee; ENSG00000185345; Expressed in sural nerve and 107 other cell types or tissues. DR ExpressionAtlas; O60260; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:1990452; C:Parkin-FBXW7-Cul1 ubiquitin ligase complex; IPI:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0097602; F:cullin family protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990444; F:F-box domain binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0031072; F:heat shock protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042826; F:histone deacetylase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0043274; F:phospholipase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0017124; F:SH3 domain binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0003714; F:transcription corepressor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0015631; F:tubulin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IMP:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008270; F:zinc ion binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IMP:BHF-UCL. DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome. DR GO; GO:0000422; P:autophagy of mitochondrion; IDA:UniProtKB. DR GO; GO:1903351; P:cellular response to dopamine; TAS:ParkinsonsUK-UCL. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:1905232; P:cellular response to L-glutamate; IEA:Ensembl. DR GO; GO:1904845; P:cellular response to L-glutamine; IEA:Ensembl. DR GO; GO:0071287; P:cellular response to manganese ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; TAS:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; IMP:ParkinsonsUK-UCL. DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL. DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc. DR GO; GO:0042417; P:dopamine metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl. DR GO; GO:0036503; P:ERAD pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0010994; P:free ubiquitin chain polymerization; IMP:ParkinsonsUK-UCL. DR GO; GO:0044828; P:host-mediated suppression of viral genome replication; IDA:AgBase. DR GO; GO:0007612; P:learning; IEA:Ensembl. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0000266; P:mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IEA:Ensembl. DR GO; GO:0051646; P:mitochondrion localization; IEA:Ensembl. DR GO; GO:0007005; P:mitochondrion organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IDA:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProtKB. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0032232; P:negative regulation of actin filament bundle assembly; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903382; P:negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:1903542; P:negative regulation of exosomal secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0033132; P:negative regulation of glucokinase activity; IDA:MGI. DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:MGI. DR GO; GO:1905366; P:negative regulation of intralumenal vesicle formation; IMP:ParkinsonsUK-UCL. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IEA:Ensembl. DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IEA:Ensembl. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:BHF-UCL. DR GO; GO:1904049; P:negative regulation of spontaneous neurotransmitter secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0051967; P:negative regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:ParkinsonsUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:ParkinsonsUK-UCL. DR GO; GO:0042415; P:norepinephrine metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0010636; P:positive regulation of mitochondrial fusion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IEA:Ensembl. DR GO; GO:1901526; P:positive regulation of mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0051582; P:positive regulation of neurotransmitter uptake; IMP:ParkinsonsUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; IGI:ParkinsonsUK-UCL. DR GO; GO:1905477; P:positive regulation of protein localization to membrane; IMP:ParkinsonsUK-UCL. DR GO; GO:1905281; P:positive regulation of retrograde transport, endosome to Golgi; NAS:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:BHF-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0016579; P:protein deubiquitination; TAS:Reactome. DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0044314; P:protein K27-linked ubiquitination; IDA:UniProt. DR GO; GO:0035519; P:protein K29-linked ubiquitination; TAS:ParkinsonsUK-UCL. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0085020; P:protein K6-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; IEA:Ensembl. DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:ParkinsonsUK-UCL. DR GO; GO:0010906; P:regulation of glucose metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0032368; P:regulation of lipid transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome. DR GO; GO:0099072; P:regulation of postsynaptic membrane neurotransmitter receptor levels; IEA:Ensembl. DR GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IMP:ParkinsonsUK-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; NAS:ParkinsonsUK-UCL. DR GO; GO:0140251; P:regulation protein catabolic process at presynapse; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:1904643; P:response to curcumin; IEA:Ensembl. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:ParkinsonsUK-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0001964; P:startle response; IEA:Ensembl. DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0061734; P:type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd20340; BRcat_RBR_parkin; 1. DR CDD; cd20357; Rcat_RBR_parkin; 1. DR CDD; cd16627; RING-HC_RBR_parkin; 1. DR CDD; cd21382; RING0_parkin; 1. DR CDD; cd01798; Ubl_parkin; 1. DR DisProt; DP01849; -. DR FunFam; 1.20.120.1750:FF:000009; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 2.20.25.20:FF:000008; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 3.10.20.90:FF:000142; E3 ubiquitin-protein ligase parkin; 1. DR Gene3D; 1.20.120.1750; -; 1. DR Gene3D; 2.20.25.20; -; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00008; -. DR InterPro; IPR047534; BRcat_RBR_parkin. DR InterPro; IPR002867; IBR_dom. DR InterPro; IPR003977; Parkin. DR InterPro; IPR054694; Parkin-like_IBR. DR InterPro; IPR041565; Parkin_Znf-RING. DR InterPro; IPR047536; Rcat_RBR_parkin. DR InterPro; IPR047535; RING-HC_RBR_parkin. DR InterPro; IPR044066; TRIAD_supradom. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR041170; Znf-RING_14. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR PANTHER; PTHR10677:SF40; UBIQUITIN-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF22605; IBR_2; 1. DR Pfam; PF00240; ubiquitin; 1. DR Pfam; PF17976; zf-RING_12; 1. DR Pfam; PF17978; zf-RING_14; 1. DR PIRSF; PIRSF037880; Parkin; 1. DR PRINTS; PR01475; PARKIN. DR SMART; SM00647; IBR; 2. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cell projection; Cytoplasm; KW Disease variant; Endoplasmic reticulum; Isopeptide bond; Membrane; KW Metal-binding; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW S-nitrosylation; Synapse; Transcription; Transcription regulation; KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..465 FT /note="E3 ubiquitin-protein ligase parkin" FT /id="PRO_0000058576" FT DOMAIN 1..76 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT ZN_FING 141..225 FT /note="RING-type 0; atypical" FT ZN_FING 238..293 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 313..377 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 418..449 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 77..237 FT /note="Necessary for PINK1-dependent localization to FT mitochondria" FT /evidence="ECO:0000269|PubMed:18957282" FT REGION 77..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 204..238 FT /note="SYT11 binding 1" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 234..465 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 257..293 FT /note="SYT11 binding 2" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 378..410 FT /note="REP" FT /evidence="ECO:0000250|UniProtKB:Q9JK66" FT ACT_SITE 431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 238 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 241 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 253 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 257 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 260 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 263 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 289 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 293 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 332 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 337 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 352 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 360 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 365 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 368 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 373 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 418 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 421 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 436 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 441 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 446 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 449 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 457 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 461 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT MOD_RES 65 FT /note="Phosphoserine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MOD_RES 175 FT /note="Phosphothreonine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282" FT MOD_RES 217 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:18957282" FT CROSSLNK 349 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT CROSSLNK 369 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT VAR_SEQ 1..191 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011705" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011706" FT VAR_SEQ 58..206 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_041563" FT VAR_SEQ 179..206 FT /note="Missing (in isoform 2 and isoform 7)" FT /evidence="ECO:0000303|PubMed:9560156, ECO:0000303|Ref.4" FT /id="VSP_011707" FT VAR_SEQ 290 FT /note="V -> VGTGDTVVLRGALGGFRRGV (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011708" FT VAR_SEQ 291..297 FT /note="AGCPNSL -> VCLLPGM (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011709" FT VAR_SEQ 298..465 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011710" FT VAR_SEQ 312..361 FT /note="Missing (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_053651" FT VAR_SEQ 362..368 FT /note="FAFCREC -> YGQRRTK (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011711" FT VAR_SEQ 369..465 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011712" FT VARIANT 15 FT /note="V -> M (in PARK2; dbSNP:rs532703934)" FT /evidence="ECO:0000269|PubMed:12397156" FT /id="VAR_019733" FT VARIANT 33 FT /note="R -> Q (in PARK2; dbSNP:rs147757966)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019734" FT VARIANT 37 FT /note="P -> L (in PARK2; dbSNP:rs148990138)" FT /evidence="ECO:0000269|PubMed:12112109" FT /id="VAR_019735" FT VARIANT 42 FT /note="R -> P (in PARK2 and PARK; induces a conformational FT change in the PSMD4-binding site of Ubl resulting in FT impaired proteasomal binding; decreases ubiquitination and FT degradation; increased aggregation; impairs the ability to FT ubiquitinate and degrade SYT11; dbSNP:rs368134308)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:29311685" FT /id="VAR_019736" FT VARIANT 46 FT /note="A -> P (in PARK2)" FT /evidence="ECO:0000269|PubMed:12362318" FT /id="VAR_019737" FT VARIANT 56 FT /note="V -> E (in PARK2; dbSNP:rs137853059)" FT /evidence="ECO:0000269|PubMed:12056932" FT /id="VAR_070078" FT VARIANT 82 FT /note="A -> E (in PARK2; dbSNP:rs55774500)" FT /evidence="ECO:0000269|PubMed:11487568, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12730996" FT /id="VAR_019738" FT VARIANT 92 FT /note="A -> V (in PARK2; dbSNP:rs566229879)" FT /id="VAR_019739" FT VARIANT 100 FT /note="Q -> H (in dbSNP:rs1256316516)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019740" FT VARIANT 161 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs137853057)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974" FT /id="VAR_019741" FT VARIANT 167 FT /note="S -> N (in dbSNP:rs1801474)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10511432, ECO:0000269|PubMed:10965160, FT ECO:0000269|PubMed:12629236" FT /id="VAR_019742" FT VARIANT 192 FT /note="M -> L (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:11971093" FT /id="VAR_054107" FT VARIANT 192 FT /note="M -> V (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019743" FT VARIANT 211 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; loss FT of activity towards MIRO1; dbSNP:rs137853060)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:12114481, FT ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:20404107, FT ECO:0000269|PubMed:22396657" FT /id="VAR_019744" FT VARIANT 212 FT /note="C -> Y (in PARK2; dbSNP:rs137853058)" FT /evidence="ECO:0000269|PubMed:11163284, FT ECO:0000269|PubMed:12056932" FT /id="VAR_019746" FT VARIANT 240 FT /note="T -> M (in PARK2; dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019747" FT VARIANT 240 FT /note="T -> R (in PARK2; impairs the ability to FT ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; FT severely compromises the mitochondrial localization; FT dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974, FT ECO:0000269|PubMed:9731209" FT /id="VAR_019748" FT VARIANT 253 FT /note="C -> Y (in PARK; late onset; dbSNP:rs747427602)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019749" FT VARIANT 256 FT /note="R -> C (in PARK2 and PARK; uncertain significance; FT impairs the ability to ubiquitinate SNCAIP and ZNF746; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs150562946)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972" FT /id="VAR_019750" FT VARIANT 271 FT /note="R -> S (in dbSNP:rs772622421)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019751" FT VARIANT 275 FT /note="R -> W (in PARK2 and PARK; impairs the ability to FT ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional FT repression; impairs the ability to ubiquitinate and degrade FT SYT11; dbSNP:rs34424986)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11179010, FT ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:29311685" FT /id="VAR_019752" FT VARIANT 280 FT /note="D -> N (in PARK; does not affect PINK-1 dependent FT localization to depolarized mitochondria; FT dbSNP:rs72480422)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20404107" FT /id="VAR_019753" FT VARIANT 284 FT /note="G -> R (in PARK2; dbSNP:rs751037529)" FT /id="VAR_019754" FT VARIANT 289 FT /note="C -> G (in PARK2; increased aggregation; fails to FT ubiquitinate SYT11; loses ability to bind SYT11; impaired FT relocalization to damaged mitochondria; loss of function in FT mitophagy; dbSNP:rs55961220)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:20889486" FT /id="VAR_019755" FT VARIANT 311 FT /note="Q -> R (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062672" FT VARIANT 328 FT /note="G -> E (in PARK2; does not affect PINK-1 dependent FT localization to depolarized mitochondria)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:20404107" FT /id="VAR_019756" FT VARIANT 334 FT /note="R -> C (in dbSNP:rs199657839)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:27535533" FT /id="VAR_019757" FT VARIANT 339 FT /note="A -> S (in dbSNP:rs1554274880)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019758" FT VARIANT 351 FT /note="T -> P (in PARK2; impairs folding of IBR domain; FT dbSNP:rs1554274861)" FT /evidence="ECO:0000269|PubMed:12112109, FT ECO:0000269|PubMed:17360614" FT /id="VAR_019759" FT VARIANT 366 FT /note="R -> W (in dbSNP:rs56092260)" FT /evidence="ECO:0000269|PubMed:10965160" FT /id="VAR_019760" FT VARIANT 371 FT /note="A -> T (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062673" FT VARIANT 380 FT /note="V -> L (in dbSNP:rs1801582)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10965160, ECO:0000269|PubMed:12397156, FT ECO:0000269|PubMed:12730996" FT /id="VAR_019761" FT VARIANT 394 FT /note="D -> N (in dbSNP:rs1801334)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12730996" FT /id="VAR_019762" FT VARIANT 402 FT /note="R -> C (in PARK2; dbSNP:rs55830907)" FT /evidence="ECO:0000269|PubMed:15584030" FT /id="VAR_070079" FT VARIANT 415 FT /note="T -> N (in PARK2; loss of activity and self- FT ubiquitination; impairs the ability to ubiquitinate SNCAIP; FT no effect on polyubiquitination or mitophagy; does not FT affect turnover of CDCRE1; impairs PINK1-dependent FT localization to dysfunctional depolarized mitochondria; FT dbSNP:rs778125254)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19966284, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23770917, FT ECO:0000269|PubMed:32047033" FT /id="VAR_019763" FT VARIANT 418 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; fails FT to ubiquitinate SYT11 but does not loose ability to bind FT SYT11; dbSNP:rs1554252200)" FT /evidence="ECO:0000269|PubMed:12925569, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19801972" FT /id="VAR_070080" FT VARIANT 430 FT /note="G -> D (in PARK2; loss of self-ubiquitination; FT impairs PINK1-dependent localization to dysfunctional FT depolarized mitochondria; impaired E3 ubiquitin-protein FT ligase toward ZNF746; dbSNP:rs191486604)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12730996, FT ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:21376232, FT ECO:0000269|PubMed:23770917" FT /id="VAR_019764" FT VARIANT 431 FT /note="C -> F (in PARK2; impaired E3 ubiquitin-protein FT ligase toward ZNF746 and BCL2; dbSNP:rs397514694)" FT /evidence="ECO:0000269|PubMed:10939576, FT ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232" FT /id="VAR_019765" FT VARIANT 437 FT /note="P -> L (in PARK2; impaired E3 ubiquitin-protein FT ligase toward BCL2; dbSNP:rs149953814)" FT /evidence="ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12629236, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20889974" FT /id="VAR_019766" FT VARIANT 441 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; FT dbSNP:rs778305273)" FT /evidence="ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:19801972" FT /id="VAR_019767" FT MUTAGEN 65 FT /note="S->A: Loss of phosphorylation. Undergoes FT autoubiquitination in the presence of phosphorylated FT ubiquitin." FT /evidence="ECO:0000269|PubMed:25474007" FT MUTAGEN 65 FT /note="S->E: Phosphomimetic mutant; still requires PINK1 FT for activation. PRKN is activated in presence of FT phosphorylated ubiquitin." FT /evidence="ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MUTAGEN 175 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 175 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 238 FT /note="C->S: Loss of mitochondrial localization." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 332 FT /note="C->S: Impairs folding of IBR domain." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 337 FT /note="C->A: Impairs the ability to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439" FT MUTAGEN 365 FT /note="C->S: Impairs protein folding." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 403 FT /note="W->A: Decreased autoinhibition and increased E3 FT activity." FT /evidence="ECO:0000269|PubMed:24784582" FT MUTAGEN 421 FT /note="C->A: Impairs the ability of self-ubiquitination and FT to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:18541373" FT MUTAGEN 429 FT /note="G->E: Reduced self-ubiquitination." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->S: Impairs the ability to ubiquitinate target FT proteins. No effect on translocation to mitochondria." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:23727886, ECO:0000269|PubMed:23770887, FT ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:32047033" FT MUTAGEN 433 FT /note="H->N,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT MUTAGEN 444 FT /note="E->Q,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT CONFLICT 223 FT /note="S -> P (in Ref. 1; BAA25751 and 3; AAM21458/ FT AAM21457)" FT /evidence="ECO:0000305" FT CONFLICT 289..290 FT /note="CV -> MI (in Ref. 2; AAM21461)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="A -> V (in Ref. 9; AAS88422)" FT /evidence="ECO:0000305" FT STRAND 2..11 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 13..16 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 19..21 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 23..34 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 38..40 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 41..45 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 48..50 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 52..55 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 62..64 FT /evidence="ECO:0007829|PDB:5N2W" FT STRAND 66..71 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 147..150 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 156..166 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 174..178 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 183..187 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 188..190 FT /evidence="ECO:0007829|PDB:8WZO" FT STRAND 192..196 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5N38" FT STRAND 205..212 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:4I1H" FT TURN 239..241 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 257..260 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 261..273 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 281..283 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 290..292 FT /evidence="ECO:0007829|PDB:6N13" FT HELIX 301..307 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 309..326 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 348..351 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 355..358 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 366..368 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 374..376 FT /evidence="ECO:0007829|PDB:6GLC" FT HELIX 379..381 FT /evidence="ECO:0007829|PDB:4BM9" FT HELIX 395..400 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 403..406 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 414..417 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 419..421 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 424..426 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 429..431 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 433..435 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 439..441 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 447..449 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 455..461 FT /evidence="ECO:0007829|PDB:4I1F" SQ SEQUENCE 465 AA; 51641 MW; 9A8BB802A3FC84C3 CRC64; MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG CEWNRVCMGD HWFDV // ID PSN1_HUMAN Reviewed; 467 AA. AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 263. DE RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240}; DE Short=PS-1 {ECO:0000303|PubMed:9298817}; DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335}; DE AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356}; DE Contains: DE RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372}; DE Short=PS1-CTF12; GN Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3 RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=7596406; DOI=10.1038/375754a0; RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F., RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Cloning of a gene bearing missense mutations in early-onset familial RT Alzheimer's disease."; RL Nature 375:754-760(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY. RC TISSUE=Blood, and Brain; RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3; RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., RA Shirasawa T., Mori H.; RT "Identification and characterization of presenilin I-467, I-463 and I- RT 374."; RL FEBS Lett. 381:7-11(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Powell C.S., Gegg M.E., Palmer M.S.; RT "Human presenilin 1 gene encodes an alternative protein-minilin."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A., RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.; RT "Complete sequence of the gene for presenilin 1."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043; RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.; RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential RT expression in oogenesis and embryogenesis."; RL Biochem. Biophys. Res. Commun. 231:392-396(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6 RP AND 7). RC TISSUE=Megakaryocyte, and Platelet; RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9; RA Vidal R., Ghiso J., Wisniewski T., Frangione B.; RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. RT Identification of a novel splice variant."; RL FEBS Lett. 393:19-23(1996). RN [12] RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, RP AND SUBCELLULAR LOCATION. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [14] RP PROTEOLYTIC PROCESSING. RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129; RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.; RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 RT and Ala299 and occur as stable N- and C-terminal fragments in normal and RT Alzheimer brain tissue."; RL Neurobiol. Dis. 3:325-337(1997). RN [15] RP PHOSPHORYLATION. RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349; RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.; RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1 RT generates an in vivo substrate for protein kinase C."; RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997). RN [16] RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385. RX PubMed=9485372; DOI=10.1021/bi972106l; RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.; RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa RT C-terminal fragment are death substrates for proteases of the caspase RT family."; RL Biochemistry 37:2263-2270(1998). RN [17] RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2; RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.; RT "Direct association of presenilin-1 with beta-catenin."; RL FEBS Lett. 433:73-77(1998). RN [18] RP INTERACTION WITH FLNA AND FLNB. RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [19] RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING. RX PubMed=10545183; DOI=10.1021/bi9914210; RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., RA Loetscher H., Jacobsen H., Haass C.; RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 RT in the absence of endoproteolysis."; RL Biochemistry 38:14600-14605(1999). RN [20] RP INTERACTION WITH MTCH1. RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543; RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.; RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting RT with the C terminus of presenilin-1."; RL J. Biol. Chem. 274:32543-32546(1999). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH. RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801; RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., RA Selkoe D.J., Kopan R., Goate A.M.; RT "Cell surface presenilin-1 participates in the gamma-secretase-like RT proteolysis of Notch."; RL J. Biol. Chem. 274:36801-36807(1999). RN [22] RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x; RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., RA St George-Hyslop P.H.; RT "Presenilins interact with armadillo proteins including neural-specific RT plakophilin-related protein and beta-catenin."; RL J. Neurochem. 72:999-1008(1999). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10206644; DOI=10.1038/19077; RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., RA Selkoe D.J.; RT "Two transmembrane aspartates in presenilin-1 required for presenilin RT endoproteolysis and gamma-secretase activity."; RL Nature 398:513-517(1999). RN [24] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x; RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.; RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both RT impair notch1 proteolysis and nuclear translocation with relative RT preservation of notch1 signaling."; RL J. Neurochem. 75:583-593(2000). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286. RX PubMed=10811883; DOI=10.1073/pnas.100049897; RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., RA Capell A., Steiner H., Haass C.; RT "Separation of presenilin function in amyloid beta-peptide generation and RT endoproteolysis of Notch."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000). RN [27] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [28] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486; RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.; RT "Identification of the presenilins in hematopoietic cells with localization RT of presenilin 1 to neutrophil and platelet granules."; RL Blood Cells Mol. Dis. 28:28-38(2002). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1 RP AND CTNNB1. RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948; RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.; RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin RT intracellular domain and regulates disassembly of adherens junctions."; RL EMBO J. 21:1948-1956(2002). RN [30] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [31] RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS RP AD3 VAL-79 AND LEU-82. RX PubMed=12058025; DOI=10.1074/jbc.m112121200; RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., RA Jorgensen A.L.; RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon, RT interacts with the presenilin proteins."; RL J. Biol. Chem. 277:29983-29991(2002). RN [32] RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385. RX PubMed=14515347; DOI=10.1002/jnr.10753; RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., RA Shibasaki H., Shimohama S.; RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to RT the plasma membrane."; RL J. Neurosci. Res. 74:184-191(2003). RN [33] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION, RP AND SUBUNIT. RX PubMed=12679784; DOI=10.1038/ncb960; RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.; RT "Reconstitution of gamma-secretase activity."; RL Nat. Cell Biol. 5:486-488(2003). RN [34] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN. RX PubMed=12740439; DOI=10.1073/pnas.1037392100; RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., RA Selkoe D.J.; RT "Gamma-secretase is a membrane protein complex comprised of presenilin, RT nicastrin, Aph-1, and Pen-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003). RN [35] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION RP OF VARIANTS AD3 LEU-117 AND SER-117. RX PubMed=15004326; DOI=10.3233/jad-2004-6105; RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.; RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture RT phenotypes of Pro117Leu and Pro117Ser mutations."; RL J. Alzheimers Dis. 6:31-43(2004). RN [37] RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND RP SER-346. RX PubMed=14576165; DOI=10.1074/jbc.m306653200; RA Fluhrer R., Friedlein A., Haass C., Walter J.; RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates RT its proteolytic processing and the progression of apoptosis."; RL J. Biol. Chem. 279:1585-1593(2004). RN [38] RP TOPOLOGY. RX PubMed=15385547; DOI=10.1074/jbc.m407898200; RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., RA Martoglio B.; RT "Consensus analysis of signal peptide peptidase and homologous human RT aspartic proteases reveals opposite topology of catalytic domains compared RT with presenilins."; RL J. Biol. Chem. 279:50790-50798(2004). RN [39] RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256; RP ASP-257; ASP-385 AND TYR-389. RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x; RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., RA De Strooper B., Shearman M.S., Beher D.; RT "Conserved residues within the putative active site of gamma-secretase RT differentially influence enzyme activity and inhibitor binding."; RL J. Neurochem. 90:1312-1320(2004). RN [40] RP INTERACTION WITH CDH1 AND CTNNB1. RX PubMed=16126725; DOI=10.1074/jbc.m507503200; RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., RA Robakis N.K.; RT "Cadherins mediate both the association between PS1 and beta-catenin and RT the effects of PS1 on beta-catenin stability."; RL J. Biol. Chem. 280:36007-36012(2005). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [42] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [43] RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND RP CHARACTERIZATION OF VARIANT AD3 PHE-435. RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x; RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.; RT "C-terminal PAL motif of presenilin and presenilin homologues required for RT normal active site conformation."; RL J. Neurochem. 96:218-227(2006). RN [44] RP VARIANTS AD3 ILE-139 AND CYS-289. RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449; RA Cruts M., Hendriks L., Van Broeckhoven C.; RT "The presenilin genes: a new gene family involved in Alzheimer disease RT pathology."; RL Hum. Mol. Genet. 5:1449-1455(1996). RN [45] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [49] RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2. RX PubMed=20299451; DOI=10.1074/jbc.m109.038760; RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S., RA Okochi M., Takeda M., Roepman R., Nishimura M.; RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein RT by binding to the presenilin complex."; RL J. Biol. Chem. 285:14920-14931(2010). RN [50] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [51] RP INVOLVEMENT IN ACNINV3. RX PubMed=20929727; DOI=10.1126/science.1196284; RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y., RA Qu T., Chen M., Sun M., Shen Y., Zhang X.; RT "Gamma-secretase gene mutations in familial acne inversa."; RL Science 330:1065-1065(2010). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [53] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1. RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x; RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M., RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O., RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.; RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 RT accumulation and aggresome formation."; RL Traffic 12:330-348(2011). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [55] RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND RP CHARACTERIZATION OF VARIANT AD3 ASP-206. RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1; RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C., RA Cheng I.H.; RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation."; RL Mol. Neurobiol. 52:1835-1849(2015). RN [56] {ECO:0007744|PDB:2KR6} RP STRUCTURE BY NMR OF 292-467. RA Doetsch V.; RT "Solution structure of presenilin-1 CTF subunit."; RL Submitted (DEC-2009) to the PDB data bank. RN [57] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, SUBUNIT, AND TOPOLOGY. RX PubMed=25043039; DOI=10.1038/nature13567; RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., RA Scheres S.H., Shi Y.; RT "Three-dimensional structure of human gamma-secretase."; RL Nature 512:166-170(2014). RN [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5} RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY. RX PubMed=26623517; DOI=10.7554/elife.11182; RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.; RT "Sampling the conformational space of the catalytic subunit of human gamma- RT secretase."; RL Elife 4:0-0(2015). RN [59] {ECO:0007744|PDB:5A63} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202; RP LEU-226; LEU-248 AND LEU-424. RX PubMed=26280335; DOI=10.1038/nature14892; RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H., RA Shi Y.; RT "An atomic structure of human gamma-secretase."; RL Nature 525:212-217(2015). RN [60] {ECO:0007744|PDB:4UIS} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND RP TOPOLOGY. RX PubMed=25918421; DOI=10.1073/pnas.1506242112; RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S., RA Li X., Shi Y.; RT "Structural basis of human gamma-secretase assembly."; RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015). RN [61] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290; RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN. RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8; RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.; RT "Structural basis of Notch recognition by human gamma-secretase."; RL Nature 565:192-197(2019). RN [62] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND RP 432-LEU--ALA-434. RX PubMed=30630874; DOI=10.1126/science.aaw0930; RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.; RT "Recognition of the amyloid precursor protein by human gamma-secretase."; RL Science 0:0-0(2019). RN [63] RP VARIANTS AD3 THR-143 AND ALA-384. RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363; RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., RA Van Broeckhoven C.; RT "Molecular genetic analysis of familial early-onset Alzheimer's disease RT linked to chromosome 14q24.3."; RL Hum. Mol. Genet. 4:2363-2372(1995). RN [64] RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 RP AND TYR-410. RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373; RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M., RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.; RT "Mutations of the presenilin I gene in families with early-onset RT Alzheimer's disease."; RL Hum. Mol. Genet. 4:2373-2377(1995). RN [65] RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392. RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [66] RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280. RX PubMed=7550356; DOI=10.1038/ng1095-219; RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J., RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., RA Hardy J., Goate A.M.; RT "The structure of the presenilin 1 (S182) gene and identification of six RT novel mutations in early onset AD families."; RL Nat. Genet. 11:219-222(1995). RN [67] RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3. RX PubMed=8837617; DOI=10.1038/nm1096-1146; RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C., RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C., RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.; RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 RT deposition and severe cerebellar pathology."; RL Nat. Med. 2:1146-1150(1996). RN [68] RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213. RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8; RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.; RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's RT disease families."; RL Neurosci. Lett. 208:195-198(1996). RN [69] RP VARIANT AD3 ASP-135. RX PubMed=9225696; DOI=10.1002/ana.410420121; RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., RA Hutton M., Haltia T., Hardy J., Galasko D.; RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site RT corresponding to the Volga German presenilin-2 mutation."; RL Ann. Neurol. 42:124-128(1997). RN [70] RP VARIANT AD3 ALA-280. RX PubMed=9298817; RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h; RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., RA Ossa J., Ruiz A., Goate A.M., Lopera F.; RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not RT modified by ApoE alleles."; RL Hum. Mutat. 10:186-195(1997). RN [71] RP VARIANTS AD3 THR-233 AND THR-278. RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043; RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., RA Schofield P.R., Martins R.N.; RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset RT Alzheimer's disease pedigrees and preliminary evidence for association of RT presenilin-1 mutations with a novel phenotype."; RL NeuroReport 8:1537-1542(1997). RN [72] RP VARIANT AD3 PRO-171. RX PubMed=9833068; RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., RA Cantu J.M.; RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with RT early onset Alzheimer disease."; RL Ann. Genet. 41:149-153(1998). RN [73] RP VARIANT GLY-318. RX PubMed=9851443; DOI=10.1002/ana.410440617; RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.; RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause RT Alzheimer's disease."; RL Ann. Neurol. 44:965-967(1998). RN [74] RP VARIANT GLY-318. RX PubMed=9851450; DOI=10.1002/ana.410440624; RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.; RT "Missense mutation E318G of the presenilin-1 gene appears to be a RT nonpathogenic polymorphism."; RL Ann. Neurol. 44:985-986(1998). RN [75] RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [76] RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND RP PRO-426. RX PubMed=9521423; RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f; RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., RA White J., Heston L., Bird T.D., Schellenberg G.D.; RT "Missense mutations in the chromosome 14 familial Alzheimer's disease RT presenilin 1 gene."; RL Hum. Mutat. 11:216-221(1998). RN [77] RP VARIANT AD3 GLU-378. RX PubMed=10200054; RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q; RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.; RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a RT French family with early-onset Alzheimer's disease and transmission study RT by mismatch enhanced allele specific amplification."; RL Hum. Mutat. 11:481-481(1998). RN [78] RP VARIANT AD3 LYS-139. RX PubMed=9719376; DOI=10.1136/jmg.35.8.672; RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.; RT "De novo presenilin 1 mutations are rare in clinically sporadic, early RT onset Alzheimer's disease cases."; RL J. Med. Genet. 35:672-673(1998). RN [79] RP VARIANT AD3 LEU-117. RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008; RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.; RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial RT Alzheimer's disease and leads to death as early as the age of 28 years."; RL NeuroReport 9:217-221(1998). RN [80] RP VARIANTS AD3 LEU-169 AND GLN-436. RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034; RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., RA Martins R.N.; RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with RT very early onset Alzheimer's disease."; RL NeuroReport 9:3335-3339(1998). RN [81] RP VARIANT GLY-318. RX PubMed=9915968; DOI=10.1086/302200; RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., RA van Duijn C.M., van Broeckhoven C.; RT "The Glu318Gly substitution in presenilin 1 is not causally related to RT Alzheimer disease."; RL Am. J. Hum. Genet. 64:290-292(1999). RN [82] RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND RP TYR-410, AND VARIANT GLY-318. RX PubMed=10441572; DOI=10.1086/302553; RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., RA Brice A., Frebourg T.; RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic RT heterogeneity, and mutation spectrum."; RL Am. J. Hum. Genet. 65:664-670(1999). RN [83] RP VARIANTS AD3 PHE-143 AND SER-436. RX PubMed=10090481; RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p; RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., RA Fox N.C., Harvey R., Rossor M.N., Collinge J.; RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset RT Alzheimer's disease in the UK."; RL Hum. Mutat. 13:256-256(1999). RN [84] RP VARIANT AD3 ARG-209. RX PubMed=10447269; RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s; RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., RA Iseki E., Kosaka K.; RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a RT Japanese family with presenile familial Alzheimer's disease."; RL Hum. Mutat. 14:90-90(1999). RN [85] RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318. RX PubMed=10533070; RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k; RA Aldudo J., Bullido M.J., Valdivieso F.; RT "DGGE method for the mutational analysis of the coding and proximal RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel RT mutations."; RL Hum. Mutat. 14:433-439(1999). RN [86] RP VARIANT AD3 PRO-169. RX PubMed=10025789; DOI=10.1212/wnl.52.3.566; RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.; RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and RT myoclonic seizures."; RL Neurology 52:566-570(1999). RN [87] RP VARIANT AD3 PRO-219. RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011; RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.; RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of RT the presenilin-1 gene."; RL NeuroReport 10:503-507(1999). RN [88] RP VARIANT AD3 ASN-116. RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006; RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., RA Havsager A.-M., Joergensen A.L.; RT "A presenilin-1 Thr116Asn substitution in a family with early-onset RT Alzheimer's disease."; RL NeuroReport 10:2255-2260(1999). RN [89] RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [90] RP VARIANT AD3 SER-405. RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220; RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., RA Maeda K., Tanaka C.; RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition RT but limited cerebral amyloid angiopathy."; RL J. Neurol. Neurosurg. Psych. 68:220-223(2000). RN [91] RP VARIANT AD3 SER-92. RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646; RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.; RT "The presenilin 1 C92S mutation increases abeta 42 production."; RL Biochem. Biophys. Res. Commun. 277:261-263(2000). RN [92] RP VARIANT FTD1 PRO-113. RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577; RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., RA Hannequin D., Brice A., Frebourg T., Campion D.; RT "Dementia with prominent frontotemporal features associated with L113P RT presenilin 1 mutation."; RL Neurology 55:1577-1578(2000). RN [93] RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318. RX PubMed=11568920; RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8; RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E., RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.; RT "Systematic genetic study of Alzheimer disease in Latin America: mutation RT frequencies of the amyloid beta precursor protein and presenilin genes in RT Colombia."; RL Am. J. Med. Genet. 103:138-143(2001). RN [94] RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282. RX PubMed=11701593; DOI=10.1093/brain/124.12.2383; RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U., RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.; RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease RT due to a novel presenilin 1 mutation."; RL Brain 124:2383-2392(2001). RN [95] RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431. RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.; RL Hum. Genet. 109:242-242(2001). RN [96] RP VARIANT AD3 ALA-206. RX PubMed=11710891; DOI=10.1001/jama.286.18.2257; RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K., RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.; RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease RT in unrelated Caribbean Hispanic families."; RL JAMA 286:2257-2263(2001). RN [97] RP VARIANT AD3 ILE-237. RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556; RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y., RA Otomo E., Matsushita M., Komatsuzaki Y.; RT "Very early onset Alzheimer's disease with spastic paraparesis associated RT with a novel presenilin 1 mutation (Phe237Ile)."; RL J. Neurol. Neurosurg. Psych. 71:556-557(2001). RN [98] RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318. RX PubMed=11524469; DOI=10.1212/wnl.57.4.621; RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y., RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W., RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.; RT "Screening for PS1 mutations in a referral-based series of AD cases: 21 RT novel mutations."; RL Neurology 57:621-625(2001). RN [99] RP VARIANT AD3 SER-266. RX PubMed=11920851; DOI=10.1002/ajmg.10250; RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., RA Kohara K., Miyoshi K., Miki T.; RT "Molecular evidence of presenilin 1 mutation in familial early onset RT dementia."; RL Am. J. Med. Genet. 114:292-298(2002). RN [100] RP VARIANT AD3 LEU-89. RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266; RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I., RA Acarin N., Pasarin L., Blesa R., Oliva R.; RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early RT onset Alzheimer's disease and marked behavioural disturbances."; RL J. Neurol. Neurosurg. Psych. 72:266-269(2002). RN [101] RP VARIANT AD3 GLY-280. RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108; RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M., RA Collinge J., Rossor M.N., Hutchinson M.; RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white- RT matter abnormalities."; RL Neurology 59:1108-1110(2002). RN [102] RP VARIANT AD3 PRO-166. RX PubMed=12048239; DOI=10.1073/pnas.112686799; RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.; RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the RT Notch and APP intracellular domains independent of their effect on Abeta 42 RT production."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002). RN [103] RP VARIANT AD3 MET-174. RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6; RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., RA van Duijn C.M., Heredero Baute L., Heutink P.; RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early RT onset Alzheimer disease."; RL Neurogenetics 4:97-104(2002). RN [104] RP VARIANT AD3 VAL-271. RX PubMed=12493737; DOI=10.1074/jbc.m211827200; RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., RA Gandy S.E., Schofield P.R.; RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy."; RL J. Biol. Chem. 278:6748-6754(2003). RN [105] RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND RP VAL-378, AND VARIANT GLY-318. RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3; RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.; RT "Early onset familial Alzheimer's disease: Mutation frequency in 31 RT families."; RL Neurology 60:235-239(2003). RN [106] RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282, RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183. RX PubMed=15122701; DOI=10.1002/ana.20083; RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R., RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K., RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.; RT "A novel presenilin 1 mutation associated with Pick's disease but not beta- RT amyloid plaques."; RL Ann. Neurol. 55:617-626(2004). RN [107] RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85. RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773; RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T., RA Kawabata K., Mori H., Miki T.; RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease RT with spastic paraparesis."; RL Arch. Neurol. 61:1773-1776(2004). RN [108] RP VARIANT AD3 ILE-278. RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a; RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C., RA Rossor M.N.; RT "A presenilin 1 R278I mutation presenting with language impairment."; RL Neurology 63:1702-1704(2004). RN [109] RP VARIANT AD3 ASN-154. RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057; RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K., RA Kowa H., Nakashima K.; RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset RT Alzheimer's disease with spastic paraparesis."; RL Neurosci. Lett. 368:319-322(2004). RN [110] RP VARIANT AD3 PHE-170. RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821; RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R., RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.; RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy RT bodies in the third decade of life."; RL Arch. Neurol. 62:1821-1830(2005). RN [111] RP VARIANT AD3 LEU-97. RX PubMed=15851849; DOI=10.3233/jad-2005-7204; RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.; RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial RT Alzheimer's disease."; RL J. Alzheimers Dis. 7:119-124(2005). RN [112] RP VARIANT CMD1U GLY-333. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [113] RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; RP PHE-263; VAL-282 AND ALA-384. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [114] RP VARIANT AD3 GLU-431. RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3; RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A., RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.; RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing RT early-onset Alzheimer's disease in Mexican families."; RL Neurogenetics 7:195-200(2006). RN [115] RP VARIANT AD3 GLU-431. RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1; RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L., RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.; RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease RT originating in Jalisco State, Mexico: an additional fifteen families."; RL Neurogenetics 7:277-279(2006). RN [116] RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79. RX PubMed=17366635; DOI=10.1002/ana.21099; RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M., RA Holtzman D.M., Morris J.C., Goate A.M.; RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late- RT onset Alzheimer's disease presenilin 1 mutation."; RL Ann. Neurol. 61:446-453(2007). RN [117] RP VARIANT AD3 PHE-170. RX PubMed=17502474; DOI=10.1001/archneur.64.5.738; RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R., RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P., RA Russo C., Ghetti B., Tabaton M.; RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer RT disease molecular phenotype."; RL Arch. Neurol. 64:738-745(2007). RN [118] RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257. RX PubMed=17428795; DOI=10.1074/jbc.m611449200; RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T., RA Wang R., Ludwig A., Robakis N.K.; RT "Ligand binding and calcium influx induce distinct ectodomain/gamma- RT secretase-processing pathways of EphB2 receptor."; RL J. Biol. Chem. 282:16155-16163(2007). RN [119] RP VARIANT GLY-318. RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014; RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., RA Emans J.B., Turnpenny P.D., Pourquie O.; RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin RT syndrome."; RL Am. J. Hum. Genet. 82:1334-1341(2008). RN [120] RP CHARACTERIZATION OF VARIANT AD3 THR-213. RX PubMed=18430735; DOI=10.1074/jbc.m801279200; RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M., RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.; RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in RT cell models and knock-in mouse brains: familial Alzheimer disease-linked RT mutation impairs gamma-site cleavage of amyloid precursor protein C- RT terminal fragment beta."; RL J. Biol. Chem. 283:16488-16496(2008). RN [121] RP VARIANT AD3 VAL-381. RX PubMed=19797784; DOI=10.1177/1533317509341464; RA Dintchov Traykov L., Mehrabian S., Van den Broeck M., RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A., RA Van Broeckhoven C.; RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs."; RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009). RN [122] RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217. RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba; RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E., RA Goate A.; RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool RT plaques."; RL Neurology 73:480-482(2009). RN [123] RP VARIANT AD3 LEU-146. RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785; RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F., RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R., RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G., RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G., RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P., RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G., RA Puccio G.; RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability RT for a founder mutation."; RL Neurology 74:798-806(2010). RN [124] RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION. RX PubMed=20460383; DOI=10.1074/jbc.m110.116962; RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III; RT "A presenilin-1 mutation identified in familial Alzheimer disease with RT cotton wool plaques causes a nearly complete loss of gamma-secretase RT activity."; RL J. Biol. Chem. 285:22350-22359(2010). RN [125] RP VARIANT AD3 ASP-206. RX PubMed=21335660; DOI=10.3233/jad-2011-102031; RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.; RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in RT pathologically confirmed familial Alzheimer's disease."; RL J. Alzheimers Dis. 25:145-150(2011). RN [126] RP VARIANT CYS-315. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [127] RP VARIANT AD3 ARG-235. RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084; RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N., RA Fortea J., Molinuevo J.L., Sanchez-Valle R.; RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 496:40-42(2011). RN [128] RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280. RX PubMed=22461631; DOI=10.1074/jbc.m111.300483; RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.; RT "Familial Alzheimer disease presenilin-1 mutations alter the active site RT conformation of gamma-secretase."; RL J. Biol. Chem. 287:17288-17296(2012). RN [129] RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [130] RP VARIANT AD3 PHE-159. RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037; RA Kerchner G.A., Holbrook K.; RT "Novel presenilin-1 Y159F sequence variant associated with early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 531:142-144(2012). RN [131] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF RP ASP-257 AND ASP-385. RX PubMed=22529981; DOI=10.1371/journal.pone.0035133; RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.; RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic RT loss of activity in purified gamma-secretase complexes."; RL PLoS ONE 7:E35133-E35133(2012). RN [132] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; RP TYR-410 AND PHE-435. RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013; RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III; RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma- RT secretase activity and Abeta production."; RL J. Neurosci. 33:11606-11617(2013). RN [133] RP VARIANT AD3 PHE-381. RX PubMed=24121961; DOI=10.3233/jad-131340; RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J., RA Wen G.Y., Alexov E., Zuchner S., Velinov M.; RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very RT early onset and unusually fast progressing dementia as well as lysosomal RT inclusions typically seen in Kufs disease."; RL J. Alzheimers Dis. 39:23-27(2014). RN [134] RP VARIANT AD3 VAL-153. RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016; RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M., RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.; RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a RT Peruvian family with early-onset Alzheimer's disease."; RL Neurosci. Lett. 563:140-143(2014). RN [135] RP VARIANT AD3 VAL-275. RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034; RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H., RA Boelmans K.; RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial RT Alzheimer disease."; RL Neurosci. Lett. 566:115-119(2014). RN [136] RP VARIANT AD3 THR-83. RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007; RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M., RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R., RA Belal S.; RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset RT Alzheimer's disease."; RL Neurobiol. Aging 36:2904.E09-2904.E11(2015). RN [137] RP VARIANTS AD3 ALA-206 AND VAL-378. RX PubMed=27073747; RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E., RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A., RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W., RA Rademakers R.; RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset RT Alzheimer's disease in Hispanics in Florida."; RL Am. J. Neurodegener. Dis. 5:94-101(2016). RN [138] RP VARIANT AD3 THR-408. RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004; RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A., RA Sorbi S., Nacmias B.; RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late- RT onset Alzheimer's disease."; RL Neurosci. Lett. 610:150-153(2016). RN [139] RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND RP FUNCTION. RX PubMed=28269784; DOI=10.3233/jad-161188; RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.; RT "A novel PSEN1 K311R mutation discovered in Chinese families with late- RT onset Alzheimer's disease affects amyloid-beta production and tau RT phosphorylation."; RL J. Alzheimers Dis. 57:613-623(2017). RN [140] RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439, RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99; RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437. RX PubMed=27930341; DOI=10.1073/pnas.1618657114; RA Sun L., Zhou R., Yang G., Shi Y.; RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro RT production of Abeta42 and Abeta40 peptides by gamma-secretase."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017). RN [141] RP VARIANT AD3 ILE-116. RX PubMed=30200536; DOI=10.3390/ijms19092604; RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A., RA Kim S.; RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset RT Alzheimer's disease."; RL Int. J. Mol. Sci. 19:0-0(2018). RN [142] RP VARIANT AD3 ASN-116. RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z; RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P., RA Jadhav S., Novak P., Attems J., Zilka N.; RT "Neuropathology and biochemistry of early onset familial Alzheimer's RT disease caused by presenilin-1 missense mutation Thr116Asn."; RL J. Neural Transm. 125:965-976(2018). RN [143] RP VARIANTS AD3 PHE-142 AND ASP-206. RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011; RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J., RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.; RT "Genetic screening in two Iranian families with early-onset Alzheimer's RT disease identified a novel PSEN1 mutation."; RL Neurobiol. Aging 62:E15-E17(2018). RN [144] RP VARIANT AD3 ALA-417. RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003; RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.; RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset RT Alzheimer's disease with parkinsonism."; RL Neurobiol. Aging 72:E13-E17(2018). RN [145] RP VARIANT AD3 PHE-170. RX PubMed=29466804; DOI=10.1159/000485899; RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.; RT "Phenotypic variability in autosomal dominant familial Alzheimer disease RT due to the S170F mutation of presenilin-1."; RL Neurodegener. Dis. 18:57-68(2018). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10206644, PubMed:10545183, CC PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, CC PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). CC Requires the presence of the other members of the gamma-secretase CC complex for protease activity (PubMed:15274632, PubMed:25043039, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in CC Notch and Wnt signaling cascades and regulation of downstream processes CC via its role in processing key regulatory proteins, and by regulating CC cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, CC PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its CC interaction with CDH1; this stabilizes the complexes between CDH1 (E- CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby CC negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). CC Required for normal embryonic brain and skeleton development, and for CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The CC holoprotein functions as a calcium-leak channel that allows the passive CC movement of calcium from endoplasmic reticulum to cytosol and is CC therefore involved in calcium homeostasis (PubMed:16959576, CC PubMed:25394380). Involved in the regulation of neurite outgrowth CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic CC facilitation, spike transmission and synaptic vesicles replenishment in CC a process that depends on gamma-secretase activity. It acts through the CC control of SYT7 presynaptic expression (By similarity). CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, CC ECO:0000269|PubMed:9738936}. CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal CC complex is sufficient for secretase activity (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Other components which are CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2 CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment CC (PubMed:15274632). Associates with proteolytic processed C-terminal CC fragments C83 and C99 of the amyloid precursor protein (APP) (via CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates CC with cadherin/catenin adhesion complexes through direct binding to CDH1 CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for CC trafficking of CDH2 from the endoplasmic reticulum to the plasma CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471, CC PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059, CC PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its CC N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with CC DOCK3; this interaction mediates the membrane association of DOCK3 CC (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1 CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725, CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9738936}. CC -!- INTERACTION: CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690; CC P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935; CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613; CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641; CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139; CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634; CC P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477; CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452; CC P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432; CC P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089; CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440; CC P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447; CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468; CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285; CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825; CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422; CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387; CC P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480; CC P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760; CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669; CC P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357; CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439; CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613; CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320; CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939; CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943; CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453; CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644; CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279; CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722; CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068; CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304; CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195; CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640; CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377; CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720; CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407; CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714; CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682; CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491; CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063; CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768; CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290; CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468; CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400; CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984; CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324; CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463; CC P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545; CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983; CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123; CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185; CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299; CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794; CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709; CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi CC apparatus membrane {ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic CC granule {ECO:0000269|PubMed:11987239}. Cell membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314, CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass CC membrane protein {ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone CC {ECO:0000269|PubMed:15004326}. Early endosome CC {ECO:0000269|PubMed:25394380}. Early endosome membrane CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 CC from the endoplasmic reticulum and/or Golgi to the cell surface CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the CC proximity of the plasma membrane (PubMed:9738936). Also present in CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures CC called aggresomes (PubMed:21143716). Also highly enriched in CC mitochondria-associated endoplasmic reticulum membrane contact site (By CC similarity). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; Synonyms=I-467; CC IsoId=P49768-1; Sequence=Displayed; CC Name=2; Synonyms=I-463; CC IsoId=P49768-2; Sequence=VSP_005191; CC Name=3; Synonyms=I-374; CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192; CC Name=4; Synonyms=Minilin; CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987; CC Name=5; CC IsoId=P49768-5; Sequence=VSP_005192; CC Name=6; CC IsoId=P49768-6; Sequence=VSP_012288; CC Name=7; CC IsoId=P49768-7; Sequence=VSP_041440; CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239). CC Expressed in a wide range of tissues including various regions of the CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969, CC PubMed:8641442). {ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:8641442}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000269|PubMed:16305624}. CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between CC PSEN1 transmembrane domains and via the first lumenal loop and the CC cytoplasmic loop between the sixth and seventh transmembrane domains. CC Substrate binding causes a conformation change and formation of an CC intermolecular antiparallel beta-sheet between PSEN1 and its CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa, CC respectively. During apoptosis, the C-terminal fragment (CTF) is CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12. CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}. CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165, CC ECO:0000269|PubMed:9144240}. CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, CC ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170, CC ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, CC ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, CC ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, CC ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, CC ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting CC the gene represented in this entry. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461, CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic CC relapsing inflammatory disease of the hair follicles characterized by CC recurrent draining sinuses, painful skin abscesses, and disfiguring CC scars. Manifestations typically appear after puberty. CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented CC in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L42110; AAB46416.1; -; mRNA. DR EMBL; L76517; AAB46370.1; -; mRNA. DR EMBL; L76528; AAB46371.1; -; Genomic_DNA. DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; U40379; AAB05894.1; -; mRNA. DR EMBL; U40380; AAB05895.1; -; mRNA. DR EMBL; AJ008005; CAA07825.1; -; mRNA. DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA. DR EMBL; AF416717; AAL16811.1; -; mRNA. DR EMBL; AK312531; BAG35430.1; -; mRNA. DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA. DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA. DR EMBL; BC011729; AAH11729.1; -; mRNA. DR EMBL; D84149; BAA20883.1; -; Genomic_DNA. DR CCDS; CCDS9812.1; -. [P49768-1] DR CCDS; CCDS9813.1; -. [P49768-2] DR PIR; S58396; S58396. DR PIR; S63683; S63683. DR PIR; S63684; S63684. DR RefSeq; NP_000012.1; NM_000021.4. [P49768-1] DR RefSeq; NP_015557.2; NM_007318.3. [P49768-2] DR RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1] DR RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2] DR RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1] DR RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2] DR RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2] DR RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1] DR RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1] DR RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2] DR RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1] DR RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1] DR RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1] DR RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1] DR RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2] DR RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2] DR RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2] DR RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2] DR PDB; 2KR6; NMR; -; A=292-467. DR PDB; 4UIS; EM; 4.40 A; B=81-463. DR PDB; 5A63; EM; 3.40 A; B=1-467. DR PDB; 5FN2; EM; 4.20 A; B=1-467. DR PDB; 5FN3; EM; 4.10 A; B=1-467. DR PDB; 5FN4; EM; 4.00 A; B=1-467. DR PDB; 5FN5; EM; 4.30 A; B=1-467. DR PDB; 6IDF; EM; 2.70 A; B=1-467. DR PDB; 6IYC; EM; 2.60 A; B=1-467. DR PDB; 6LQG; EM; 3.10 A; B=1-467. DR PDB; 6LR4; EM; 3.00 A; B=1-467. DR PDB; 7C9I; EM; 3.10 A; B=1-467. DR PDB; 7D8X; EM; 2.60 A; B=1-467. DR PDB; 7Y5T; EM; 2.90 A; B=1-467. DR PDB; 8IM7; EM; 3.40 A; B=1-467. DR PDB; 8K8E; EM; 2.60 A; B=1-467. DR PDB; 8KCO; EM; 2.80 A; B=1-467. DR PDB; 8KCP; EM; 3.00 A; B=1-467. DR PDB; 8KCS; EM; 2.40 A; B=1-467. DR PDB; 8KCT; EM; 2.60 A; B=1-467. DR PDB; 8KCU; EM; 2.70 A; B=1-467. DR PDB; 8OQY; EM; 3.30 A; B=1-467. DR PDB; 8OQZ; EM; 3.40 A; B=1-467. DR PDB; 8X52; EM; 2.90 A; B=1-467. DR PDB; 8X53; EM; 3.00 A; B=1-467. DR PDB; 8X54; EM; 2.90 A; B=1-467. DR PDBsum; 2KR6; -. DR PDBsum; 4UIS; -. DR PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR PDBsum; 6LQG; -. DR PDBsum; 6LR4; -. DR PDBsum; 7C9I; -. DR PDBsum; 7D8X; -. DR PDBsum; 7Y5T; -. DR PDBsum; 8IM7; -. DR PDBsum; 8K8E; -. DR PDBsum; 8KCO; -. DR PDBsum; 8KCP; -. DR PDBsum; 8KCS; -. DR PDBsum; 8KCT; -. DR PDBsum; 8KCU; -. DR PDBsum; 8OQY; -. DR PDBsum; 8OQZ; -. DR PDBsum; 8X52; -. DR PDBsum; 8X53; -. DR PDBsum; 8X54; -. DR AlphaFoldDB; P49768; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-17112; -. DR EMDB; EMD-17113; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-35572; -. DR EMDB; EMD-36948; -. DR EMDB; EMD-37106; -. DR EMDB; EMD-37107; -. DR EMDB; EMD-37108; -. DR EMDB; EMD-37109; -. DR EMDB; EMD-37110; -. DR EMDB; EMD-38059; -. DR EMDB; EMD-38060; -. DR EMDB; EMD-38061; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; P49768; -. DR BioGRID; 111642; 203. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; P49768; -. DR DIP; DIP-1134N; -. DR ELM; P49768; -. DR FunCoup; P49768; 2287. DR IntAct; P49768; 299. DR MINT; P49768; -. DR STRING; 9606.ENSP00000326366; -. DR BindingDB; P49768; -. DR ChEMBL; CHEMBL2473; -. DR DrugBank; DB11893; Avagacestat. DR DrugBank; DB12263; Begacestat. DR DrugBank; DB05171; E-2012. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12819; GSI-136. DR DrugBank; DB16825; Itanapraced. DR DrugBank; DB12852; MK-0752. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB11870; RG-4733. DR DrugBank; DB12463; Semagacestat. DR DrugBank; DB05289; Tarenflurbil. DR GuidetoPHARMACOLOGY; 2402; -. DR MEROPS; A22.001; -. DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family. DR iPTMnet; P49768; -. DR PhosphoSitePlus; P49768; -. DR SwissPalm; P49768; -. DR BioMuta; PSEN1; -. DR DMDM; 1709856; -. DR jPOST; P49768; -. DR MassIVE; P49768; -. DR PaxDb; 9606-ENSP00000326366; -. DR PeptideAtlas; P49768; -. DR ProteomicsDB; 56106; -. [P49768-1] DR ProteomicsDB; 56107; -. [P49768-2] DR ProteomicsDB; 56108; -. [P49768-3] DR ProteomicsDB; 56109; -. [P49768-4] DR ProteomicsDB; 56110; -. [P49768-5] DR ProteomicsDB; 56111; -. [P49768-6] DR ProteomicsDB; 56112; -. [P49768-7] DR Pumba; P49768; -. DR Antibodypedia; 3480; 972 antibodies from 47 providers. DR DNASU; 5663; -. DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4] DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3] DR Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6] DR Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2] DR GeneID; 5663; -. DR KEGG; hsa:5663; -. DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1. DR UCSC; uc001xnq.5; human. [P49768-1] DR AGR; HGNC:9508; -. DR ClinPGx; PA33855; -. DR CTD; 5663; -. DR DisGeNET; 5663; -. DR GeneCards; PSEN1; -. DR GeneReviews; PSEN1; -. DR HGNC; HGNC:9508; PSEN1. DR HPA; ENSG00000080815; Low tissue specificity. DR MalaCards; PSEN1; -. DR MIM; 104311; gene. DR MIM; 172700; phenotype. DR MIM; 600274; phenotype. DR MIM; 607822; phenotype. DR MIM; 613694; phenotype. DR MIM; 613737; phenotype. DR OpenTargets; ENSG00000080815; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000080815; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000158751; -. DR HOGENOM; CLU_022975_3_0_1; -. DR InParanoid; P49768; -. DR OMA; NATCNQQ; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49768; 26 GO annotations based on evolutionary models. DR PhylomeDB; P49768; -. DR PathwayCommons; P49768; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49768; -. DR SIGNOR; P49768; -. DR Agora; ENSG00000080815; -. DR BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN1; human. DR EvolutionaryTrace; P49768; -. DR GeneWiki; PSEN1; -. DR GenomeRNAi; 5663; -. DR Pharos; P49768; Tchem. DR PRO; PR:P49768; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P49768; protein. DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues. DR ExpressionAtlas; P49768; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:UniProtKB. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IMP:CAFA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB. DR GO; GO:0045296; F:cadherin binding; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL. DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl. DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl. DR GO; GO:0015871; P:choline transport; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL. DR GO; GO:0040011; P:locomotion; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0007613; P:memory; IGI:ARUK-UCL. DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0001764; P:neuron migration; IEA:Ensembl. DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL. DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0015031; P:protein transport; IEA:Ensembl. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl. DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl. DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl. DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL. DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl. DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR DisProt; DP01292; -. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR002031; Pept_A22A_PS1. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF18; PRESENILIN-1; 1. DR Pfam; PF01080; Presenilin; 1. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01073; PRESENILIN1. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..298 FT /note="Presenilin-1 NTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025591" FT CHAIN 299..467 FT /note="Presenilin-1 CTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025592" FT CHAIN 346..467 FT /note="Presenilin-1 CTF12" FT /evidence="ECO:0000269|PubMed:9485372" FT /id="PRO_0000236055" FT TOPO_DOM 1..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 83..103 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 104..132 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 133..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 154..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 167..189 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 190..194 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 195..216 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 217..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 221..241 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 242..248 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 249..272 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 273..380 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 402..407 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 408..428 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 429..432 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 433..453 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 454..467 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT REGION 13..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 288..290 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 305..333 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 322..450 FT /note="Required for interaction with CTNNB1" FT /evidence="ECO:0000269|PubMed:9738936" FT REGION 372..399 FT /note="Required for interaction with CTNND2" FT /evidence="ECO:0000269|PubMed:10037471" FT REGION 377..381 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 432..434 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 464..467 FT /note="Interaction with MTCH1" FT /evidence="ECO:0000269|PubMed:10551805" FT MOTIF 433..435 FT /note="PAL" FT /evidence="ECO:0000305|PubMed:16305624" FT COMPBIAS 13..29 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 30..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 257 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515" FT ACT_SITE 385 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515, FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874" FT SITE 291..292 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 292..293 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 298..299 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 345..346 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000269|PubMed:9485372" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 51 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97887" FT MOD_RES 310 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 346 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 367 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 26..29 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442" FT /id="VSP_005191" FT VAR_SEQ 162..184 FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT FT (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007986" FT VAR_SEQ 185..467 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007987" FT VAR_SEQ 257..289 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000305" FT /id="VSP_041440" FT VAR_SEQ 319..467 FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3 FT and isoform 5)" FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5" FT /id="VSP_005192" FT VAR_SEQ 319..376 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_012288" FT VARIANT 35 FT /note="R -> Q (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750592)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075260" FT VARIANT 79 FT /note="A -> V (in AD3; also found in late-onset Alzheimer FT disease; impaired protease activity with APP; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; no effect on interaction with FT GFAP; dbSNP:rs63749824)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602" FT /id="VAR_006413" FT VARIANT 82 FT /note="V -> L (in AD3; decreased protease activity with FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006414" FT VARIANT 83 FT /note="I -> T (in AD3)" FT /evidence="ECO:0000269|PubMed:26145164" FT /id="VAR_075261" FT VARIANT 85 FT /note="L -> P (in AD3; the patient also manifest spastic FT paraparesis and apraxia; loss of protease activity with APP FT in vitro; altered amyloid-beta production in cells FT transfected with the mutant and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs63750599)" FT /evidence="ECO:0000269|PubMed:15534188, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081228" FT VARIANT 89 FT /note="V -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750815)" FT /evidence="ECO:0000269|PubMed:11796781" FT /id="VAR_081229" FT VARIANT 92 FT /note="C -> S (in AD3; loss of protease activity with APP; FT dbSNP:rs63751141)" FT /evidence="ECO:0000269|PubMed:11027672, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016214" FT VARIANT 94 FT /note="V -> M (in AD3; uncertain significance; reduced FT protease activity with APP; no relevant change in amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)" FT /evidence="ECO:0000269|PubMed:11568920" FT /id="VAR_081230" FT VARIANT 96 FT /note="V -> F (in AD3; loss of protease activity with APP; FT dbSNP:rs63750601)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006415" FT VARIANT 97 FT /note="V -> L (in AD3; uncertain significance; slightly FT reduced protease activity with APP; dbSNP:rs63750852)" FT /evidence="ECO:0000269|PubMed:15851849, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081231" FT VARIANT 105 FT /note="F -> L (in AD3; dbSNP:rs63750321)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_009208" FT VARIANT 113 FT /note="L -> P (in FTD1; dbSNP:rs63751399)" FT /evidence="ECO:0000269|PubMed:11094121" FT /id="VAR_016215" FT VARIANT 115 FT /note="Y -> C (in AD3; dbSNP:rs63750450)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602" FT /id="VAR_006416" FT VARIANT 115 FT /note="Y -> H (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712" FT /id="VAR_006417" FT VARIANT 116 FT /note="T -> I (in AD3; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:30200536" FT /id="VAR_081232" FT VARIANT 116 FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques FT detected in one patient's brain; severe decrease of FT protease activity with APP; results in increased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:10439444, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29404783" FT /id="VAR_010120" FT VARIANT 117 FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/ FT CTF1; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired FT regulation of neurite outgrowth; dbSNP:rs63749805)" FT /evidence="ECO:0000269|PubMed:15004326, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958" FT /id="VAR_009209" FT VARIANT 117 FT /note="P -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; impaired regulation of neurite outgrowth; FT dbSNP:rs63750550)" FT /evidence="ECO:0000269|PubMed:15004326" FT /id="VAR_081233" FT VARIANT 120 FT /note="E -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751272)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423" FT /id="VAR_006418" FT VARIANT 120 FT /note="E -> K (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750800)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006419" FT VARIANT 134 FT /note="L -> R (in AD3; uncertain significance; loss of FT protease activity with APP; dbSNP:rs1595002439)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:27930341" FT /id="VAR_070023" FT VARIANT 135 FT /note="N -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750353)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9225696" FT /id="VAR_010121" FT VARIANT 139 FT /note="M -> I (in AD3; dbSNP:rs63750522)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_006420" FT VARIANT 139 FT /note="M -> K (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:9719376" FT /id="VAR_010122" FT VARIANT 139 FT /note="M -> T (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006421" FT VARIANT 139 FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751037)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356" FT /id="VAR_006422" FT VARIANT 142 FT /note="V -> F (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29175279" FT /id="VAR_081234" FT VARIANT 143 FT /note="I -> F (in AD3; dbSNP:rs63750322)" FT /evidence="ECO:0000269|PubMed:10090481" FT /id="VAR_006423" FT VARIANT 143 FT /note="I -> T (in AD3; impaired protease activity with APP; FT results in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006424" FT VARIANT 146 FT /note="M -> I (in AD3; dbSNP:rs63750391)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037" FT /id="VAR_006425" FT VARIANT 146 FT /note="M -> L (in AD3; disease phenotype shows high FT clinical variability; founder mutation originating from FT Southern Italy and distributed worldwide; alters the FT conformation of the active site; slightly increased FT protease activity with APP; decreased activity for Notch1 FT cleavage; no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006426" FT VARIANT 146 FT /note="M -> V (in AD3; loss of function as calcium-leak FT channel; results in calcium overload in the endoplasmic FT reticulum; dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356" FT /id="VAR_006427" FT VARIANT 147 FT /note="T -> I (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750907)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010123" FT VARIANT 153 FT /note="L -> V (in AD3; abolishes protease activity with APP FT resulting in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63751441)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341" FT /id="VAR_081235" FT VARIANT 154 FT /note="Y -> C (in AD3; uncertain significance; FT dbSNP:rs63751292)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081236" FT VARIANT 154 FT /note="Y -> N (in AD3; disease phenotype includes spastic FT paraparesis; abolishes protease activity with APP resulting FT in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63750588)" FT /evidence="ECO:0000269|PubMed:15364419, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081237" FT VARIANT 156 FT /note="Y -> FTY (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075262" FT VARIANT 159 FT /note="Y -> F (in AD3; uncertain significance; FT dbSNP:rs778630379)" FT /evidence="ECO:0000269|PubMed:23123781" FT /id="VAR_081238" FT VARIANT 163 FT /note="H -> R (in AD3; abolishes protease activity with FT APP; decreased activity for Notch cleavage; FT dbSNP:rs63750590)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712, FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423" FT /id="VAR_006428" FT VARIANT 163 FT /note="H -> Y (in AD3; slightly increased protease activity FT with APP and slightly increased amyloid-beta 42 production; FT dbSNP:rs63749885)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006429" FT VARIANT 165 FT /note="W -> C (in AD3; dbSNP:rs63751484)" FT /evidence="ECO:0000269|PubMed:10441572" FT /id="VAR_010124" FT VARIANT 166 FT /note="L -> P (in AD3; onset in adolescence; severe FT decrease of protease activity with APP; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; results in reduced Notch FT proteolysis; dbSNP:rs63750265)" FT /evidence="ECO:0000269|PubMed:12048239, FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016216" FT VARIANT 168 FT /note="Missing (in AD3; uncertain significance; abolishes FT protease activity with APP resulting in decreased amyloid- FT beta 42 and amyloid-beta 40 production)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081239" FT VARIANT 169 FT /note="S -> L (in AD3; dbSNP:rs63751210)" FT /evidence="ECO:0000269|PubMed:9831473" FT /id="VAR_006430" FT VARIANT 169 FT /note="S -> P (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750418)" FT /evidence="ECO:0000269|PubMed:10025789, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006431" FT VARIANT 170 FT /note="S -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750577)" FT /evidence="ECO:0000269|PubMed:16344340, FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29466804" FT /id="VAR_081240" FT VARIANT 171 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750963)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068" FT /id="VAR_006432" FT VARIANT 173 FT /note="L -> W (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750299)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010125" FT VARIANT 174 FT /note="L -> M (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751144)" FT /evidence="ECO:0000269|PubMed:12484344, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016217" FT VARIANT 177 FT /note="F -> L (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749911)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075263" FT VARIANT 177 FT /note="F -> S (in AD3; uncertain significance; FT dbSNP:rs63749806)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075264" FT VARIANT 178 FT /note="S -> P (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750155)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075265" FT VARIANT 183 FT /note="G -> V (in PIDB and AD3; uncertain significance; FT neuropathologic examination of brain sections from a FT patient shows the presence of Pick bodies and absence of FT beta-amyloid plaques; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro; dbSNP:rs63751068)" FT /evidence="ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081241" FT VARIANT 184 FT /note="E -> D (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750311)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081242" FT VARIANT 205 FT /note="F -> L (in dbSNP:rs1042864)" FT /id="VAR_011876" FT VARIANT 206 FT /note="G -> A (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016218" FT VARIANT 206 FT /note="G -> D (in AD3; affects APP processing resulting in FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not FT affect NOTCH processing; does not affect endoproteolysis; FT reduced interaction with PEN2; results in decreased protein FT levels in the endoplasmic reticulum but increased levels in FT early endosome; reduced ability to maintain ER calcium FT homeostasis; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:21335660, FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279" FT /id="VAR_081243" FT VARIANT 206 FT /note="G -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750569)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075266" FT VARIANT 209 FT /note="G -> E (in AD3; uncertain significance; FT dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075267" FT VARIANT 209 FT /note="G -> R (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749880)" FT /evidence="ECO:0000269|PubMed:10447269, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009210" FT VARIANT 209 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006433" FT VARIANT 213 FT /note="I -> L (in AD3; increases protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075268" FT VARIANT 213 FT /note="I -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)" FT /evidence="ECO:0000269|PubMed:18430735, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006434" FT VARIANT 214 FT /note="H -> Y (found in a patient with dementia; uncertain FT significance; dbSNP:rs63751003)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070024" FT VARIANT 217 FT /note="G -> R (in AD3; with unusual amyloid cotton wool FT plaques; decreased protease activity with APP resulting in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)" FT /evidence="ECO:0000269|PubMed:19667325, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081244" FT VARIANT 219 FT /note="L -> P (in AD3; dbSNP:rs63750761)" FT /evidence="ECO:0000269|PubMed:10208579" FT /id="VAR_010126" FT VARIANT 222 FT /note="Q -> R (in AD3; uncertain significance; slightly FT increased protease activity with APP and slightly increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075269" FT VARIANT 229 FT /note="I -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081245" FT VARIANT 231 FT /note="A -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006435" FT VARIANT 231 FT /note="A -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750799)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006436" FT VARIANT 233 FT /note="M -> L (in AD3; slightly decreased protease activity FT with APP resulting in altered amyloid-beta production and FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751287)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_009211" FT VARIANT 233 FT /note="M -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170" FT /id="VAR_006437" FT VARIANT 235 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63749835)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_006438" FT VARIANT 235 FT /note="L -> R (in AD3; abolishes protease activity with FT APP)" FT /evidence="ECO:0000269|PubMed:21501661, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081246" FT VARIANT 235 FT /note="L -> V (in AD3; reduced APP cleavage resulting in FT decreased amyloid-beta 42 and amyloid-beta 40 production; FT no relevant change in amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751130)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081247" FT VARIANT 237 FT /note="F -> I (in AD3; uncertain significance; disease FT phenotype includes spastic paraparesis; severe decrease of FT protease activity with APP; results in decreased amyloid- FT beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:11561050, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_081248" FT VARIANT 237 FT /note="F -> L (in AD3; uncertain significance; FT dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081249" FT VARIANT 246 FT /note="A -> E (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750526)" FT /evidence="ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006439" FT VARIANT 250 FT /note="L -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751163)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006440" FT VARIANT 260 FT /note="A -> V (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423" FT /id="VAR_006441" FT VARIANT 261 FT /note="V -> F (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750964)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075270" FT VARIANT 262 FT /note="L -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006442" FT VARIANT 262 FT /note="L -> V (in AD3)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070025" FT VARIANT 263 FT /note="C -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751102)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:16752394" FT /id="VAR_081250" FT VARIANT 263 FT /note="C -> R (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750543)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006443" FT VARIANT 264 FT /note="P -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006444" FT VARIANT 266 FT /note="G -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs121917807)" FT /evidence="ECO:0000269|PubMed:11920851, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016219" FT VARIANT 267 FT /note="P -> S (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751229)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006445" FT VARIANT 269 FT /note="R -> G (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751019)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006447" FT VARIANT 269 FT /note="R -> H (in AD3; dbSNP:rs63750900)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_006448" FT VARIANT 271 FT /note="L -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750886)" FT /evidence="ECO:0000269|PubMed:12493737, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016220" FT VARIANT 274 FT /note="T -> R (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750284)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075271" FT VARIANT 275 FT /note="A -> V (in AD3; uncertain significance; reduced FT protease activity with APP resulting in reduced amyloid- FT beta 40 levels but no relevant changes in amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs1555355869)" FT /evidence="ECO:0000269|PubMed:24582897, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081251" FT VARIANT 278 FT /note="R -> I (in AD3; atypical phenotype presenting as FT language impairment, impaired frontal executive function FT and relative preservation of memory; severe decrease of APP FT and Notch proteolysis; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:15534260, FT ECO:0000269|PubMed:23843529" FT /id="VAR_081252" FT VARIANT 278 FT /note="R -> T (in AD3; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:9172170" FT /id="VAR_006449" FT VARIANT 280 FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42 FT is observed in brain regions of AD3 patients; decreased FT protease activity with APP resulting in altered amyloid- FT beta production and increased amyloid-beta 42/amyloid-beta FT 40 ratio; decreased activity for Notch1 cleavage; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356, FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817" FT /id="VAR_006450" FT VARIANT 280 FT /note="E -> G (in AD3; some AD3 patients manifest spastic FT paraparesis and unusual amyloid plaques with prominent FT amyloid angiopathy on brain biopsy; decreased protease FT activity with APP; increased amyloid-beta 42/amyloid-beta FT 40 ratio; impaired ability to cleave Ephb2/CTF1; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:12370477, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006451" FT VARIANT 282 FT /note="L -> R (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750050)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009212" FT VARIANT 282 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749937)" FT /evidence="ECO:0000269|PubMed:11701593, FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394" FT /id="VAR_081253" FT VARIANT 285 FT /note="A -> V (in AD3; slightly decreased protease activity FT with APP and slightly decreased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751139)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006452" FT VARIANT 286 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751235)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406" FT /id="VAR_006453" FT VARIANT 289 FT /note="S -> C (in AD3)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_010127" FT VARIANT 311 FT /note="K -> R (found in patients with late-onset Alzheimer FT disease; uncertain significance; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs115865530)" FT /evidence="ECO:0000269|PubMed:28269784" FT /id="VAR_081254" FT VARIANT 315 FT /note="Y -> C (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064747" FT VARIANT 318 FT /note="E -> G (in dbSNP:rs17125721)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326, FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443, FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968" FT /id="VAR_006454" FT VARIANT 333 FT /note="D -> G (in CMD1U; results in slightly decreased FT protease activity with APP and slightly decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:27930341" FT /id="VAR_064902" FT VARIANT 352 FT /note="R -> RR (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075272" FT VARIANT 354 FT /note="T -> I (in AD3; uncertain significance; results in FT decreased protease activity with APP and decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075273" FT VARIANT 358 FT /note="R -> Q (in AD3; uncertain significance; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs63751174)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075274" FT VARIANT 365 FT /note="S -> Y (in AD3; uncertain significance; FT dbSNP:rs63750941)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075275" FT VARIANT 377 FT /note="R -> M (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081255" FT VARIANT 378 FT /note="G -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10200054, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006455" FT VARIANT 378 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750323)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341" FT /id="VAR_081256" FT VARIANT 381 FT /note="L -> F (in AD3; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:24121961" FT /id="VAR_081257" FT VARIANT 381 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:19797784, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081258" FT VARIANT 384 FT /note="G -> A (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750646)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006456" FT VARIANT 390 FT /note="S -> I (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750883)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010128" FT VARIANT 392 FT /note="L -> V (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751416)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712" FT /id="VAR_006457" FT VARIANT 394 FT /note="G -> V (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750929)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075276" FT VARIANT 396 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_070026" FT VARIANT 405 FT /note="N -> S (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63751254)" FT /evidence="ECO:0000269|PubMed:10644793, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010129" FT VARIANT 408 FT /note="I -> T (in AD3; dbSNP:rs906454643)" FT /evidence="ECO:0000269|PubMed:26549787" FT /id="VAR_075277" FT VARIANT 409 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750227)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009213" FT VARIANT 410 FT /note="C -> Y (in AD3; results in reduced APP and Notch FT proteolysis; dbSNP:rs661)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006458" FT VARIANT 417 FT /note="G -> A (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30180983" FT /id="VAR_081259" FT VARIANT 418 FT /note="L -> F (in AD3; uncertain significance; nearly FT abolishes protease activity with APP; dbSNP:rs63751316)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075278" FT VARIANT 426 FT /note="A -> P (in AD3; uncertain significance; slightly FT decreased protease activity with APP; dbSNP:rs63751223)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006459" FT VARIANT 431 FT /note="A -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750083)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084, FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95" FT /id="VAR_025605" FT VARIANT 435 FT /note="L -> F (in AD3; with unusual amyloid cotton wool FT plaques; almost abolishes gamma-secretase activity; no FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no FT detectable amyloid-beta; dbSNP:rs63750001)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341" FT /id="VAR_075280" FT VARIANT 436 FT /note="P -> Q (in AD3; severe decrease of protease activity FT with APP; dbSNP:rs121917808)" FT /evidence="ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:9831473" FT /id="VAR_006460" FT VARIANT 436 FT /note="P -> S (in AD3; partially abolishes gamma-secretase FT activity; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63749925)" FT /evidence="ECO:0000269|PubMed:10090481, FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341" FT /id="VAR_008141" FT VARIANT 439 FT /note="I -> V (in AD3; uncertain significance; no FT significant change of protease activity with APP; FT dbSNP:rs63750249)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075282" FT MUTAGEN 66..72 FT /note="Missing: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 76..77 FT /note="KY->AA: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82..83 FT /note="VI->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82 FT /note="V->K,E: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 84..85 FT /note="ML->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 99 FT /note="T->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 105 FT /note="F->I: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 108 FT /note="R->Q: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 112 FT /note="Q->C: Formation of an artifactual disulfide bond FT with a substrate protein." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 113 FT /note="L->Q: Severe decrease of protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 117 FT /note="P->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 123 FT /note="E->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 131 FT /note="H->R: Severe decrease of protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 136 FT /note="A->G: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 143 FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 150 FT /note="L->P: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 165 FT /note="W->G: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 168 FT /note="I->T: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 176 FT /note="F->L: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 184 FT /note="E->G: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 202 FT /note="I->F: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 212 FT /note="S->Y: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 214 FT /note="H->D: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 219 FT /note="L->F: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 223 FT /note="Q->R: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 226 FT /note="L->F: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 230 FT /note="S->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 238 FT /note="I->M: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 239 FT /note="K->N: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 245 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 248 FT /note="L->R: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 256 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 256 FT /note="Y->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 257 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Reduces production of NICD in NOTCH1 FT processing. Impaired ability to cleave Ephb2/CTF1." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981" FT MUTAGEN 257 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515" FT MUTAGEN 272 FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 273 FT /note="E->A: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 278 FT /note="R->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 284 FT /note="P->S: No significant change of protease activity FT with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 286 FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta FT in APP processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 286 FT /note="L->E,R: Reduces production of NICD in NOTCH1 FT processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 288..290 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 291 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 292 FT /note="M->D: Loss of endoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10545183" FT MUTAGEN 310 FT /note="S->A: Abolishes PKA-mediated phosphorylation; no FT effect on caspase-mediated cleavage." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 345 FT /note="D->N: Abolishes caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 346 FT /note="S->A: Abolishes PKC-mediated phosphorylation; no FT effect on PKA-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 346 FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates FT progression of apoptosis." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 352 FT /note="R->C: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 365 FT /note="S->A: Slightly increased protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 373 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 377..381 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 377 FT /note="R->W: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 385 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of FT the N-cadherin/PS1 complex at the cell surface. Impairs FT CDH2 processing." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 386 FT /note="F->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 389 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 391 FT /note="V->F: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 412 FT /note="V->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 420 FT /note="L->R: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 424 FT /note="L->V: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 432..434 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 432 FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 433 FT /note="P->A: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Slightly increased FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 433 FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP, FT nor NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:20460383" FT MUTAGEN 433 FT /note="P->G: Very little endoproteolysis. Little APP FT processing. No NOTCH1 processing. Very low levels amyloid- FT beta protein 40 and no detectable amyloid-beta protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->C: Some loss of endoproteolytic cleavage. Some FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 434 FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->G: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta FT protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->A: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. FT Greatly reduced amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very FT little APP and NOTCH1 processing. Very low levels of FT amyloid-beta protein 40 and no detectable amyloid-beta FT protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->I: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->R: No endoproteolytic cleavage; no APP, nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:20460383" FT MUTAGEN 435 FT /note="L->V: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. Some FT increase in amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 437 FT /note="I->V: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT CONFLICT 128 FT /note="R -> G (in Ref. 7; AAL16811)" FT /evidence="ECO:0000305" FT STRAND 77..80 FT /evidence="ECO:0007829|PDB:6LR4" FT HELIX 83..102 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:8X52" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 125..155 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 159..175 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 177..188 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 195..214 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 219..240 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 243..262 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 267..277 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:6IDF" FT TURN 284..286 FT /evidence="ECO:0007829|PDB:8KCU" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 293..299 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 341..345 FT /evidence="ECO:0007829|PDB:2KR6" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 383..398 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:8OQY" FT HELIX 403..428 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 435..451 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8KCS" SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64; MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID S20A2_HUMAN Reviewed; 652 AA. AC Q08357; DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 184. DE RecName: Full=Sodium-dependent phosphate transporter 2; DE AltName: Full=Gibbon ape leukemia virus receptor 2; DE Short=GLVR-2; DE AltName: Full=Phosphate transporter 2; DE Short=PiT-2; DE Short=Pit2; DE Short=hPit2; DE AltName: Full=Solute carrier family 20 member 2; GN Name=SLC20A2; Synonyms=GLVR2, PIT2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION AS RETROVIRAL RECEPTOR (MICROBIAL RP FUNCTION). RC TISSUE=Placenta; RX PubMed=8302848; DOI=10.1073/pnas.91.3.1168; RA van Zeijl M., Johann S.V., Closs E., Cunningham J., Eddy R., Shows T.B., RA O'Hara B.; RT "A human amphotropic retrovirus receptor is a second member of the gibbon RT ape leukemia virus receptor family."; RL Proc. Natl. Acad. Sci. U.S.A. 91:1168-1172(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP TOPOLOGY, GLYCOSYLATION AT ASN-81, AND MUTAGENESIS OF ASN-81. RX PubMed=11356966; DOI=10.1128/jvi.75.12.5584-5592.2001; RA Salauen C., Rodrigues P., Heard J.M.; RT "Transmembrane topology of PiT-2, a phosphate transporter-retrovirus RT receptor."; RL J. Virol. 75:5584-5592(2001). RN [5] RP TOPOLOGY, SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=9151850; DOI=10.1128/jvi.71.6.4564-4570.1997; RA Chien M.L., Foster J.L., Douglas J.L., Garcia J.V.; RT "The amphotropic murine leukemia virus receptor gene encodes a 71- RT kilodalton protein that is induced by phosphate depletion."; RL J. Virol. 71:4564-4570(1997). RN [6] RP FUNCTION AS RETROVIRAL RECEPTOR (MICROBIAL FUNCTION). RX PubMed=11435563; DOI=10.1128/jvi.75.15.6841-6849.2001; RA Sugai J., Eiden M., Anderson M.M., Van Hoeven N., Meiering C.D., RA Overbaugh J.; RT "Identification of envelope determinants of feline leukemia virus subgroup RT B that permit infection and gene transfer to cells expressing human Pit1 or RT Pit2."; RL J. Virol. 75:6841-6849(2001). RN [7] RP FUNCTION AS SODIUM-PHOSPHATE SYMPORTER, FUNCTION AS RETROVIRAL RECEPTOR RP (MICROBIAL FUNCTION), SUBUNIT, MUTAGENESIS OF GLU-55 AND GLU-575, AND RP TRANSPORTER ACTIVITY. RX PubMed=12205090; DOI=10.1074/jbc.m207096200; RA Boettger P., Pedersen L.; RT "Two highly conserved glutamate residues critical for type III sodium- RT dependent phosphate transport revealed by uncoupling transport function RT from retroviral receptor function."; RL J. Biol. Chem. 277:42741-42747(2002). RN [8] RP FUNCTION AS SODIUM-PHOSPHATE SYMPORTER, FUNCTION AS RETROVIRAL RECEPTOR RP (MICROBIAL FUNCTION), SUBUNIT, MUTAGENESIS OF ASP-506, CHARACTERIZATION OF RP VARIANT IBGC1 ASN-28, AND TRANSPORTER ACTIVITY. RX PubMed=15955065; DOI=10.1111/j.1742-4658.2005.04720.x; RA Boettger P., Pedersen L.; RT "Evolutionary and experimental analyses of inorganic phosphate transporter RT PiT family reveals two related signature sequences harboring highly RT conserved aspartic acids critical for sodium-dependent phosphate transport RT function of human PiT2."; RL FEBS J. 272:3060-3074(2005). RN [9] RP FUNCTION AS SODIUM-PHOSPHATE SYMPORTER, BIOPHYSICOCHEMICAL PROPERTIES, RP MUTAGENESIS OF GLU-55; GLU-91 AND GLU-575, AND TRANSPORTER ACTIVITY. RX PubMed=16790504; DOI=10.1152/ajpcell.00015.2006; RA Boettger P., Hede S.E., Grunnet M., Hoyer B., Klaerke D.A., Pedersen L.; RT "Characterization of transport mechanisms and determinants critical for RT Na+-dependent Pi symport of the PiT family paralogs human PiT1 and PiT2."; RL Am. J. Physiol. 291:C1377-C1387(2006). RN [10] RP FUNCTION AS SODIUM-PHOSPHATE SYMPORTER, TRANSPORTER ACTIVITY, AND RP STOICHIOMETRY. RX PubMed=17494632; DOI=10.1152/ajpcell.00064.2007; RA Ravera S., Virkki L.V., Murer H., Forster I.C.; RT "Deciphering PiT transport kinetics and substrate specificity using RT electrophysiology and flux measurements."; RL Am. J. Physiol. 293:C606-C620(2007). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-256; SER-259; SER-268; RP SER-316 AND SER-385, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259 AND SER-316, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [15] RP VARIANTS IBGC1 VAL-42 DEL; ARG-498; LYS-575; MET-595; TRP-601 AND LEU-601, RP CHARACTERIZATION OF VARIANTS IBGC1 VAL-42 DEL; ARG-498; LYS-575; MET-595; RP TRP-601 AND LEU-601, FUNCTION AS SODIUM-PHOSPHATE SYMPORTER, AND RP TRANSPORTER ACTIVITY. RX PubMed=22327515; DOI=10.1038/ng.1077; RA Wang C., Li Y., Shi L., Ren J., Patti M., Wang T., de Oliveira J.R., RA Sobrido M.J., Quintans B., Baquero M., Cui X., Zhang X.Y., Wang L., Xu H., RA Wang J., Yao J., Dai X., Liu J., Zhang L., Ma H., Gao Y., Ma X., Feng S., RA Liu M., Wang Q.K., Forster I.C., Zhang X., Liu J.Y.; RT "Mutations in SLC20A2 link familial idiopathic basal ganglia calcification RT with phosphate homeostasis."; RL Nat. Genet. 44:254-256(2012). RN [16] RP INVOLVEMENT IN IBGC1. RX PubMed=23406454; DOI=10.1111/ene.12044; RA Lemos R.R., Oliveira M.F., Oliveira J.R.; RT "Reporting a new mutation at the SLC20A2 gene in familial idiopathic basal RT ganglia calcification."; RL Eur. J. Neurol. 20:E43-43(2013). RN [17] RP VARIANTS IBGC1 LEU-11; ASN-28 AND PRO-62. RX PubMed=23939468; DOI=10.1016/j.gene.2013.07.071; RA Chen W.J., Yao X.P., Zhang Q.J., Ni W., He J., Li H.F., Liu X.Y., RA Zhao G.X., Murong S.X., Wang N., Wu Z.Y.; RT "Novel SLC20A2 mutations identified in southern Chinese patients with RT idiopathic basal ganglia calcification."; RL Gene 529:159-162(2013). RN [18] RP VARIANTS IBGC1 GLN-382; GLN-502; LEU-568 AND LEU-601. RX PubMed=23334463; DOI=10.1007/s10048-012-0349-2; RA Hsu S.C., Sears R.L., Lemos R.R., Quintans B., Huang A., Spiteri E., RA Nevarez L., Mamah C., Zatz M., Pierce K.D., Fullerton J.M., Adair J.C., RA Berner J.E., Bower M., Brodaty H., Carmona O., Dobricic V., Fogel B.L., RA Garcia-Estevez D., Goldman J., Goudreau J.L., Hopfer S., Jankovic M., RA Jauma S., Jen J.C., Kirdlarp S., Klepper J., Kostic V., Lang A.E., RA Linglart A., Maisenbacher M.K., Manyam B.V., Mazzoni P., Miedzybrodzka Z., RA Mitarnun W., Mitchell P.B., Mueller J., Novakovic I., Paucar M., RA Paulson H., Simpson S.A., Svenningsson P., Tuite P., Vitek J., RA Wetchaphanphesat S., Williams C., Yang M., Schofield P.R., RA de Oliveira J.R., Sobrido M.J., Geschwind D.H., Coppola G.; RT "Mutations in SLC20A2 are a major cause of familial idiopathic basal RT ganglia calcification."; RL Neurogenetics 14:11-22(2013). RN [19] RP VARIANTS IBGC1 ASN-28; LEU-184; SER-194 AND SER-571. RX PubMed=24065723; DOI=10.1093/brain/awt255; RG French IBGC Study Group; RA Nicolas G., Pottier C., Charbonnier C., Guyant-Marechal L., Le Ber I., RA Pariente J., Labauge P., Ayrignac X., Defebvre L., Maltete D., RA Martinaud O., Lefaucheur R., Guillin O., Wallon D., Chaumette B., RA Rondepierre P., Derache N., Fromager G., Schaeffer S., Krystkowiak P., RA Verny C., Jurici S., Sauvee M., Verin M., Lebouvier T., Rouaud O., RA Thauvin-Robinet C., Rousseau S., Rovelet-Lecrux A., Frebourg T., RA Campion D., Hannequin D.; RT "Phenotypic spectrum of probable and genetically-confirmed idiopathic basal RT ganglia calcification."; RL Brain 136:3395-3407(2013). RN [20] RP VARIANTS IBGC1 TRP-434 AND MET-595. RX PubMed=25284758; DOI=10.1002/mds.26053; RA Taglia I., Mignarri A., Olgiati S., Menci E., Petrocelli P.L., RA Breedveld G.J., Scaglione C., Martinelli P., Federico A., Bonifati V., RA Dotti M.T.; RT "Primary familial brain calcification: Genetic analysis and clinical RT spectrum."; RL Mov. Disord. 29:1691-1695(2014). RN [21] RP VARIANTS IBGC1 VAL-51; HIS-71; MET-115 AND ARG-637. RX PubMed=24463626; DOI=10.1212/wnl.0000000000000143; RA Yamada M., Tanaka M., Takagi M., Kobayashi S., Taguchi Y., Takashima S., RA Tanaka K., Touge T., Hatsuta H., Murayama S., Hayashi Y., Kaneko M., RA Ishiura H., Mitsui J., Atsuta N., Sobue G., Shimozawa N., Inuzuka T., RA Tsuji S., Hozumi I.; RT "Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia RT calcification in Japan."; RL Neurology 82:705-712(2014). RN [22] RP CHARACTERIZATION OF VARIANT IBGC1 GLN-PHE-VAL-THR-629 INS, FUNCTION AS RP SODIUM-PHOSPHATE SYMPORTER, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=28722801; DOI=10.1002/jcp.26104; RA Taglia I., Formichi P., Battisti C., Peppoloni G., Barghigiani M., RA Tessa A., Federico A.; RT "Primary familial brain calcification with a novel SLC20A2 mutation: RT Analysis of PiT-2 expression and localization."; RL J. Cell. Physiol. 233:2324-2331(2018). RN [23] RP CHARACTERIZATION OF VARIANTS IBGC1 MET-115 AND ARG-637, FUNCTION AS RP SODIUM-PHOSPHATE SYMPORTER, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=30704756; DOI=10.1016/j.bbrc.2019.01.096; RA Sekine S.I., Nishii K., Masaka T., Kurita H., Inden M., Hozumi I.; RT "SLC20A2 variants cause dysfunctional phosphate transport activity in RT endothelial cells induced from Idiopathic Basal Ganglia Calcification RT patients-derived iPSCs."; RL Biochem. Biophys. Res. Commun. 510:303-308(2019). CC -!- FUNCTION: Sodium-phosphate symporter which preferentially transports CC the monovalent form of phosphate with a stoichiometry of two sodium CC ions per phosphate ion (PubMed:12205090, PubMed:15955065, CC PubMed:16790504, PubMed:17494632, PubMed:22327515, PubMed:28722801, CC PubMed:30704756). Plays a critical role in the determination of bone CC quality and strength by providing phosphate for bone mineralization (By CC similarity). Required to maintain normal cerebrospinal fluid phosphate CC levels (By similarity). Mediates phosphate-induced calcification of CC vascular smooth muscle cells (VCMCs) and can functionally compensate CC for loss of SLC20A1 in VCMCs (By similarity). CC {ECO:0000250|UniProtKB:Q80UP8, ECO:0000269|PubMed:12205090, CC ECO:0000269|PubMed:15955065, ECO:0000269|PubMed:16790504, CC ECO:0000269|PubMed:17494632, ECO:0000269|PubMed:22327515, CC ECO:0000269|PubMed:28722801, ECO:0000269|PubMed:30704756}. CC -!- FUNCTION: (Microbial infection) Functions as a retroviral receptor and CC confers human cells susceptibility to infection to amphotropic murine CC leukemia virus (A-MuLV), 10A1 murine leukemia virus (10A1 MLV) and some CC feline leukemia virus subgroup B (FeLV-B) variants. CC {ECO:0000269|PubMed:11435563, ECO:0000269|PubMed:12205090, CC ECO:0000269|PubMed:15955065, ECO:0000269|PubMed:8302848}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 Na(+)(out) + phosphate(out) = 2 Na(+)(in) + phosphate(in); CC Xref=Rhea:RHEA:71259, ChEBI:CHEBI:29101, ChEBI:CHEBI:43474; CC Evidence={ECO:0000269|PubMed:12205090, ECO:0000269|PubMed:15955065, CC ECO:0000269|PubMed:16790504, ECO:0000269|PubMed:17494632, CC ECO:0000269|PubMed:22327515, ECO:0000269|PubMed:28722801, CC ECO:0000269|PubMed:30704756}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=163.5 uM for phosphate {ECO:0000269|PubMed:16790504}; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:12205090, CC ECO:0000269|PubMed:15955065}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:28722801, CC ECO:0000269|PubMed:30704756, ECO:0000269|PubMed:9151850}; Multi-pass CC membrane protein {ECO:0000269|PubMed:9151850}. Apical cell membrane CC {ECO:0000250|UniProtKB:Q63488}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC -!- INDUCTION: Increased by phosphate depletion in osteosarcoma cell lines. CC {ECO:0000269|PubMed:9151850}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 1 (IBGC1) CC [MIM:213600]: A form of basal ganglia calcification, an autosomal CC dominant condition characterized by symmetric calcification in the CC basal ganglia and other brain regions. Affected individuals can either CC be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, CC including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, CC seizures, and chronic headache. Serum levels of calcium, phosphate, CC alkaline phosphatase and parathyroid hormone are normal. The CC neuropathological hallmark of the disease is vascular and pericapillary CC calcification, mainly of calcium phosphate, in the affected brain CC areas. {ECO:0000269|PubMed:15955065, ECO:0000269|PubMed:22327515, CC ECO:0000269|PubMed:23334463, ECO:0000269|PubMed:23406454, CC ECO:0000269|PubMed:23939468, ECO:0000269|PubMed:24065723, CC ECO:0000269|PubMed:24463626, ECO:0000269|PubMed:25284758, CC ECO:0000269|PubMed:28722801, ECO:0000269|PubMed:30704756}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the inorganic phosphate transporter (PiT) (TC CC 2.A.20) family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L20852; AAA18018.1; -; mRNA. DR EMBL; AK291202; BAF83891.1; -; mRNA. DR EMBL; BC028600; AAH28600.1; -; mRNA. DR CCDS; CCDS6132.1; -. DR PIR; A37000; A37000. DR RefSeq; NP_001244109.1; NM_001257180.2. DR RefSeq; NP_001244110.1; NM_001257181.2. DR RefSeq; NP_006740.1; NM_006749.5. DR RefSeq; XP_005273670.1; XM_005273613.4. DR RefSeq; XP_016869237.1; XM_017013748.2. DR RefSeq; XP_024303003.1; XM_024447235.2. DR RefSeq; XP_024303004.1; XM_024447236.2. DR RefSeq; XP_047278076.1; XM_047422120.1. DR RefSeq; XP_047278077.1; XM_047422121.1. DR RefSeq; XP_047278078.1; XM_047422122.1. DR RefSeq; XP_054217019.1; XM_054361044.1. DR RefSeq; XP_054217020.1; XM_054361045.1. DR RefSeq; XP_054217021.1; XM_054361046.1. DR RefSeq; XP_054217022.1; XM_054361047.1. DR RefSeq; XP_054217023.1; XM_054361048.1. DR RefSeq; XP_054217024.1; XM_054361049.1. DR RefSeq; XP_054217025.1; XM_054361050.1. DR AlphaFoldDB; Q08357; -. DR SMR; Q08357; -. DR BioGRID; 112463; 130. DR FunCoup; Q08357; 652. DR IntAct; Q08357; 80. DR MINT; Q08357; -. DR STRING; 9606.ENSP00000429754; -. DR BindingDB; Q08357; -. DR ChEMBL; CHEMBL4295806; -. DR DrugBank; DB11348; Calcium Phosphate. DR DrugBank; DB14481; Calcium phosphate dihydrate. DR DrugBank; DB14502; Sodium phosphate, dibasic. DR DrugBank; DB09449; Sodium phosphate, monobasic. DR DrugBank; DB14503; Sodium phosphate, monobasic, unspecified form. DR DrugBank; DB09436; Technetium Tc-99m succimer. DR TCDB; 2.A.20.2.3; the inorganic phosphate transporter (pit) family. DR GlyCosmos; Q08357; 1 site, No reported glycans. DR GlyGen; Q08357; 3 sites, 1 N-linked glycan (1 site). DR iPTMnet; Q08357; -. DR PhosphoSitePlus; Q08357; -. DR BioMuta; SLC20A2; -. DR DMDM; 74735615; -. DR jPOST; Q08357; -. DR MassIVE; Q08357; -. DR PaxDb; 9606-ENSP00000340465; -. DR PeptideAtlas; Q08357; -. DR ProteomicsDB; 58600; -. DR Pumba; Q08357; -. DR Antibodypedia; 11470; 154 antibodies from 27 providers. DR DNASU; 6575; -. DR Ensembl; ENST00000342228.7; ENSP00000340465.3; ENSG00000168575.12. DR Ensembl; ENST00000517366.2; ENSP00000427756.2; ENSG00000168575.12. DR Ensembl; ENST00000518384.2; ENSP00000430462.2; ENSG00000168575.12. DR Ensembl; ENST00000518717.2; ENSP00000430166.2; ENSG00000168575.12. DR Ensembl; ENST00000520179.5; ENSP00000429712.1; ENSG00000168575.12. DR Ensembl; ENST00000520262.6; ENSP00000429754.1; ENSG00000168575.12. DR Ensembl; ENST00000713988.1; ENSP00000519279.1; ENSG00000168575.12. DR GeneID; 6575; -. DR KEGG; hsa:6575; -. DR MANE-Select; ENST00000520262.6; ENSP00000429754.1; NM_001257180.2; NP_001244109.1. DR UCSC; uc003xpe.5; human. DR AGR; HGNC:10947; -. DR ClinPGx; PA35834; -. DR CTD; 6575; -. DR DisGeNET; 6575; -. DR GeneCards; SLC20A2; -. DR GeneReviews; SLC20A2; -. DR HGNC; HGNC:10947; SLC20A2. DR HPA; ENSG00000168575; Tissue enhanced (choroid plexus, skeletal muscle). DR MalaCards; SLC20A2; -. DR MIM; 158378; gene. DR MIM; 213600; phenotype. DR OpenTargets; ENSG00000168575; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000168575; -. DR eggNOG; KOG2493; Eukaryota. DR GeneTree; ENSGT00390000014879; -. DR HOGENOM; CLU_015355_3_1_1; -. DR InParanoid; Q08357; -. DR OMA; MQAFCIA; -. DR OrthoDB; 260807at2759; -. DR PAN-GO; Q08357; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q08357; -. DR BioCyc; MetaCyc:ENSG00000168575-MONOMER; -. DR PathwayCommons; Q08357; -. DR Reactome; R-HSA-427652; Sodium-coupled phosphate cotransporters. DR Reactome; R-HSA-5619111; Defective SLC20A2 causes idiopathic basal ganglia calcification 1 (IBGC1). DR SignaLink; Q08357; -. DR SIGNOR; Q08357; -. DR Agora; ENSG00000168575; -. DR BioGRID-ORCS; 6575; 14 hits in 1159 CRISPR screens. DR ChiTaRS; SLC20A2; human. DR GeneWiki; SLC20A2; -. DR GenomeRNAi; 6575; -. DR Pharos; Q08357; Tbio. DR PRO; PR:Q08357; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q08357; protein. DR Bgee; ENSG00000168575; Expressed in left lobe of thyroid gland and 198 other cell types or tissues. DR ExpressionAtlas; Q08357; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0031526; C:brush border membrane; ISS:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IMP:UniProtKB. DR GO; GO:0005315; F:phosphate transmembrane transporter activity; IBA:GO_Central. DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc. DR GO; GO:0005436; F:sodium:phosphate symporter activity; IDA:UniProtKB. DR GO; GO:0001618; F:virus receptor activity; IMP:UniProtKB. DR GO; GO:0006811; P:monoatomic ion transport; TAS:Reactome. DR GO; GO:0035435; P:phosphate ion transmembrane transport; IBA:GO_Central. DR GO; GO:0030501; P:positive regulation of bone mineralization; ISS:UniProtKB. DR InterPro; IPR001204; Phos_transporter. DR PANTHER; PTHR11101; PHOSPHATE TRANSPORTER; 1. DR PANTHER; PTHR11101:SF83; SODIUM-DEPENDENT PHOSPHATE TRANSPORTER 2; 1. DR Pfam; PF01384; PHO4; 1. PE 1: Evidence at protein level; KW Cell membrane; Disease variant; Glycoprotein; KW Host cell receptor for virus entry; Host-virus interaction; Ion transport; KW Membrane; Phosphate transport; Phosphoprotein; Proteomics identification; KW Receptor; Reference proteome; Sodium; Sodium transport; Symport; KW Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..652 FT /note="Sodium-dependent phosphate transporter 2" FT /id="PRO_0000341268" FT TOPO_DOM 1..5 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 6..26 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 27..46 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 47..67 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 68..86 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 87..107 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 108..109 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 110..130 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 131..142 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 143..163 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 164..190 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 191..211 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 212..213 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 214..234 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 235..482 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 483..503 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 504..530 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 531..551 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 552..571 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 572..586 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 587..593 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 594..609 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 610..621 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 622..642 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 643..652 FT /note="Extracellular" FT /evidence="ECO:0000255" FT REGION 273..307 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 458..477 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 295..304 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 253 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q63488" FT MOD_RES 256 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 259 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 268 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 316 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 385 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CARBOHYD 81 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11356966" FT VARIANT 11 FT /note="I -> L (in IBGC1; dbSNP:rs201836672)" FT /evidence="ECO:0000269|PubMed:23939468" FT /id="VAR_072255" FT VARIANT 28 FT /note="D -> N (in IBGC1; Impairs phosphate transport; no FT effect on retroviral receptor function; FT dbSNP:rs1554561099)" FT /evidence="ECO:0000269|PubMed:15955065, FT ECO:0000269|PubMed:23939468, ECO:0000269|PubMed:24065723" FT /id="VAR_072256" FT VARIANT 42 FT /note="Missing (in IBGC1; substantially impaired phosphate FT transport)" FT /evidence="ECO:0000269|PubMed:22327515" FT /id="VAR_067545" FT VARIANT 51 FT /note="A -> V (in IBGC1)" FT /evidence="ECO:0000269|PubMed:24463626" FT /id="VAR_072257" FT VARIANT 62 FT /note="L -> P (in IBGC1)" FT /evidence="ECO:0000269|PubMed:23939468" FT /id="VAR_072258" FT VARIANT 71 FT /note="R -> H (in IBGC1)" FT /evidence="ECO:0000269|PubMed:24463626" FT /id="VAR_072259" FT VARIANT 115 FT /note="T -> M (in IBGC1; loss of sodium-dependent phosphate FT transport but no effect on cell membrane localization; FT dbSNP:rs775911275)" FT /evidence="ECO:0000269|PubMed:24463626, FT ECO:0000269|PubMed:30704756" FT /id="VAR_072260" FT VARIANT 184 FT /note="P -> L (in IBGC1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:24065723" FT /id="VAR_075396" FT VARIANT 194 FT /note="N -> S (in IBGC1; uncertain significance; FT dbSNP:rs748252183)" FT /evidence="ECO:0000269|PubMed:24065723" FT /id="VAR_075397" FT VARIANT 382 FT /note="R -> Q (in IBGC1; dbSNP:rs200010919)" FT /evidence="ECO:0000269|PubMed:23334463" FT /id="VAR_072261" FT VARIANT 434 FT /note="S -> W (in IBGC1; dbSNP:rs1357615935)" FT /evidence="ECO:0000269|PubMed:25284758" FT /id="VAR_072262" FT VARIANT 498 FT /note="G -> R (in IBGC1; substantially impaired phosphate FT transport)" FT /evidence="ECO:0000269|PubMed:22327515" FT /id="VAR_067546" FT VARIANT 502 FT /note="H -> Q (in IBGC1)" FT /evidence="ECO:0000269|PubMed:23334463" FT /id="VAR_072263" FT VARIANT 568 FT /note="P -> L (in IBGC1; dbSNP:rs763252801)" FT /evidence="ECO:0000269|PubMed:23334463" FT /id="VAR_072264" FT VARIANT 571 FT /note="G -> S (in IBGC1; dbSNP:rs1388992742)" FT /evidence="ECO:0000269|PubMed:24065723" FT /id="VAR_075398" FT VARIANT 575 FT /note="E -> K (in IBGC1; substantially impaired phosphate FT transport; dbSNP:rs387906653)" FT /evidence="ECO:0000269|PubMed:22327515" FT /id="VAR_067547" FT VARIANT 595 FT /note="T -> M (in IBGC1; substantially impaired phosphate FT transport; dbSNP:rs387906654)" FT /evidence="ECO:0000269|PubMed:22327515, FT ECO:0000269|PubMed:25284758" FT /id="VAR_067548" FT VARIANT 601 FT /note="S -> L (in IBGC1; substantially impaired phosphate FT transport; dbSNP:rs387906652)" FT /evidence="ECO:0000269|PubMed:22327515, FT ECO:0000269|PubMed:23334463" FT /id="VAR_067549" FT VARIANT 601 FT /note="S -> W (in IBGC1; substantially impaired phosphate FT transport; dbSNP:rs387906652)" FT /evidence="ECO:0000269|PubMed:22327515" FT /id="VAR_067550" FT VARIANT 629 FT /note="T -> TWFVT (in IBGC1; uncertain significance; FT reduced sodium-dependent phosphate transport and cell FT membrane localization)" FT /evidence="ECO:0000269|PubMed:28722801" FT /id="VAR_088078" FT VARIANT 637 FT /note="S -> R (in IBGC1; loss of sodium-dependent phosphate FT transport but no effect on cell membrane localization)" FT /evidence="ECO:0000269|PubMed:24463626, FT ECO:0000269|PubMed:30704756" FT /id="VAR_072265" FT MUTAGEN 55 FT /note="E->D,K: Abolishes sodium-dependent phosphate FT transport; no effect on retroviral receptor function." FT /evidence="ECO:0000269|PubMed:12205090, FT ECO:0000269|PubMed:16790504" FT MUTAGEN 55 FT /note="E->Q: Abolishes phosphate but not sodium uptake; FT when associated with Q-91 and Q-575." FT /evidence="ECO:0000269|PubMed:12205090, FT ECO:0000269|PubMed:16790504" FT MUTAGEN 81 FT /note="N->V: Abolishes N-glycosylation." FT /evidence="ECO:0000269|PubMed:11356966" FT MUTAGEN 91 FT /note="E->Q: Abolishes phosphate but not sodium uptake; FT when associated with Q-55 and Q-575." FT /evidence="ECO:0000269|PubMed:16790504" FT MUTAGEN 506 FT /note="D->N: Impairs phosphate transport; no effect on FT retroviral receptor function." FT /evidence="ECO:0000269|PubMed:15955065" FT MUTAGEN 575 FT /note="E->D,K: Abolishes sodium-dependent phosphate FT transport; no effect on retroviral receptor function." FT /evidence="ECO:0000269|PubMed:12205090, FT ECO:0000269|PubMed:16790504" FT MUTAGEN 575 FT /note="E->Q: Abolishes phosphate but not sodium uptake; FT when associated with Q-55 and Q-91." FT /evidence="ECO:0000269|PubMed:12205090, FT ECO:0000269|PubMed:16790504" SQ SEQUENCE 652 AA; 70392 MW; A0A870C7927DE39C CRC64; MAMDEYLWMV ILGFIIAFIL AFSVGANDVA NSFGTAVGSG VVTLRQACIL ASIFETTGSV LLGAKVGETI RKGIIDVNLY NETVETLMAG EVSAMVGSAV WQLIASFLRL PISGTHCIVG STIGFSLVAI GTKGVQWMEL VKIVASWFIS PLLSGFMSGL LFVLIRIFIL KKEDPVPNGL RALPVFYAAT IAINVFSIMY TGAPVLGLVL PMWAIALISF GVALLFAFFV WLFVCPWMRR KITGKLQKEG ALSRVSDESL SKVQEAESPV FKELPGAKAN DDSTIPLTGA AGETLGTSEG TSAGSHPRAA YGRALSMTHG SVKSPISNGT FGFDGHTRSD GHVYHTVHKD SGLYKDLLHK IHIDRGPEEK PAQESNYRLL RRNNSYTCYT AAICGLPVHA TFRAADSSAP EDSEKLVGDT VSYSKKRLRY DSYSSYCNAV AEAEIEAEEG GVEMKLASEL ADPDQPREDP AEEEKEEKDA PEVHLLFHFL QVLTACFGSF AHGGNDVSNA IGPLVALWLI YKQGGVTQEA ATPVWLLFYG GVGICTGLWV WGRRVIQTMG KDLTPITPSS GFTIELASAF TVVIASNIGL PVSTTHCKVG SVVAVGWIRS RKAVDWRLFR NIFVAWFVTV PVAGLFSAAV MALLMYGILP YV // ID S53A1_HUMAN Reviewed; 696 AA. AC Q9UBH6; O95719; Q7L8K9; Q8IW20; Q9NT19; Q9UFB9; DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 172. DE RecName: Full=Solute carrier family 53 member 1 {ECO:0000303|PubMed:31043717}; DE AltName: Full=Phosphate exporter SLC53A1 {ECO:0000305|PubMed:31043717}; DE AltName: Full=Protein SYG1 homolog; DE AltName: Full=Xenotropic and polytropic murine leukemia virus receptor X3; DE Short=X-receptor; DE AltName: Full=Xenotropic and polytropic retrovirus receptor 1; GN Name=XPR1 {ECO:0000303|PubMed:31043717}; GN Synonyms=SLC53A1 {ECO:0000303|PubMed:31043717}, SYG1, X3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9988277; DOI=10.1038/6005; RA Yang Y.-L., Guo L., Xu S., Holland C.A., Kitamura T., Hunter K., RA Cunningham J.M.; RT "Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by RT a single gene at Rmc1."; RL Nat. Genet. 21:216-219(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND RP DEVELOPMENTAL STAGE. RC TISSUE=Lymphocyte; RX PubMed=9927670; DOI=10.1073/pnas.96.3.927; RA Tailor C.S., Nouri A., Lee C.G., Kozak C., Kabat D.; RT "Cloning and characterization of a cell surface receptor for xenotropic and RT polytropic murine leukemia viruses."; RL Proc. Natl. Acad. Sci. U.S.A. 96:927-932(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL RP STAGE, AND VARIANT ALA-491. RC TISSUE=Cervix carcinoma; RX PubMed=9990033; DOI=10.1073/pnas.96.4.1385; RA Battini J.-L., Rasko J.E.J., Miller A.D.; RT "A human cell-surface receptor for xenotropic and polytropic murine RT leukemia viruses: possible role in G protein-coupled signal transduction."; RL Proc. Natl. Acad. Sci. U.S.A. 96:1385-1390(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 103-696 (ISOFORM 1). RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-690, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-668 AND THR-690, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-690, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=23791524; DOI=10.1016/j.celrep.2013.05.035; RA Giovannini D., Touhami J., Charnet P., Sitbon M., Battini J.L.; RT "Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans."; RL Cell Rep. 3:1866-1873(2013). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-668, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, INVOLVEMENT IN IBGC6, VARIANTS IBGC6 RP ASN-136; PRO-140; PRO-145 AND SER-218, AND CHARACTERIZATION OF VARIANTS RP IBGC6 ASN-136; PRO-140; PRO-145 AND SER-218. RX PubMed=25938945; DOI=10.1038/ng.3289; RA Legati A., Giovannini D., Nicolas G., Lopez-Sanchez U., Quintans B., RA Oliveira J.R., Sears R.L., Ramos E.M., Spiteri E., Sobrido M.J., RA Carracedo A., Castro-Fernandez C., Cubizolle S., Fogel B.L., Goizet C., RA Jen J.C., Kirdlarp S., Lang A.E., Miedzybrodzka Z., Mitarnun W., Paucar M., RA Paulson H., Pariente J., Richard A.C., Salins N.S., Simpson S.A., RA Striano P., Svenningsson P., Tison F., Unni V.K., Vanakker O., RA Wessels M.W., Wetchaphanphesat S., Yang M., Boller F., Campion D., RA Hannequin D., Sitbon M., Geschwind D.H., Battini J.L., Coppola G.; RT "Mutations in XPR1 cause primary familial brain calcification associated RT with altered phosphate export."; RL Nat. Genet. 47:579-581(2015). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INVOLVEMENT IN IBGC6, RP VARIANTS IBGC6 CYS-459; ASP-619 AND SER-629, CHARACTERIZATION OF VARIANTS RP IBGC6 CYS-459; ASP-619 AND SER-629, AND MUTAGENESIS OF 612-LEU--THR-696. RX PubMed=31043717; DOI=10.1038/s41598-019-43255-x; RA Lopez-Sanchez U., Nicolas G., Richard A.C., Maltete D., Charif M., RA Ayrignac X., Goizet C., Touhami J., Labesse G., Battini J.L., Sitbon M.; RT "Characterization of XPR1/SLC53A1 variants located outside of the SPX RT domain in patients with primary familial brain calcification."; RL Sci. Rep. 9:6776-6776(2019). RN [16] {ECO:0007744|PDB:5IJH} RP X-RAY CRYSTALLOGRAPHY (2.43 ANGSTROMS) OF 1-207, DOMAIN, AND FUNCTION. RX PubMed=27080106; DOI=10.1126/science.aad9858; RA Wild R., Gerasimaite R., Jung J.Y., Truffault V., Pavlovic I., Schmidt A., RA Saiardi A., Jessen H.J., Poirier Y., Hothorn M., Mayer A.; RT "Control of eukaryotic phosphate homeostasis by inositol polyphosphate RT sensor domains."; RL Science 352:986-990(2016). RN [17] {ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F} RP STRUCTURE BY ELECTRON MICROSCOPY (2.84 ANGSTROMS) IN COMPLEXES WITH RP PHOSPHATE AND INOSITOL HEXAKISPHOSPHATE, FUNCTION, TRANSPORTER ACTIVITY, RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, TOPOLOGY, AND RP MUTAGENESIS OF TYR-22; LYS-158; GLY-238; GLY-242; ARG-270; ARG-273; RP PHE-394; ASP-398; ARG-459; ARG-466; SER-497; ASP-533; ARG-570; TRP-573; RP THR-582; ARG-603; ARG-604; ARG-611 AND PHE-623. RX PubMed=39169184; DOI=10.1038/s41586-024-07852-9; RA Yan R., Chen H., Liu C., Zhao J., Wu D., Jiang J., Gong J., Jiang D.; RT "Human XPR1 structures reveal phosphate export mechanism."; RL Nature 633:960-967(2024). RN [18] {ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IWS} RP STRUCTURE BY ELECTRON MICROSCOPY (2.86 ANGSTROMS) OF 1-631 IN COMPLEX WITH RP INOSITOL HEXAKISPHOSPHATE, FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY RP REGULATION, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, TOPOLOGY, AND RP MUTAGENESIS OF ARG-211; ARG-219; LYS-482; ARG-570; TRP-573; ARG-603 AND RP ARG-604. RX PubMed=39325866; DOI=10.1126/science.adp3252; RA Lu Y., Yue C.X., Zhang L., Yao D., Xia Y., Zhang Q., Zhang X., Li S., RA Shen Y., Cao M., Guo C.R., Qin A., Zhao J., Zhou L., Yu Y., Cao Y.; RT "Structural basis for inositol pyrophosphate gating of the phosphate RT channel XPR1."; RL Science 386:eadp3252-eadp3252(2024). RN [19] {ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53} RP STRUCTURE BY ELECTRON MICROSCOPY (2.90 ANGSTROMS) IN COMPLEX WITH RP PHOSPHATE, FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, RP TOPOLOGY, AND MUTAGENESIS OF ARG-270; ASN-401; ARG-448; GLN-452; ARG-459; RP TYR-483; ARG-570; TRP-573; GLN-576; GLU-600 AND ARG-603. RX PubMed=39747008; DOI=10.1038/s41467-024-55471-9; RA Zhang W., Chen Y., Guan Z., Wang Y., Tang M., Du Z., Zhang J., Cheng M., RA Zuo J., Liu Y., Wang Q., Liu Y., Zhang D., Yin P., Ma L., Liu Z.; RT "Structural insights into the mechanism of phosphate recognition and RT transport by XPR1."; RL Nat. Commun. 16:18-18(2025). RN [20] {ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS) IN COMPLEX WITH RP PHOSPHATE, FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, RP DOMAIN, TOPOLOGY, AND MUTAGENESIS OF LYS-158; LYS-161; LYS-165; PHE-235; RP LEU-239; LYS-482; ARG-570; TRP-573; ARG-603 AND ARG-604. RX PubMed=39814721; DOI=10.1038/s41467-025-55995-8; RA He Q., Zhang R., Tury S., Courgnaud V., Liu F., Battini J.L., Li B., RA Chen Q.; RT "Structural basis of phosphate export by human XPR1."; RL Nat. Commun. 16:683-683(2025). CC -!- FUNCTION: Inorganic ion transporter that mediates phosphate ion export CC across the plasma membrane (PubMed:23791524, PubMed:25938945, CC PubMed:27080106, PubMed:31043717, PubMed:39169184, PubMed:39325866, CC PubMed:39747008, PubMed:39814721). Plays a major role in phosphate CC homeostasis, preventing intracellular phosphate accumulation and CC possible calcium phosphate precipitation, ultimately preserving calcium CC signaling (PubMed:27080106). Binds inositol hexakisphosphate (Ins6P) CC and similar inositol polyphosphates, such as 5-diphospho-inositol CC pentakisphosphate (5-InsP7), which are important intracellular CC signaling molecules involved in regulation of phosphate flux CC (PubMed:27080106, PubMed:39169184, PubMed:39325866). CC {ECO:0000269|PubMed:23791524, ECO:0000269|PubMed:25938945, CC ECO:0000269|PubMed:27080106, ECO:0000269|PubMed:31043717, CC ECO:0000269|PubMed:39169184, ECO:0000269|PubMed:39325866, CC ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721}. CC -!- CATALYTIC ACTIVITY: CC Reaction=phosphate(in) = phosphate(out); Xref=Rhea:RHEA:32823, CC ChEBI:CHEBI:43474; Evidence={ECO:0000269|PubMed:23791524, CC ECO:0000269|PubMed:25938945, ECO:0000269|PubMed:31043717, CC ECO:0000269|PubMed:39169184, ECO:0000269|PubMed:39325866, CC ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32824; CC Evidence={ECO:0000305|PubMed:23791524, ECO:0000305|PubMed:25938945, CC ECO:0000305|PubMed:31043717}; CC -!- ACTIVITY REGULATION: Allosterically activated by inositol CC hexakisphosphate (Ins6P). {ECO:0000269|PubMed:39169184, CC ECO:0000269|PubMed:39325866}. CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:39169184, CC ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, CC ECO:0000269|PubMed:39814721}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23791524, CC ECO:0000269|PubMed:31043717}; Multi-pass membrane protein CC {ECO:0000269|PubMed:39169184, ECO:0000269|PubMed:39325866, CC ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9UBH6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UBH6-2; Sequence=VSP_030748; CC -!- TISSUE SPECIFICITY: Widely expressed. Detected in spleen, lymph node, CC thymus, leukocytes, bone marrow, heart, kidney, pancreas and skeletal CC muscle. {ECO:0000269|PubMed:9927670, ECO:0000269|PubMed:9990033}. CC -!- DEVELOPMENTAL STAGE: Expressed in fetal liver. CC {ECO:0000269|PubMed:9927670, ECO:0000269|PubMed:9990033}. CC -!- DOMAIN: The SPX domain plays a role in the regulation of phosphate flux CC (PubMed:39169184, PubMed:39325866, PubMed:39814721). Inositol CC hexakisphosphate (Ins6P) is bound between two SPX domains of the CC homodimer (PubMed:39169184, PubMed:39325866). The SPX domain has high CC affinity for inositol polyphosphates and its affinity for inorganic CC phosphate is two to three orders of magnitude lower (PubMed:27080106). CC {ECO:0000269|PubMed:27080106, ECO:0000269|PubMed:39169184, CC ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39814721}. CC -!- DISEASE: Basal ganglia calcification, idiopathic, 6 (IBGC6) CC [MIM:616413]: A form of basal ganglia calcification, an autosomal CC dominant condition characterized by symmetric calcification in the CC basal ganglia and other brain regions. Affected individuals can either CC be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, CC including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, CC seizures, and chronic headache. Serum levels of calcium, phosphate, CC alkaline phosphatase and parathyroid hormone are normal. The CC neuropathological hallmark of the disease is vascular and pericapillary CC calcification, mainly of calcium phosphate, in the affected brain CC areas. {ECO:0000269|PubMed:25938945, ECO:0000269|PubMed:31043717}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the SYG1 (TC 2.A.94) family. {ECO:0000305}. CC -!- CAUTION: Confers susceptibility to xenotropic murine leukemia CC retrovirus (X-MLV) infection in vitro, but it is unclear whether its CC ability to act as a receptor for xenotropic and polytropic murine CC leukemia retroviruses is relevant in vivo and whether such viruses can CC infect human. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF115389; AAD17211.1; -; mRNA. DR EMBL; AF089744; AAD10196.1; -; mRNA. DR EMBL; AF099082; AAD08928.1; -; mRNA. DR EMBL; AL590085; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL162431; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL358434; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471067; EAW91086.1; -; Genomic_DNA. DR EMBL; BC041142; AAH41142.1; -; mRNA. DR EMBL; AL133058; CAB61383.1; -; mRNA. DR EMBL; AL137583; CAB70825.1; -; mRNA. DR CCDS; CCDS1340.1; -. [Q9UBH6-1] DR CCDS; CCDS44284.1; -. [Q9UBH6-2] DR PIR; T42660; T42660. DR RefSeq; NP_001129141.1; NM_001135669.2. [Q9UBH6-2] DR RefSeq; NP_004727.2; NM_004736.3. [Q9UBH6-1] DR PDB; 5IJH; X-ray; 2.43 A; A/B=1-207. DR PDB; 8TYU; X-ray; 1.40 A; A/B=1-94, A/B=130-207. DR PDB; 8TYV; X-ray; 1.85 A; A/B=1-94, A/B=130-207. DR PDB; 8X5B; EM; 2.84 A; A/F=229-696. DR PDB; 8X5E; EM; 3.61 A; A=229-696. DR PDB; 8X5F; EM; 2.96 A; A/B=1-696. DR PDB; 8YET; EM; 4.16 A; A/B=1-620. DR PDB; 8YEX; EM; 3.68 A; A/B=228-619. DR PDB; 8YF4; EM; 3.41 A; A/B=227-619. DR PDB; 8YFD; EM; 3.57 A; A/B=227-622. DR PDB; 8YFU; EM; 4.59 A; A/B=21-620. DR PDB; 8YFW; EM; 3.65 A; A/B=21-620. DR PDB; 8YFX; EM; 3.56 A; A/B=227-622. DR PDB; 8ZTO; EM; 3.55 A; A/B=1-696. DR PDB; 9DVJ; EM; 2.52 A; A/B=1-696. DR PDB; 9DVK; EM; 3.06 A; A/B=1-696. DR PDB; 9DVL; EM; 2.97 A; A/B=1-696. DR PDB; 9DVM; EM; 2.92 A; A/B=1-696. DR PDB; 9DVN; EM; 2.75 A; A/B=1-696. DR PDB; 9DVO; EM; 3.10 A; A/B=1-696. DR PDB; 9DVP; EM; 2.81 A; A/B=1-696. DR PDB; 9IJY; EM; 2.64 A; A/B=1-696. DR PDB; 9IJZ; EM; 2.91 A; A/B=1-696. DR PDB; 9INE; EM; 3.32 A; A/B=1-696. DR PDB; 9INF; EM; 3.36 A; A/B=1-696. DR PDB; 9INH; EM; 3.68 A; A/D=1-696. DR PDB; 9ITG; EM; 3.03 A; A/B=1-696. DR PDB; 9IUC; EM; 3.80 A; A/B=1-696. DR PDB; 9IWS; EM; 2.86 A; A/B=1-631. DR PDB; 9J4X; EM; 2.90 A; A/B=1-696. DR PDB; 9J51; EM; 3.10 A; A/B=1-696. DR PDB; 9J52; EM; 3.10 A; A/B=1-696. DR PDB; 9J53; EM; 3.30 A; A/B=1-696. DR PDB; 9J97; EM; 3.30 A; A/B=1-696. DR PDB; 9J98; EM; 3.33 A; A/B=1-696. DR PDBsum; 5IJH; -. DR PDBsum; 8TYU; -. DR PDBsum; 8TYV; -. DR PDBsum; 8X5B; -. DR PDBsum; 8X5E; -. DR PDBsum; 8X5F; -. DR PDBsum; 8YET; -. DR PDBsum; 8YEX; -. DR PDBsum; 8YF4; -. DR PDBsum; 8YFD; -. DR PDBsum; 8YFU; -. DR PDBsum; 8YFW; -. DR PDBsum; 8YFX; -. DR PDBsum; 8ZTO; -. DR PDBsum; 9DVJ; -. DR PDBsum; 9DVK; -. DR PDBsum; 9DVL; -. DR PDBsum; 9DVM; -. DR PDBsum; 9DVN; -. DR PDBsum; 9DVO; -. DR PDBsum; 9DVP; -. DR PDBsum; 9IJY; -. DR PDBsum; 9IJZ; -. DR PDBsum; 9INE; -. DR PDBsum; 9INF; -. DR PDBsum; 9INH; -. DR PDBsum; 9ITG; -. DR PDBsum; 9IUC; -. DR PDBsum; 9IWS; -. DR PDBsum; 9J4X; -. DR PDBsum; 9J51; -. DR PDBsum; 9J52; -. DR PDBsum; 9J53; -. DR PDBsum; 9J97; -. DR PDBsum; 9J98; -. DR AlphaFoldDB; Q9UBH6; -. DR EMDB; EMD-38065; -. DR EMDB; EMD-38067; -. DR EMDB; EMD-38068; -. DR EMDB; EMD-39203; -. DR EMDB; EMD-39204; -. DR EMDB; EMD-39210; -. DR EMDB; EMD-39220; -. DR EMDB; EMD-39230; -. DR EMDB; EMD-39231; -. DR EMDB; EMD-39232; -. DR EMDB; EMD-45656; -. DR EMDB; EMD-45657; -. DR EMDB; EMD-47208; -. DR EMDB; EMD-47209; -. DR EMDB; EMD-47210; -. DR EMDB; EMD-47211; -. DR EMDB; EMD-47212; -. DR EMDB; EMD-47213; -. DR EMDB; EMD-47214; -. DR EMDB; EMD-60469; -. DR EMDB; EMD-60645; -. DR EMDB; EMD-60646; -. DR EMDB; EMD-60704; -. DR EMDB; EMD-60705; -. DR EMDB; EMD-60707; -. DR EMDB; EMD-60861; -. DR EMDB; EMD-60897; -. DR EMDB; EMD-60962; -. DR EMDB; EMD-61138; -. DR EMDB; EMD-61139; -. DR EMDB; EMD-61140; -. DR EMDB; EMD-61141; -. DR EMDB; EMD-61859; -. DR EMDB; EMD-61860; -. DR EMDB; EMD-61861; -. DR EMDB; EMD-61862; -. DR EMDB; EMD-61863; -. DR EMDB; EMD-61864; -. DR EMDB; EMD-61865; -. DR EMDB; EMD-61866; -. DR EMDB; EMD-61867; -. DR EMDB; EMD-61868; -. DR EMDB; EMD-61869; -. DR EMDB; EMD-61870; -. DR EMDB; EMD-61871; -. DR EMDB; EMD-61875; -. DR SMR; Q9UBH6; -. DR BioGRID; 114647; 230. DR FunCoup; Q9UBH6; 2397. DR IntAct; Q9UBH6; 181. DR MINT; Q9UBH6; -. DR STRING; 9606.ENSP00000356562; -. DR TCDB; 2.A.94.1.6; the phosphate permease (pho1) family. DR iPTMnet; Q9UBH6; -. DR PhosphoSitePlus; Q9UBH6; -. DR SwissPalm; Q9UBH6; -. DR BioMuta; XPR1; -. DR DMDM; 74753221; -. DR jPOST; Q9UBH6; -. DR MassIVE; Q9UBH6; -. DR PaxDb; 9606-ENSP00000356562; -. DR PeptideAtlas; Q9UBH6; -. DR ProteomicsDB; 83970; -. [Q9UBH6-1] DR ProteomicsDB; 83971; -. [Q9UBH6-2] DR Pumba; Q9UBH6; -. DR Antibodypedia; 20589; 190 antibodies from 29 providers. DR DNASU; 9213; -. DR Ensembl; ENST00000367589.3; ENSP00000356561.3; ENSG00000143324.15. [Q9UBH6-2] DR Ensembl; ENST00000367590.9; ENSP00000356562.4; ENSG00000143324.15. [Q9UBH6-1] DR GeneID; 9213; -. DR KEGG; hsa:9213; -. DR MANE-Select; ENST00000367590.9; ENSP00000356562.4; NM_004736.4; NP_004727.2. DR UCSC; uc001goi.4; human. [Q9UBH6-1] DR AGR; HGNC:12827; -. DR ClinPGx; PA37420; -. DR CTD; 9213; -. DR DisGeNET; 9213; -. DR GeneCards; XPR1; -. DR GeneReviews; XPR1; -. DR HGNC; HGNC:12827; XPR1. DR HPA; ENSG00000143324; Low tissue specificity. DR MalaCards; XPR1; -. DR MIM; 605237; gene. DR MIM; 616413; phenotype. DR OpenTargets; ENSG00000143324; -. DR Orphanet; 1980; Bilateral striopallidodentate calcinosis. DR VEuPathDB; HostDB:ENSG00000143324; -. DR eggNOG; KOG1162; Eukaryota. DR GeneTree; ENSGT00500000044895; -. DR HOGENOM; CLU_006116_3_0_1; -. DR InParanoid; Q9UBH6; -. DR OMA; ETSHFYT; -. DR OrthoDB; 9970435at2759; -. DR PAN-GO; Q9UBH6; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q9UBH6; -. DR PathwayCommons; Q9UBH6; -. DR SignaLink; Q9UBH6; -. DR Agora; ENSG00000143324; -. DR BioGRID-ORCS; 9213; 63 hits in 1164 CRISPR screens. DR ChiTaRS; XPR1; human. DR GenomeRNAi; 9213; -. DR Pharos; Q9UBH6; Tbio. DR PRO; PR:Q9UBH6; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9UBH6; protein. DR Bgee; ENSG00000143324; Expressed in cortical plate and 192 other cell types or tissues. DR ExpressionAtlas; Q9UBH6; baseline and differential. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0015562; F:efflux transmembrane transporter activity; IMP:UniProtKB. DR GO; GO:0000822; F:inositol hexakisphosphate binding; IDA:UniProtKB. DR GO; GO:0005315; F:phosphate transmembrane transporter activity; IMP:UniProtKB. DR GO; GO:0001618; F:virus receptor activity; IEA:Ensembl. DR GO; GO:0016036; P:cellular response to phosphate starvation; IBA:GO_Central. DR GO; GO:0030643; P:intracellular phosphate ion homeostasis; IMP:UniProtKB. DR GO; GO:0035435; P:phosphate ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0006817; P:phosphate ion transport; IBA:GO_Central. DR GO; GO:0009615; P:response to virus; IEA:Ensembl. DR CDD; cd14477; SPX_XPR1_like; 1. DR InterPro; IPR004342; EXS_C. DR InterPro; IPR004331; SPX_dom. DR PANTHER; PTHR10783:SF103; SOLUTE CARRIER FAMILY 53 MEMBER 1; 1. DR PANTHER; PTHR10783; XENOTROPIC AND POLYTROPIC RETROVIRUS RECEPTOR 1-RELATED; 1. DR Pfam; PF03124; EXS; 1. DR Pfam; PF03105; SPX; 3. DR PROSITE; PS51380; EXS; 1. DR PROSITE; PS51382; SPX; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Disease variant; KW Membrane; Phosphate transport; Phosphoprotein; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..696 FT /note="Solute carrier family 53 member 1" FT /id="PRO_0000315853" FT TOPO_DOM 1..228 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 229..259 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 260..264 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 265..296 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 297..309 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 310..337 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 338..343 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 344..365 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT INTRAMEM 366..383 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 384..388 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 389..422 FT /note="Discontinuously helical; Name=5" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 423..429 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 430..471 FT /note="Discontinuously helical; Name=6" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 472 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 473..503 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 504..506 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 507..534 FT /note="Helical; Name=8" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 535..553 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 554..585 FT /note="Discontinuously helical; Name=9" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 586..587 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TRANSMEM 588..626 FT /note="Helical; Name=10" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT TOPO_DOM 627..696 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5E, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:8YET, ECO:0007744|PDB:8YEX, FT ECO:0007744|PDB:8YF4, ECO:0007744|PDB:8YFD, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:8YFX, ECO:0007744|PDB:9IJY, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9IWS, FT ECO:0007744|PDB:9J4X, ECO:0007744|PDB:9J51, FT ECO:0007744|PDB:9J52, ECO:0007744|PDB:9J53" FT DOMAIN 2..224 FT /note="SPX" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0007744|PDB:8X5B, FT ECO:0007744|PDB:8X5F, ECO:0007744|PDB:8YET, FT ECO:0007744|PDB:8YFU, ECO:0007744|PDB:8YFW, FT ECO:0007744|PDB:9IWS" FT DOMAIN 439..643 FT /note="EXS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00712" FT REGION 158..165 FT /note="Important for inositol polyphosphate binding" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866" FT REGION 673..696 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 398 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT BINDING 401 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT BINDING 482 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT BINDING 483 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT BINDING 570 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT BINDING 603 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJZ, ECO:0007744|PDB:9J52" FT BINDING 604 FT /ligand="phosphate" FT /ligand_id="ChEBI:CHEBI:43474" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008, ECO:0000269|PubMed:39814721, FT ECO:0007744|PDB:8X5B, ECO:0007744|PDB:8X5F, FT ECO:0007744|PDB:9IJY, ECO:0007744|PDB:9IJZ, FT ECO:0007744|PDB:9J52" FT SITE 573 FT /note="Gating residue for phosphate transport" FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721" FT MOD_RES 668 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 690 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231" FT VAR_SEQ 437..501 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_030748" FT VARIANT 136 FT /note="S -> N (in IBGC6; phosphate efflux is impaired; FT present at the plasma membrane; dbSNP:rs786205902)" FT /evidence="ECO:0000269|PubMed:25938945" FT /id="VAR_073840" FT VARIANT 140 FT /note="L -> P (in IBGC6; phosphate efflux is impaired; FT present at the plasma membrane; dbSNP:rs786205903)" FT /evidence="ECO:0000269|PubMed:25938945" FT /id="VAR_073841" FT VARIANT 145 FT /note="L -> P (in IBGC6; dominant negative; phosphate FT efflux is impaired; loss of localization to the plasma FT membrane; dbSNP:rs786205901)" FT /evidence="ECO:0000269|PubMed:25938945" FT /id="VAR_073842" FT VARIANT 218 FT /note="L -> S (in IBGC6; phosphate efflux is impaired; FT present at the plasma membrane; dbSNP:rs786205904)" FT /evidence="ECO:0000269|PubMed:25938945" FT /id="VAR_073843" FT VARIANT 459 FT /note="R -> C (in IBGC6; phosphate efflux is decreased; FT present at the plasma membrane)" FT /evidence="ECO:0000269|PubMed:31043717" FT /id="VAR_087987" FT VARIANT 491 FT /note="T -> A (in dbSNP:rs1061012)" FT /evidence="ECO:0000269|PubMed:9990033" FT /id="VAR_038350" FT VARIANT 619 FT /note="N -> D (in IBGC6; phosphate efflux is impaired; FT present at the plasma membrane)" FT /evidence="ECO:0000269|PubMed:31043717" FT /id="VAR_087988" FT VARIANT 629 FT /note="I -> S (in IBGC6; phosphate efflux is decreased; FT present at the plasma membrane)" FT /evidence="ECO:0000269|PubMed:31043717" FT /id="VAR_087989" FT MUTAGEN 22 FT /note="Y->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 158 FT /note="K->A: Decreases phosphate efflux. Decreases FT phosphate efflux; when associated with A-161 and A-165." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39814721" FT MUTAGEN 161 FT /note="K->A: Decreases phosphate efflux; when associated FT with A-158 and A-165." FT /evidence="ECO:0000269|PubMed:39814721" FT MUTAGEN 165 FT /note="K->A: Decreases phosphate efflux; when associated FT with A-158 and A-161." FT /evidence="ECO:0000269|PubMed:39814721" FT MUTAGEN 211 FT /note="R->E: Increases phosphate efflux; when associated FT with E-219." FT /evidence="ECO:0000269|PubMed:39325866" FT MUTAGEN 219 FT /note="R->E: Increases phosphate efflux; when associated FT with E-211." FT /evidence="ECO:0000269|PubMed:39325866" FT MUTAGEN 235 FT /note="F->G: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39814721" FT MUTAGEN 238 FT /note="G->F: Monomeric; decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 239 FT /note="L->G: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39814721" FT MUTAGEN 242 FT /note="G->F: Monomeric; decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 270 FT /note="R->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008" FT MUTAGEN 273 FT /note="R->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 394 FT /note="F->A: Increases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 398 FT /note="D->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 401 FT /note="N->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 448 FT /note="R->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 452 FT /note="Q->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 459 FT /note="R->A,C: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39747008" FT MUTAGEN 466 FT /note="R->A: Increases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 482 FT /note="K->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39325866, FT ECO:0000269|PubMed:39814721" FT MUTAGEN 483 FT /note="Y->F: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 497 FT /note="S->C: Decreases phosphate efflux. Decreases FT phosphate efflux; when associated with C-582." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 533 FT /note="D->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 570 FT /note="R->A,C,L: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721" FT MUTAGEN 573 FT /note="W->A,F,G,L,N,Y: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721" FT MUTAGEN 576 FT /note="Q->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 582 FT /note="T->C: Decreases phosphate efflux. Decreases FT phosphate efflux; when associated with C-497." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 600 FT /note="E->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39747008" FT MUTAGEN 603 FT /note="R->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39747008, FT ECO:0000269|PubMed:39814721" FT MUTAGEN 604 FT /note="R->A: Decreases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184, FT ECO:0000269|PubMed:39325866, ECO:0000269|PubMed:39814721" FT MUTAGEN 611 FT /note="R->A: Increases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT MUTAGEN 612..696 FT /note="Missing: Loss of localization to the plasma FT membrane." FT /evidence="ECO:0000269|PubMed:31043717" FT MUTAGEN 623 FT /note="F->A: Increases phosphate efflux." FT /evidence="ECO:0000269|PubMed:39169184" FT HELIX 4..10 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 13..18 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 22..34 FT /evidence="ECO:0007829|PDB:8TYU" FT TURN 39..41 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 44..94 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 119..122 FT /evidence="ECO:0007829|PDB:5IJH" FT HELIX 130..167 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 171..178 FT /evidence="ECO:0007829|PDB:8TYU" FT TURN 179..182 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 184..187 FT /evidence="ECO:0007829|PDB:8TYU" FT HELIX 190..199 FT /evidence="ECO:0007829|PDB:8TYU" FT TURN 206..209 FT /evidence="ECO:0007829|PDB:8X5F" FT HELIX 211..218 FT /evidence="ECO:0007829|PDB:9IWS" FT HELIX 231..256 FT /evidence="ECO:0007829|PDB:9IJY" FT STRAND 261..263 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 266..293 FT /evidence="ECO:0007829|PDB:9IJY" FT TURN 294..296 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 299..302 FT /evidence="ECO:0007829|PDB:9IJY" FT STRAND 307..309 FT /evidence="ECO:0007829|PDB:8X5B" FT HELIX 313..335 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 337..339 FT /evidence="ECO:0007829|PDB:9J4X" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 346..360 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 368..382 FT /evidence="ECO:0007829|PDB:9IJY" FT TURN 383..386 FT /evidence="ECO:0007829|PDB:9IWS" FT HELIX 391..402 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 404..418 FT /evidence="ECO:0007829|PDB:9IJY" FT STRAND 423..425 FT /evidence="ECO:0007829|PDB:8X5B" FT TURN 426..429 FT /evidence="ECO:0007829|PDB:9J98" FT HELIX 439..441 FT /evidence="ECO:0007829|PDB:9IJY" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:8X5F" FT HELIX 447..469 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 476..502 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 506..531 FT /evidence="ECO:0007829|PDB:9IJY" FT TURN 532..534 FT /evidence="ECO:0007829|PDB:9J97" FT STRAND 544..547 FT /evidence="ECO:0007829|PDB:9J4X" FT STRAND 552..554 FT /evidence="ECO:0007829|PDB:9IWS" FT HELIX 556..581 FT /evidence="ECO:0007829|PDB:9IJY" FT TURN 586..588 FT /evidence="ECO:0007829|PDB:9IJY" FT HELIX 589..617 FT /evidence="ECO:0007829|PDB:9IJY" FT TURN 620..623 FT /evidence="ECO:0007829|PDB:9IWS" SQ SEQUENCE 696 AA; 81535 MW; B5B4BABF5CA2503A CRC64; MKFAEHLSAH ITPEWRKQYI QYEAFKDMLY SAQDQAPSVE VTDEDTVKRY FAKFEEKFFQ TCEKELAKIN TFYSEKLAEA QRRFATLQNE LQSSLDAQKE STGVTTLRQR RKPVFHLSHE ERVQHRNIKD LKLAFSEFYL SLILLQNYQN LNFTGFRKIL KKHDKILETS RGADWRVAHV EVAPFYTCKK INQLISETEA VVTNELEDGD RQKAMKRLRV PPLGAAQPAP AWTTFRVGLF CGIFIVLNIT LVLAAVFKLE TDRSIWPLIR IYRGGFLLIE FLFLLGINTY GWRQAGVNHV LIFELNPRSN LSHQHLFEIA GFLGILWCLS LLACFFAPIS VIPTYVYPLA LYGFMVFFLI NPTKTFYYKS RFWLLKLLFR VFTAPFHKVG FADFWLADQL NSLSVILMDL EYMICFYSLE LKWDESKGLL PNNSEESGIC HKYTYGVRAI VQCIPAWLRF IQCLRRYRDT KRAFPHLVNA GKYSTTFFMV TFAALYSTHK ERGHSDTMVF FYLWIVFYII SSCYTLIWDL KMDWGLFDKN AGENTFLREE IVYPQKAYYY CAIIEDVILR FAWTIQISIT STTLLPHSGD IIATVFAPLE VFRRFVWNFF RLENEHLNNC GEFRAVRDIS VAPLNADDQT LLEQMMDQDD GVRNRQKNRS WKYNQSISLR RPRLASQSKA RDTKVLIEDT DDEANT // ID SNCAP_HUMAN Reviewed; 919 AA. AC Q9Y6H5; D3DSZ1; Q05BS1; Q1PSC2; Q49AC6; Q504U9; Q6L984; Q6L985; Q6L986; AC Q9HC59; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 22-JUL-2008, sequence version 2. DT 28-JAN-2026, entry version 201. DE RecName: Full=Synphilin-1; DE Short=Sph1; DE AltName: Full=Alpha-synuclein-interacting protein; GN Name=SNCAIP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH SNCA, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND VARIANT ALA-44. RC TISSUE=Brain; RX PubMed=10319874; DOI=10.1038/8820; RA Engelender S., Kaminsky Z., Guo X., Sharp A.H., Amaravi R.K., RA Kleiderlein J.J., Margolis R.L., Troncoso J.C., Lanahan A., Worley P.F., RA Dawson V.L., Dawson T.M., Ross C.A.; RT "Synphilin-1 associates with alpha-synuclein and promotes the formation of RT cytosolic inclusions."; RL Nat. Genet. 22:110-114(1999). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=10967135; DOI=10.1007/s003350010123; RA Engelender S., Wanner T., Kleiderlein J.J., Wakabayashi K., Tsuji S., RA Takahashi H., Ashworth R., Margolis R.L., Ross C.A.; RT "Organization of the human synphilin-1 gene, a candidate for Parkinson's RT disease."; RL Mamm. Genome 11:763-766(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH SNCA, RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=16595633; DOI=10.1073/pnas.0509707103; RA Eyal A., Szargel R., Avraham E., Liani E., Haskin J., Rott R., RA Engelender S.; RT "Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes RT neuronal death and is present in aggregates from alpha-synucleinopathy RT patients."; RL Proc. Natl. Acad. Sci. U.S.A. 103:5917-5922(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 4 AND 6), AND VARIANT ALA-44. RC TISSUE=Cerebellum, and Testis; RA Lim M.K., Ohsawa Y., Kawamura T., Asakawa S., Takayanagi A., Minoshima S., RA Shimizu N.; RT "Identification and characterization of alternatively spliced form of human RT synphilin-1."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 5). RC TISSUE=Brain, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH PRKN, AND UBIQUITINATION. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [8] RP INTERACTION WITH RNF19A, AND UBIQUITINATION. RX PubMed=12750386; DOI=10.1074/jbc.m302763200; RA Ito T., Niwa J., Hishikawa N., Ishigaki S., Doyu M., Sobue G.; RT "Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1."; RL J. Biol. Chem. 278:29106-29114(2003). RN [9] RP INTERACTION WITH SIAH1, AND DEGRADATION. RX PubMed=14506261; DOI=10.1074/jbc.m306347200; RA Nagano Y., Yamashita H., Takahashi T., Kishida S., Nakamura T., Iseki E., RA Hattori N., Mizuno Y., Kikuchi A., Matsumoto M.; RT "Siah-1 facilitates ubiquitination and degradation of synphilin-1."; RL J. Biol. Chem. 278:51504-51514(2003). RN [10] RP SUBCELLULAR LOCATION, UBIQUITINATION, PROTEASOMAL DEGRADATION, INTERACTION RP WITH SIAH1 AND SIAH2, AND MUTAGENESIS OF VAL-79 AND PRO-81. RX PubMed=15064394; DOI=10.1073/pnas.0401081101; RA Liani E., Eyal A., Avraham E., Shemer R., Szargel R., Berg D., RA Bornemann A., Riess O., Ross C.A., Rott R., Engelender S.; RT "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence RT in cellular inclusions and Lewy bodies imply a role in Parkinson's RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 101:5500-5505(2004). RN [11] RP FUNCTION, AND INTERACTION WITH SIAH1. RX PubMed=19224863; DOI=10.1074/jbc.m805990200; RA Szargel R., Rott R., Eyal A., Haskin J., Shani V., Balan L., Wolosker H., RA Engelender S.; RT "Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates RT alpha-synuclein monoubiquitylation and inclusion formation."; RL J. Biol. Chem. 284:11706-11716(2009). RN [12] RP STRUCTURE BY NMR OF 512-557, INTERACTION WITH SNCA, PROMOTION OF INCLUSION RP BODY FORMATION, AND SUBCELLULAR LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [13] RP VARIANT CYS-621, CHARACTERIZATION OF VARIANT CYS-621, AND POSSIBLE RP INVOLVEMENT IN SUSCEPTIBILITY TO PARKINSON DISEASE. RX PubMed=12761037; DOI=10.1093/hmg/ddg134; RA Marx F.P., Holzmann C., Strauss K.M., Li L., Eberhardt O., Gerhardt E., RA Cookson M.R., Hernandez D., Farrer M.J., Kachergus J., Engelender S., RA Ross C.A., Berger K., Schols L., Schulz J.B., Riess O., Kruger R.; RT "Identification and functional characterization of a novel R621C mutation RT in the synphilin-1 gene in Parkinson's disease."; RL Hum. Mol. Genet. 12:1223-1231(2003). RN [14] RP VARIANTS ALA-44; CYS-621 AND GLN-706, AND LACK OF ASSOCIATION WITH RP PARKINSON DISEASE. RX PubMed=18366718; DOI=10.1186/1471-2350-9-19; RA Myhre R., Klungland H., Farrer M.J., Aasly J.O.; RT "Genetic association study of synphilin-1 in idiopathic Parkinson's RT disease."; RL BMC Med. Genet. 9:19-19(2008). CC -!- FUNCTION: Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and CC inhibits proteasomal degradation of target proteins. Isoform 2 inhibits CC autoubiquitination and proteasomal degradation of SIAH1, and thereby CC increases cellular levels of SIAH. Isoform 2 modulates SNCA CC monoubiquitination by SIAH1. {ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19224863}. CC -!- SUBUNIT: Homodimer (Probable). Heterodimer of isoform 1 and isoform 2 CC (Probable). Interacts with SIAH1, SIAH2, SNCA, RNF19A and PRKN. Isoform CC 2 has a strong tendency to form aggregates and can sequester isoform 1. CC {ECO:0000269|PubMed:10319874, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12750386, ECO:0000269|PubMed:14506261, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:19762560, ECO:0000305}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10319874, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19762560}. Note=Detected in cytoplasmic inclusion CC bodies, together with SNCA. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=1a; CC IsoId=Q9Y6H5-1; Sequence=Displayed; CC Name=2; Synonyms=Synphilin-1A; CC IsoId=Q9Y6H5-2; Sequence=VSP_038839, VSP_038842, VSP_038845; CC Name=3; CC IsoId=Q9Y6H5-3; Sequence=VSP_038840, VSP_038845; CC Name=4; Synonyms=1b; CC IsoId=Q9Y6H5-4; Sequence=VSP_038841; CC Name=5; CC IsoId=Q9Y6H5-5; Sequence=VSP_038839, VSP_038842; CC Name=6; Synonyms=1c; CC IsoId=Q9Y6H5-6; Sequence=VSP_038840, VSP_038843, VSP_038844; CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level). Widely CC expressed, with highest levels in brain, heart and placenta. CC {ECO:0000269|PubMed:10319874, ECO:0000269|PubMed:16595633}. CC -!- PTM: Ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A and leading to CC its subsequent proteasomal degradation. In the absence of proteasomal CC degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion CC bodies. Isoform 2 is subject to limited ubiquitination that does not CC lead to proteasomal degradation. {ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12750386, ECO:0000269|PubMed:15064394}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12761037}. Note=Disease CC susceptibility may be associated with variants affecting the gene CC represented in this entry. CC -!- MISCELLANEOUS: Constructs encoding portions of SNCA and SNCAIP co- CC transfected in mammalian cells promote cytosolic inclusions resembling CC the Lewy bodies of Parkinson disease. Coexpression of SNCA, SNCAIP, and CC PRKN result in the formation of Lewy body-like. ubiquitin-positive CC cytosolic inclusions. SNCAIP isoform 2 is particularly aggregation- CC prone. Familial mutations in PRKN disrupt the ubiquitination of SNCAIP CC and the formation of the ubiquitin-positive inclusions. These results CC provide a molecular basis for the ubiquitination of Lewy body- CC associated proteins and link PRKN and SNCA in a common pathogenic CC mechanism through their interaction with SNCAIP. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF076929; AAD30362.1; -; mRNA. DR EMBL; AF167306; AAG17478.1; -; Genomic_DNA. DR EMBL; AF167301; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167302; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167303; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167304; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167305; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; DQ227317; ABB51162.1; -; mRNA. DR EMBL; CH471086; EAW48889.1; -; Genomic_DNA. DR EMBL; AB110788; BAD19017.1; -; mRNA. DR EMBL; AB110789; BAD19018.1; -; mRNA. DR EMBL; AB110790; BAD19019.1; -; mRNA. DR EMBL; CH471086; EAW48890.1; -; Genomic_DNA. DR EMBL; BC033743; AAH33743.1; -; mRNA. DR EMBL; BC040552; AAH40552.1; -; mRNA. DR EMBL; BC094759; AAH94759.1; -; mRNA. DR CCDS; CCDS4131.1; -. [Q9Y6H5-1] DR CCDS; CCDS78054.1; -. [Q9Y6H5-3] DR RefSeq; NP_001229864.1; NM_001242935.3. [Q9Y6H5-2] DR RefSeq; NP_001295029.1; NM_001308100.2. [Q9Y6H5-3] DR RefSeq; NP_001295034.1; NM_001308105.1. [Q9Y6H5-4] DR RefSeq; NP_001295035.1; NM_001308106.1. DR RefSeq; NP_001295036.1; NM_001308107.2. [Q9Y6H5-5] DR RefSeq; NP_001295037.1; NM_001308108.1. DR RefSeq; NP_001295038.1; NM_001308109.1. DR RefSeq; NP_005451.2; NM_005460.4. [Q9Y6H5-1] DR RefSeq; XP_011542039.1; XM_011543737.3. [Q9Y6H5-3] DR RefSeq; XP_011542040.1; XM_011543738.3. [Q9Y6H5-3] DR RefSeq; XP_011542041.1; XM_011543739.2. [Q9Y6H5-3] DR RefSeq; XP_011542043.1; XM_011543741.3. [Q9Y6H5-3] DR RefSeq; XP_011542045.1; XM_011543743.3. [Q9Y6H5-3] DR RefSeq; XP_016865571.1; XM_017010082.2. [Q9Y6H5-1] DR RefSeq; XP_024302035.1; XM_024446267.2. [Q9Y6H5-1] DR RefSeq; XP_024302036.1; XM_024446268.2. [Q9Y6H5-1] DR RefSeq; XP_047273867.1; XM_047417911.1. [Q9Y6H5-3] DR RefSeq; XP_047273879.1; XM_047417923.1. [Q9Y6H5-1] DR RefSeq; XP_047273880.1; XM_047417924.1. [Q9Y6H5-1] DR RefSeq; XP_047273881.1; XM_047417925.1. [Q9Y6H5-1] DR RefSeq; XP_047273882.1; XM_047417926.1. [Q9Y6H5-1] DR RefSeq; XP_047273883.1; XM_047417927.1. [Q9Y6H5-1] DR RefSeq; XP_047273885.1; XM_047417929.1. [Q9Y6H5-6] DR RefSeq; XP_054209830.1; XM_054353855.1. [Q9Y6H5-3] DR RefSeq; XP_054209831.1; XM_054353856.1. [Q9Y6H5-3] DR RefSeq; XP_054209832.1; XM_054353857.1. [Q9Y6H5-3] DR RefSeq; XP_054209833.1; XM_054353858.1. [Q9Y6H5-3] DR RefSeq; XP_054209834.1; XM_054353859.1. [Q9Y6H5-3] DR RefSeq; XP_054209852.1; XM_054353877.1. [Q9Y6H5-1] DR RefSeq; XP_054209853.1; XM_054353878.1. [Q9Y6H5-1] DR RefSeq; XP_054209854.1; XM_054353879.1. [Q9Y6H5-1] DR RefSeq; XP_054209855.1; XM_054353880.1. [Q9Y6H5-1] DR RefSeq; XP_054209856.1; XM_054353881.1. [Q9Y6H5-1] DR RefSeq; XP_054209857.1; XM_054353882.1. [Q9Y6H5-1] DR RefSeq; XP_054209858.1; XM_054353883.1. [Q9Y6H5-1] DR RefSeq; XP_054209859.1; XM_054353884.1. [Q9Y6H5-1] DR RefSeq; XP_054209864.1; XM_054353889.1. [Q9Y6H5-6] DR PDB; 2KES; NMR; -; A=512-557. DR PDBsum; 2KES; -. DR AlphaFoldDB; Q9Y6H5; -. DR BMRB; Q9Y6H5; -. DR SMR; Q9Y6H5; -. DR BioGRID; 114986; 39. DR CORUM; Q9Y6H5; -. DR DIP; DIP-61155N; -. DR FunCoup; Q9Y6H5; 232. DR MINT; Q9Y6H5; -. DR STRING; 9606.ENSP00000261367; -. DR ChEMBL; CHEMBL1926494; -. DR GlyGen; Q9Y6H5; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9Y6H5; -. DR PhosphoSitePlus; Q9Y6H5; -. DR BioMuta; SNCAIP; -. DR DMDM; 205831000; -. DR jPOST; Q9Y6H5; -. DR MassIVE; Q9Y6H5; -. DR PaxDb; 9606-ENSP00000261368; -. DR PeptideAtlas; Q9Y6H5; -. DR ProteomicsDB; 86680; -. [Q9Y6H5-1] DR ProteomicsDB; 86681; -. [Q9Y6H5-2] DR ProteomicsDB; 86682; -. [Q9Y6H5-3] DR ProteomicsDB; 86683; -. [Q9Y6H5-4] DR ProteomicsDB; 86684; -. [Q9Y6H5-5] DR ProteomicsDB; 86685; -. [Q9Y6H5-6] DR Antibodypedia; 1015; 225 antibodies from 33 providers. DR DNASU; 9627; -. DR Ensembl; ENST00000261367.11; ENSP00000261367.7; ENSG00000064692.21. [Q9Y6H5-3] DR Ensembl; ENST00000261368.13; ENSP00000261368.8; ENSG00000064692.21. [Q9Y6H5-1] DR Ensembl; ENST00000395469.6; ENSP00000378852.2; ENSG00000064692.21. [Q9Y6H5-6] DR GeneID; 9627; -. DR KEGG; hsa:9627; -. DR MANE-Select; ENST00000261368.13; ENSP00000261368.8; NM_005460.4; NP_005451.2. DR UCSC; uc003ksw.2; human. [Q9Y6H5-1] DR AGR; HGNC:11139; -. DR CIViC; 9627; 1 evidence item across 1 molecular profile. DR ClinPGx; PA35987; -. DR CTD; 9627; -. DR DisGeNET; 9627; -. DR GeneCards; SNCAIP; -. DR HGNC; HGNC:11139; SNCAIP. DR HPA; ENSG00000064692; Tissue enhanced (cervix, endometrium, ovary). DR MalaCards; SNCAIP; -. DR MIM; 168600; phenotype. DR MIM; 603779; gene. DR OpenTargets; ENSG00000064692; -. DR VEuPathDB; HostDB:ENSG00000064692; -. DR eggNOG; KOG0504; Eukaryota. DR GeneTree; ENSGT00390000001485; -. DR HOGENOM; CLU_012404_0_0_1; -. DR InParanoid; Q9Y6H5; -. DR OMA; SQTQYCV; -. DR OrthoDB; 10057496at2759; -. DR PAN-GO; Q9Y6H5; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q9Y6H5; -. DR PathwayCommons; Q9Y6H5; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; Q9Y6H5; -. DR SIGNOR; Q9Y6H5; -. DR Agora; ENSG00000064692; -. DR BioGRID-ORCS; 9627; 11 hits in 1148 CRISPR screens. DR ChiTaRS; SNCAIP; human. DR EvolutionaryTrace; Q9Y6H5; -. DR GeneWiki; SNCAIP; -. DR GenomeRNAi; 9627; -. DR Pharos; Q9Y6H5; Tbio. DR PRO; PR:Q9Y6H5; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q9Y6H5; protein. DR Bgee; ENSG00000064692; Expressed in ventricular zone and 174 other cell types or tissues. DR ExpressionAtlas; Q9Y6H5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:HPA. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043025; C:neuronal cell body; NAS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; NAS:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; TAS:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0008219; P:cell death; IDA:CACAO. DR GO; GO:0042417; P:dopamine metabolic process; IDA:MGI. DR GO; GO:0090083; P:regulation of inclusion body assembly; IDA:BHF-UCL. DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IDA:MGI. DR FunFam; 1.25.40.20:FF:000112; synphilin-1 isoform X1; 1. DR Gene3D; 6.10.250.750; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR040133; SNCAIP. DR InterPro; IPR032027; SNCAIP_SNCA-bd. DR PANTHER; PTHR22882; SYNPHILIN-1; 1. DR PANTHER; PTHR22882:SF3; SYNPHILIN-1; 1. DR Pfam; PF12796; Ank_2; 2. DR Pfam; PF16700; SNCAIP_SNCA_bd; 1. DR SMART; SM00248; ANK; 4. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ANK repeat; Coiled coil; Cytoplasm; KW Neurodegeneration; Parkinson disease; Parkinsonism; KW Proteomics identification; Reference proteome; Repeat; Ubl conjugation. FT CHAIN 1..919 FT /note="Synphilin-1" FT /id="PRO_0000067068" FT REPEAT 349..380 FT /note="ANK 1" FT REPEAT 384..413 FT /note="ANK 2" FT REPEAT 419..448 FT /note="ANK 3" FT REPEAT 456..485 FT /note="ANK 4" FT REPEAT 603..632 FT /note="ANK 5" FT REPEAT 699..729 FT /note="ANK 6" FT REGION 80..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 108..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 287..313 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 549..615 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 666..713 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 728..919 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 515..552 FT /evidence="ECO:0000255" FT COMPBIAS 299..308 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 555..571 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 667..685 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 686..700 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 774..785 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 833..842 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 844..854 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 874..886 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..366 FT /note="Missing (in isoform 2 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038839" FT VAR_SEQ 19 FT /note="S -> SDNRSQGNRLQKLGLEDTDREDAMGFGSHRAKLTVVAALGACHCPEN FT E (in isoform 3 and isoform 6)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4" FT /id="VSP_038840" FT VAR_SEQ 335..394 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038841" FT VAR_SEQ 367..394 FT /note="QHLTSLMGEDCLNERNTEKLTPAGLAIK -> MTYLIQSHHSRRSQNCAEDV FT IRKTKTDQ (in isoform 2 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038842" FT VAR_SEQ 476..541 FT /note="LVEYGANVTMQNHAGEKPSQSAERQGHTLCSRYLVVVETCMSLASQVVKLTK FT QLKEQTVERVTLQN -> RLKIQGTWNGSETCLFTHHFSSYPPISSGLQCQGQEGVLFI FT PDQVGAATNKQVLFQNQLPETKSSY (in isoform 6)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038843" FT VAR_SEQ 542..919 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038844" FT VAR_SEQ 919 FT /note="A -> EMYSSCINLSSNMLIEEHLCNDTRHNDINRKMKKSYSIKHIAEPESK FT ELFL (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038845" FT VARIANT 44 FT /note="V -> A (in dbSNP:rs56285021)" FT /evidence="ECO:0000269|PubMed:10319874, FT ECO:0000269|PubMed:18366718, ECO:0000269|Ref.4" FT /id="VAR_065358" FT VARIANT 235 FT /note="E -> G (in dbSNP:rs6867105)" FT /id="VAR_048312" FT VARIANT 621 FT /note="R -> C (found in patients with symptoms of Parkinson FT disease; uncertain significance; reduced number of FT cytoplasmic inclusions in cells expressing C-621 compared FT with cells expressing wild-type (wt) protein when subjected FT to proteasomal inhibition; C-621 transfected cells are more FT susceptible to staurosporine-induced cell death than cells FT expressing wt protein; dbSNP:rs28937592)" FT /evidence="ECO:0000269|PubMed:12761037, FT ECO:0000269|PubMed:18366718" FT /id="VAR_025667" FT VARIANT 706 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:18366718" FT /id="VAR_065359" FT MUTAGEN 79 FT /note="V->N: Decreases interaction with SIAH1 and formation FT of cytoplasmic inclusion bodies; when associated with N- FT 81." FT /evidence="ECO:0000269|PubMed:15064394" FT MUTAGEN 81 FT /note="P->N: Decreases interaction with SIAH1 and formation FT of cytoplasmic inclusion bodies; when associated with N- FT 79." FT /evidence="ECO:0000269|PubMed:15064394" FT CONFLICT 188 FT /note="S -> F (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 614 FT /note="E -> G (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 696 FT /note="A -> G (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 712 FT /note="D -> G (in Ref. 6; AAH94759)" FT /evidence="ECO:0000305" FT CONFLICT 801 FT /note="S -> P (in Ref. 6; AAH33743)" FT /evidence="ECO:0000305" FT CONFLICT 919 FT /note="A -> E (in Ref. 6; AAH94759)" FT /evidence="ECO:0000305" FT HELIX 512..554 FT /evidence="ECO:0007829|PDB:2KES" SQ SEQUENCE 919 AA; 100409 MW; 55C5316F250D0480 CRC64; MEAPEYLDLD EIDFSDDISY SVTSLKTIPE LCRRCDTQNE DRSVSSSSWN CGISTLITNT QKPTGIADVY SKFRPVKRVS PLKHQPETLE NNESDDQKNQ KVVEYQKGGE SDLGPQPQEL GPGDGVGGPP GKSSEPSTSL GELEHYDLDM DEILDVPYIK SSQQLASFTK VTSEKRILGL CTTINGLSGK ACSTGSSESS SSNMAPFCVL SPVKSPHLRK ASAVIHDQHK LSTEETEISP PLVKCGSAYE PENQSKDFLN KTFSDPHGRK VEKTTPDCQL RAFHLQSSAA ESKPEEQVSG LNRTSSQGPE ERSEYLKKVK SILNIVKEGQ ISLLPHLAAD NLDKIHDENG NNLLHIAASQ GHAECLQHLT SLMGEDCLNE RNTEKLTPAG LAIKNGQLEC VRWMVSETEA IAELSCSKDF PSLIHYAGCY GQEKILLWLL QFMQEQGISL DEVDQDGNSA VHVASQHGYL GCIQTLVEYG ANVTMQNHAG EKPSQSAERQ GHTLCSRYLV VVETCMSLAS QVVKLTKQLK EQTVERVTLQ NQLQQFLEAQ KSEGKSLPSS PSSPSSPASR KSQWKSPDAD DDSVAKSKPG VQEGIQVLGS LSASSRARPK AKDEDSDKIL RQLLGKEISE NVCTQEKLSL EFQDAQASSR NSKKIPLEKR ELKLARLRQL MQRSLSESDT DSNNSEDPKT TPVRKADRPR PQPIVESVES MDSAESLHLM IKKHTLASGG RRFPFSIKAS KSLDGHSPSP TSESSEPDLE SQYPGSGSIP PNQPSGDPQQ PSPDSTAAQK VATSPKSALK SPSSKRRTSQ NLKLRVTFEE PVVQMEQPSL ELNGEKDKDK GRTLQRTSTS NESGDQLKRP FGAFRSIMET LSGNQNNNNN YQAANQLKTS TLPLTSLGRK TDAKGNPASS ASKGKNKAA // ID SQSTM_HUMAN Reviewed; 440 AA. AC Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 237. DE RecName: Full=Sequestosome-1 {ECO:0000305}; DE AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575}; DE Short=EBIAP; DE Short=p60 {ECO:0000303|PubMed:8551575}; DE AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207}; DE AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207}; DE Short=p62 {ECO:0000303|PubMed:30266909}; GN Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280}; GN Synonyms=ORCA, OSIL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND RP 394-411, AND INTERACTION WITH EBI3. RC TISSUE=B-cell; RX PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996; RA Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., RA Birkenbach M.; RT "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr RT virus infection in B lymphocytes."; RL J. Virol. 70:1143-1153(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; RP 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND RP MUTAGENESIS OF TYR-9. RC TISSUE=Cervix carcinoma; RX PubMed=8650207; DOI=10.1073/pnas.93.12.5991; RA Joung I., Strominger J.L., Shin J.; RT "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck RT SH2 domain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Caudate nucleus, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Pancreas, Placenta, Skin, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION. RX PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7; RA Vadlamudi R.K., Shin J.; RT "Genomic structure and promoter analysis of the p62 gene encoding a non- RT proteasomal multiubiquitin chain binding protein."; RL FEBS Lett. 435:138-142(1998). RN [7] RP PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388. RX PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0; RA Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., RA Zatloukal K., Denk H.; RT "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. RT Demonstration of p62 as major constituent."; RL Am. J. Pathol. 154:1701-1710(1999). RN [8] RP INTERACTION WITH LCK AND RASA1. RX PubMed=8618896; DOI=10.1073/pnas.92.26.12338; RA Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.; RT "Phosphotyrosine-independent binding of a 62-kDa protein to the src RT homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of RT Ser-59 in the lck unique N-terminal region."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995). RN [9] RP INTERACTION WITH UBIQUITIN. RX PubMed=8702753; DOI=10.1074/jbc.271.34.20235; RA Vadlamudi R.K., Joung I., Strominger J.L., Shin J.; RT "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, RT belongs to a new class of ubiquitin-binding proteins."; RL J. Biol. Chem. 271:20235-20237(1996). RN [10] RP INTERACTION WITH NR2F2. RX PubMed=8910285; DOI=10.1074/jbc.271.44.27197; RA Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.; RT "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone RT receptor."; RL J. Biol. Chem. 271:27197-27200(1996). RN [11] RP INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION. RX PubMed=9566925; DOI=10.1128/mcb.18.5.3069; RA Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.; RT "Localization of atypical protein kinase C isoforms into lysosome-targeted RT endosomes through interaction with p62."; RL Mol. Cell. Biol. 18:3069-3080(1998). RN [12] RP INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND RP FUNCTION. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [13] RP INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [14] RP INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [15] RP INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [16] RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6; RA Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., RA Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.; RT "p62 Is a common component of cytoplasmic inclusions in protein aggregation RT diseases."; RL Am. J. Pathol. 160:255-263(2002). RN [17] RP INTERACTION WITH PAWR AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=11981755; DOI=10.1053/jhep.2002.32674; RA Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.; RT "Mallory body -- a disease-associated type of sequestosome."; RL Hepatology 35:1053-1062(2002). RN [19] RP INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=12471037; DOI=10.1074/jbc.m208468200; RA Geetha T., Wooten M.W.; RT "Association of the atypical protein kinase C-interacting protein p62/ZIP RT with nerve growth factor receptor TrkA regulates receptor trafficking and RT Erk5 signaling."; RL J. Biol. Chem. 278:4730-4739(2003). RN [20] RP INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF RP LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND RP GLU-82, AND DIMERIZATION. RX PubMed=12813044; DOI=10.1074/jbc.m303221200; RA Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., RA Michaelsen E., Bjoerkoey G., Johansen T.; RT "Interaction codes within the family of mammalian Phox and Bem1p domain- RT containing proteins."; RL J. Biol. Chem. 278:34568-34581(2003). RN [21] RP INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7; RP ASP-69 AND ASP-73. RX PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6; RA Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.; RT "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling RT complexes of atypical protein kinase C with Par6 and p62."; RL Mol. Cell 12:39-50(2003). RN [22] RP INDUCTION. RX PubMed=12700667; DOI=10.1038/sj.onc.1206325; RA Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.; RT "p62 overexpression in breast tumors and regulation by prostate-derived Ets RT factor in breast cancer cells."; RL Oncogene 22:2322-2333(2003). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029; RA Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K., RA Araga S., Yanagawa T., Ishii T., Nakashima K.; RT "Transcriptional activation of p62/A170/ZIP during the formation of the RT aggregates: possible mechanisms and the role in Lewy body formation in RT Parkinson's disease."; RL Brain Res. 1012:42-51(2004). RN [24] RP INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398; RP PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION. RX PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004; RA Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R., RA Wooten M.W.; RT "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in RT ubiquitin proteasome degradation."; RL Mol. Cell. Biol. 24:8055-8068(2004). RN [25] RP FUNCTION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH RP MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND RP ILE-431. RX PubMed=16286508; DOI=10.1083/jcb.200507002; RA Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A., RA Stenmark H., Johansen T.; RT "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a RT protective effect on huntingtin-induced cell death."; RL J. Cell Biol. 171:603-614(2005). RN [27] RP INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [28] RP INTERACTION WITH AJUBA AND LIMD1. RX PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005; RA Feng Y., Longmore G.D.; RT "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB RT activation by affecting the assembly and activity of the protein kinase RT Czeta/p62/TRAF6 signaling complex."; RL Mol. Cell. Biol. 25:4010-4022(2005). RN [29] RP INDUCTION, AND FUNCTION. RX PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011; RA Wang Z., Figueiredo-Pereira M.E.; RT "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of RT ubiquitinated proteins induced by prostaglandin J2 without reducing its RT neurotoxicity."; RL Mol. Cell. Neurosci. 29:222-231(2005). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [31] RP INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION. RX PubMed=15802564; DOI=10.1126/science.1110463; RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., RA Udd B., Gautel M.; RT "The kinase domain of titin controls muscle gene expression and protein RT turnover."; RL Science 308:1599-1603(2005). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [34] RP FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND RP MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337; RP TRP-338 AND SER-342. RX PubMed=17580304; DOI=10.1074/jbc.m702824200; RA Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H., RA Overvatn A., Bjorkoy G., Johansen T.; RT "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of RT ubiquitinated protein aggregates by autophagy."; RL J. Biol. Chem. 282:24131-24145(2007). RN [35] RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION). RX PubMed=24331465; DOI=10.1016/j.chom.2013.11.003; RA Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N., RA Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.; RT "The globally disseminated M1T1 clone of group A Streptococcus evades RT autophagy for intracellular replication."; RL Cell Host Microbe 14:675-682(2013). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [41] RP FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION. RX PubMed=20168092; DOI=10.4161/auto.6.3.11226; RA Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A., RA Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.; RT "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 RT bodies/ALIS and their degradation by autophagy."; RL Autophagy 6:330-344(2010). RN [42] RP INTERACTION WITH KEAP1. RX PubMed=20495340; DOI=10.4161/auto.6.5.12189; RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.; RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via RT autophagy."; RL Autophagy 6:614-621(2010). RN [43] RP FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347; RP THR-350; GLY-351 AND GLU-352. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [44] RP INTERACTION WITH FHOD3. RX PubMed=21149568; DOI=10.1083/jcb.201005060; RA Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.; RT "Formin follows function: a muscle-specific isoform of FHOD3 is regulated RT by CK2 phosphorylation and promotes myofibril maintenance."; RL J. Cell Biol. 191:1159-1172(2010). RN [45] RP INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION. RX PubMed=20357094; DOI=10.1128/jvi.02412-09; RA O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J., RA Campbell E.M.; RT "p62/sequestosome-1 associates with and sustains the expression of RT retroviral restriction factor TRIM5alpha."; RL J. Virol. 84:5997-6006(2010). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249; RP SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; RP LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425. RX PubMed=22084127; DOI=10.1001/archneurol.2011.250; RA Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., RA Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L., RA Heller S.L., Deng H.X., Siddique T.; RT "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:1440-1446(2011). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [49] RP IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR RP LOCATION. RX PubMed=21923101; DOI=10.1021/bi201137e; RA Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B., RA Layfield R., Searle M.S.; RT "Independent interactions of ubiquitin-binding domains in a ubiquitin- RT mediated ternary complex."; RL Biochemistry 50:9076-9087(2011). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207; RP THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF RP SER-403. RX PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039; RA Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.; RT "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic RT clearance of ubiquitinated proteins."; RL Mol. Cell 44:279-289(2011). RN [51] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [52] RP FUNCTION. RX PubMed=22622177; DOI=10.4161/auto.19381; RA Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D., RA Faure M., Fauvarque M.O.; RT "The deubiquitinating enzyme USP36 controls selective autophagy activation RT by ubiquitinated proteins."; RL Autophagy 8:767-779(2012). RN [53] RP INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION. RX PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015; RA Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.; RT "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the RT cells."; RL Biochim. Biophys. Acta 1823:316-326(2012). RN [54] RP INTERACTION WITH MAP1LC3A. RX PubMed=22421968; DOI=10.1038/cdd.2012.30; RA Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M., RA Carrier A., Iovanna J.L., Dusetti N.J.; RT "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins RT through the LC3-interacting region (LIR) and promotes autophagy-dependent RT cell death."; RL Cell Death Differ. 19:1525-1535(2012). RN [55] RP INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION. RX PubMed=22792322; DOI=10.1371/journal.pone.0040440; RA Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B., RA Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G., RA Reymond A., Pucci P., Merla G.; RT "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes RT the sequestration and clearance of ubiquitinated proteins into the RT aggresome."; RL PLoS ONE 7:E40440-E40440(2012). RN [56] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE RP ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [57] RP FUNCTION. RX PubMed=24128730; DOI=10.4161/auto.26085; RA Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.; RT "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody RT ring degradation by selective autophagy."; RL Autophagy 9:1955-1964(2013). RN [58] RP INTERACTION WITH SESN1 AND SESN2. RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002; RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., RA Kang D., Rhee S.G.; RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation RT of Keap1 and prevent oxidative liver damage."; RL Cell Metab. 17:73-84(2013). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [60] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND RP LEU-392. RX PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849; RG French Clinical and Genetic Research Network on FTD/FTD-ALS; RA Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G., RA Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T., RA Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.; RT "SQSTM1 mutations in French patients with frontotemporal dementia or RT frontotemporal dementia with amyotrophic lateral sclerosis."; RL JAMA Neurol. 70:1403-1410(2013). RN [61] RP LIR MOTIF. RX PubMed=23908376; DOI=10.1242/jcs.126128; RA Birgisdottir A.B., Lamark T., Johansen T.; RT "The LIR motif - crucial for selective autophagy."; RL J. Cell Sci. 126:3237-3247(2013). RN [62] RP INTERACTION WITH MAP1LC3B. RX PubMed=24089205; DOI=10.1038/nature12606; RA Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B., RA Zhong Q.; RT "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar RT satellites."; RL Nature 502:254-257(2013). RN [63] RP FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE. RX PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033; RA Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.; RT "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated RT sequestration and degradation."; RL Cell. Signal. 26:2470-2480(2014). RN [64] RP INTERACTION WITH TRIM5. RX PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013; RA Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C., RA Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B., RA Johansen T., Deretic V.; RT "TRIM proteins regulate autophagy and can target autophagic substrates by RT direct recognition."; RL Dev. Cell 30:394-409(2014). RN [65] RP INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1. RX PubMed=25040165; DOI=10.1111/febs.12905; RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S., RA Lee J.H.; RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of RT p62/sequestosome-1."; RL FEBS J. 281:3816-3827(2014). RN [66] RP INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338. RX PubMed=24668264; DOI=10.1002/embr.201338003; RA Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y., RA Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.; RT "Structural determinants in GABARAP required for the selective binding and RT recruitment of ALFY to LC3B-positive structures."; RL EMBO Rep. 15:557-565(2014). RN [67] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306 RP AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [68] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [69] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214. RX PubMed=20851865; DOI=10.3324/haematol.2010.029769; RA Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C., RA Crescenzi B., Santoro A., Chiaretti S., Mecucci C.; RT "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic RT leukemia."; RL Haematologica 95:2161-2163(2010). RN [70] RP INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL. RX PubMed=25114083; DOI=10.3233/jad-141512; RA Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K., RA Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E., RA Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.; RT "A phenotype of atypical apraxia of speech in a family carrying SQSTM1 RT mutation."; RL J. Alzheimers Dis. 43:625-630(2015). RN [71] RP FUNCTION, AND INTERACTION WITH PEX5. RX PubMed=26344566; DOI=10.1038/ncb3230; RA Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T., RA Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K., RA Pandita T.K., Kastan M.B., Walker C.L.; RT "ATM functions at the peroxisome to induce pexophagy in response to ROS."; RL Nat. Cell Biol. 17:1259-1269(2015). RN [72] RP INVOLVEMENT IN DMRV. RX PubMed=26208961; DOI=10.1212/wnl.0000000000001864; RA Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M., RA Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.; RT "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."; RL Neurology 85:665-674(2015). RN [73] RP INVOLVEMENT IN NADGP. RX PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026; RA Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P., RA Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S., RA Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H., RA Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V., RA Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C., RA Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J., RA Klopstock T.; RT "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset RT neurodegeneration with ataxia, dystonia, and gaze palsy."; RL Am. J. Hum. Genet. 99:735-743(2016). RN [74] RP FUNCTION, AND UBIQUITINATION. RX PubMed=27368102; DOI=10.1016/j.cell.2016.05.078; RA Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M., RA Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M., RA Neefjes J.; RT "An ER-associated pathway defines endosomal architecture for controlled RT cargo transport."; RL Cell 166:152-166(2016). RN [75] RP INTERACTION WITH TRIM11. RX PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019; RA Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.; RT "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent RT selective autophagy."; RL Cell Rep. 16:1988-2002(2016). RN [76] RP UBIQUITINATION, AND FUNCTION. RX PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005; RA Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C., RA Jani V., Lassen K.G., Xavier R.J.; RT "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial RT Autophagy."; RL Cell Rep. 17:2183-2194(2016). RN [77] RP FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420. RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030; RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.; RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain RT ubiquitination."; RL Cell Rep. 19:188-202(2017). RN [78] RP DOMAIN, AND UBIQUITINATION. RX PubMed=28322253; DOI=10.1038/cr.2017.40; RA Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H., RA Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H., RA Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.; RT "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor RT function and controls selective autophagy upon ubiquitin stress."; RL Cell Res. 27:657-674(2017). RN [79] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [80] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF RP SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411. RX PubMed=29507397; DOI=10.1038/s41422-018-0017-7; RA Sun D., Wu R., Zheng J., Li P., Yu L.; RT "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo RT segregation."; RL Cell Res. 28:405-415(2018). RN [81] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=29343546; DOI=10.15252/embj.201798308; RA Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M., RA Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C., RA Martens S.; RT "p62 filaments capture and present ubiquitinated cargos for autophagy."; RL EMBO J. 37:0-0(2018). RN [82] RP INTERACTION WITH TRIM16. RX PubMed=30143514; DOI=10.15252/embj.201798358; RA Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A., RA Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.; RT "TRIM16 controls assembly and degradation of protein aggregates by RT modulating the p62-NRF2 axis and autophagy."; RL EMBO J. 37:0-0(2018). RN [83] RP INTERACTION WITH LRRC25. RX PubMed=29288164; DOI=10.15252/embj.201796781; RA Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.; RT "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I RT for autophagic degradation."; RL EMBO J. 37:351-366(2018). RN [84] RP FUNCTION, INTERACTION WITH WDR81, AND DOMAIN. RX PubMed=28404643; DOI=10.1083/jcb.201608039; RA Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y., RA Luo S., Guo W., Yang C.; RT "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote RT aggrephagy."; RL J. Cell Biol. 216:1301-1320(2017). RN [85] RP INTERACTION WITH TRIM23. RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2; RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F., RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O., RA Moss J., Vaughan M., Gack M.U.; RT "TRIM23 mediates virus-induced autophagy via activation of TBK1."; RL Nat. Microbiol. 2:1543-1557(2017). RN [86] RP FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403. RX PubMed=29496741; DOI=10.15252/embj.201797858; RA Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C., RA Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R., RA Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M., RA Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.; RT "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent RT autophagy pathway activated by TBK1."; RL EMBO J. 37:0-0(2018). RN [87] RP INTERACTION WITH USP12. RX PubMed=30266909; DOI=10.1038/s41467-018-05653-z; RA Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K., RA Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P., RA Finkbeiner S.; RT "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and RT confer neuroprotection in models of Huntington's disease."; RL Nat. Commun. 9:3191-3191(2018). RN [88] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435, RP AND MUTAGENESIS OF LYS-420 AND LYS-435. RX PubMed=31857589; DOI=10.1038/s41467-019-13718-w; RA You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H., RA Peng C., Zhou T., Tang C., Liu W.; RT "Requirement for p62 acetylation in the aggregation of ubiquitylated RT proteins under nutrient stress."; RL Nat. Commun. 10:5792-5792(2019). RN [89] RP INTERACTION WITH ECSIT. RX PubMed=31281713; DOI=10.4110/in.2019.19.e16; RA Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.; RT "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the RT TRAF6-ECSIT Complex."; RL Immune Netw. 19:e16-e16(2019). RN [90] RP INTERACTION WITH CYLD. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [91] RP FUNCTION, AND INTERACTION WITH MOAP1. RX PubMed=33393215; DOI=10.15252/embr.202050854; RA Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.; RT "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and RT suppresses Nrf2 signaling."; RL EMBO Rep. 22:e50854-e50854(2021). RN [92] RP FUNCTION, AND UBIQUITINATION AT LYS-435. RX PubMed=33472082; DOI=10.1016/j.celrep.2020.108659; RA Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J., RA Berlin I.; RT "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal RT control over the endolysosomal pathway."; RL Cell Rep. 34:108659-108659(2021). RN [93] RP FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 RP (MICROBIAL INFECTION). RX PubMed=33509017; DOI=10.1080/15548627.2021.1874660; RA Ylae-Anttila P., Gupta S., Masucci M.G.; RT "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit RT selective autophagy."; RL Autophagy 17:3461-3474(2021). RN [94] RP SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION. RX PubMed=34471133; DOI=10.1038/s41467-021-25572-w; RA Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M., RA Martens S.; RT "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin RT condensate formation and autophagy initiation."; RL Nat. Commun. 12:5212-5212(2021). RN [95] RP INTERACTION WITH ASB6. RX PubMed=34164402; DOI=10.3389/fcell.2021.684885; RA Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.; RT "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to RT Regulate Cell Proliferation and Autophagy."; RL Front. Cell Dev. Biol. 9:684885-684885(2021). RN [96] RP FUNCTION. RX PubMed=34893540; DOI=10.1073/pnas.2107993118; RA Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J., RA Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.; RT "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [97] RP FUNCTION, AND INTERACTION WITH GRB2. RX PubMed=35831301; DOI=10.1038/s41420-022-01106-1; RA Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.; RT "Grb2 interacts with necrosome components and is involved in rasfonin- RT induced necroptosis."; RL Cell. Death. Discov. 8:319-319(2022). RN [98] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND RP SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407. RX PubMed=37306101; DOI=10.15252/embj.2022113349; RA Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y., RA Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T., RA Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y., RA Noda N.N., Komatsu M.; RT "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox- RT independent stress response."; RL EMBO J. 42:e113349-e113349(2023). RN [99] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND RP MUTAGENESIS OF 289-CYS-CYS-290. RX PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004; RA Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X., RA Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T., RA Neculai D., Sun Q., Kong E., Tate E.W., Yang A.; RT "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in RT mammalian autophagy."; RL Mol. Cell 83:3485-3501(2023). RN [100] RP INTERACTION WITH WDR83. RX PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023; RA Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.; RT "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases."; RL Mol. Cell 0:0-0(2023). RN [101] RP STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND RP DOMAIN. RX PubMed=12857745; DOI=10.1074/jbc.m307416200; RA Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.; RT "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and RT implications for mutations that cause Paget's disease of bone."; RL J. Biol. Chem. 278:37409-37412(2003). RN [102] RP STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN. RX PubMed=18083707; DOI=10.1074/jbc.m704973200; RA Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H., RA Layfield R., Searle M.S.; RT "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a RT novel conformational switch."; RL J. Biol. Chem. 283:5427-5440(2008). RN [103] RP STRUCTURE BY NMR OF 387-436. RX PubMed=17932931; DOI=10.1002/prot.21692; RA Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.; RT "Conformation and dynamics of the three-helix bundle UBA domain of p62 from RT experiment and simulation."; RL Proteins 71:227-240(2008). RN [104] RP STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND RP GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425. RX PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032; RA Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B., RA Williamson M.P., Layfield R., Searle M.S.; RT "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and RT regulates NF-kappaB signalling."; RL J. Mol. Biol. 396:178-194(2010). RN [105] RP VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274. RX PubMed=11992264; DOI=10.1086/340731; RA Laurin N., Brown J.P., Morissette J., Raymond V.; RT "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in RT Paget disease of bone."; RL Am. J. Hum. Genet. 70:1582-1588(2002). RN [106] RP VARIANT PDB3 LEU-392. RX PubMed=12374763; DOI=10.1093/hmg/11.22.2735; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M., RA Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W., RA Ralston S.H.; RT "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and RT sporadic Paget's disease."; RL Hum. Mol. Genet. 11:2735-2739(2002). RN [107] RP VARIANT PDB3 LEU-387. RX PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748; RA Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F., RA Singer F.R., Leach R.J.; RT "Three novel mutations in SQSTM1 identified in familial Paget's disease of RT bone."; RL J. Bone Miner. Res. 18:1748-1753(2003). RN [108] RP VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425. RX PubMed=15146436; DOI=10.1002/art.20224; RA Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C., RA Kneppers A.L.J., Papapoulos S.E.; RT "Familial Paget's disease in The Netherlands: occurrence, identification of RT new mutations in the sequestosome 1 gene, and their clinical RT associations."; RL Arthritis Rheum. 50:1650-1654(2004). RN [109] RP VARIANT PDB3 LEU-392. RX PubMed=15207768; DOI=10.1016/j.bone.2004.01.010; RA Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L., RA Kesting J.B., Andersen J., Shaw J.T.E.; RT "Identification of SQSTM1 mutations in familial Paget's disease in RT Australian pedigrees."; RL Bone 35:277-282(2004). RN [110] RP VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425. RX PubMed=15125799; DOI=10.1359/jbmr.040203; RA Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C., RA Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F., RA Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B., RA Melchiorre D., Matucci-Cerinic M., Brandi M.L.; RT "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an RT Italian series of patients affected by Paget's disease of bone (PDB)."; RL J. Bone Miner. Res. 19:1013-1017(2004). RN [111] RP VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF RP VARIANTS VAL-404; SER-411 AND ARG-425. RX PubMed=15176995; DOI=10.1359/jbmr.0403015; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C., RA Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W., RA Searle M.S., Layfield R., Ralston S.H.; RT "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype RT phenotype correlation, functional analysis, and structural consequences."; RL J. Bone Miner. Res. 19:1122-1127(2004). RN [112] RP VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17488105; DOI=10.1021/pr0700908; RA Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A., RA Hendrickson R.C., Stephenson J.L. Jr.; RT "Detection and validation of non-synonymous coding SNPs from orthogonal RT analysis of shotgun proteomics data."; RL J. Proteome Res. 6:2331-2340(2007). RN [113] RP INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; RP TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; RP ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND RP VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; RP GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; RP 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 RP DEL; THR-349 AND LEU-439. RX PubMed=24899140; DOI=10.1007/s00401-014-1298-7; RA van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W., RA Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K., RA Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M., RA Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A., RA Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I., RA Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S., RA Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H., RA Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C., RA Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B., RA Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I., RA Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A., RA Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A., RA Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P., RA Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R., RA De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.; RT "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar RT degeneration."; RL Acta Neuropathol. 128:397-410(2014). CC -!- FUNCTION: Molecular adapter required for selective macroautophagy CC (aggrephagy) by acting as a bridge between polyubiquitinated proteins CC and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, CC PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, CC PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the CC recruitment of ubiquitinated cargo proteins to autophagosomes via CC multiple domains that bridge proteins and organelles in different steps CC (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, CC PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, CC PubMed:37802024). SQSTM1 first mediates the assembly and removal of CC ubiquitinated proteins by undergoing liquid-liquid phase separation CC upon binding to ubiquitinated proteins via its UBA domain, leading to CC the formation of insoluble cytoplasmic inclusions, known as p62 bodies CC (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, CC PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). CC SQSTM1 then interacts with ATG8 family proteins on autophagosomes via CC its LIR motif, leading to p62 body recruitment to autophagosomes, CC followed by autophagic clearance of ubiquitinated proteins CC (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself CC degraded along with its ubiquitinated cargos (PubMed:16286508, CC PubMed:17580304, PubMed:37802024). Also required to recruit CC ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). CC Also involved in autophagy of peroxisomes (pexophagy) in response to CC reactive oxygen species (ROS) by acting as a bridge between CC ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts CC as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: CC interaction inactivates the BCR(KEAP1) complex by sequestering the CC complex in inclusion bodies, promoting nuclear accumulation of CC NFE2L2/NRF2 and subsequent expression of cytoprotective genes CC (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). CC Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to CC autophagosomes (PubMed:29496741). Involved in endosome organization by CC retaining vesicles in the perinuclear cloud: following ubiquitination CC by RNF26, attracts specific vesicle-associated adapters, forming a CC molecular bridge that restrains cognate vesicles in the perinuclear CC region and organizes the endosomal pathway for efficient cargo CC transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 CC into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal CC degradation (PubMed:25101860). May regulate the activation of NFKB1 by CC TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, CC PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, CC PubMed:19931284). May play a role in titin/TTN downstream signaling in CC muscle cells (PubMed:15802564). Adapter that mediates the interaction CC between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, CC ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177, CC ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102, CC ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082, CC ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133, CC ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. CC -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays CC (PubMed:12887891, PubMed:19931284). Dimerization interferes with CC ubiquitin binding (PubMed:19931284). Component of a ternary complex CC with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, CC PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 CC and CYLD (By similarity). Identified in a heterotrimeric complex with CC ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the CC same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) CC with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, CC including GABARAP, GABARAPL1 and GABARAPL2; these interactions are CC necessary for the recruitment MAP1 LC3 family members to inclusion CC bodies containing polyubiquitinated protein aggregates and for their CC degradation by autophagy (PubMed:16286508, PubMed:17580304, CC PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly CC with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, CC PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, CC NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, CC PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, CC PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with CC RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF- CC R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the CC proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with CC TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked CC polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 CC (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts CC with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, CC PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with CC UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct CC and regulates the interaction of SQSTM1 with ubiquitinated proteins CC (PubMed:28404643). Interacts with WDFY3; this interaction is required CC to recruit WDFY3 to cytoplasmic bodies and to PML bodies CC (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts CC with STING1; leading to relocalization of STING1 to autophagosomes CC (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with CC KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex CC by sequestering KEAP1 in inclusion bodies, promoting its degradation CC (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with CC MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester CC KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts CC with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; CC specifically binds PEX5 ubiquitinated at 'Lys-209' in response to CC reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 CC domain) with TNS2; the interaction leads to sequestration of TNS2 in CC cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and CC proteasomal degradation (PubMed:25101860). Interacts with IRS1; the CC interaction is disrupted by the presence of tensin TNS2 CC (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, CC PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting CC AIM2 recruitment to autophagosomes and autophagy-dependent degradation CC of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). CC Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 CC (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts CC with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction CC inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT CC complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By CC similarity). Interacts with WDR83 (PubMed:38103557). Interacts with CC GRB2 (PubMed:35831301). Interacts with USP12; the interaction is CC independent of USP12 deubiquitinase activity and may be involved in CC regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 CC (PubMed:34164402). {ECO:0000250|UniProtKB:O08623, CC ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531, CC ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044, CC ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, CC ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101, CC ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085, CC ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264, CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865, CC ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090, CC ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909, CC ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402, CC ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557, CC ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896, CC ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285, CC ECO:0000269|PubMed:9566925}. CC -!- INTERACTION: CC Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613; CC Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964; CC Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185; CC Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634; CC Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440; CC Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940; CC Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310; CC Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445; CC Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462; CC Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541; CC Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505; CC Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001; CC Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969; CC Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116; CC Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499; CC Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029; CC Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279; CC Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001; CC Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863; CC Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372; CC Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768; CC Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144; CC Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996; CC Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294; CC Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698; CC Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125; CC Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226; CC Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974; CC Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987; CC Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705; CC Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199; CC Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227; CC Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453; CC Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642; CC Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595; CC Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161; CC Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879; CC Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104; CC Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085; CC Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276; CC Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864; CC Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054; CC Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357; CC Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397; CC Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256; CC Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701; CC Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773; CC Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771; CC Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684; CC Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110; CC Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238; CC Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715; CC Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771; CC Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, CC ECO:0000269|PubMed:37802024}. Preautophagosomal structure CC {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML CC body {ECO:0000269|PubMed:20168092}. Late endosome CC {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome CC {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm, CC myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac CC muscle, localizes to the sarcomeric band (By similarity). Localizes to CC cytoplasmic membraneless inclusion bodies, known as p62 bodies, CC containing polyubiquitinated protein aggregates (PubMed:11786419, CC PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:37306101, PubMed:37802024). In CC neurodegenerative diseases, detected in Lewy bodies in Parkinson CC disease, neurofibrillary tangles in Alzheimer disease, and HTT CC aggregates in Huntington disease (PubMed:15158159). In protein CC aggregate diseases of the liver, found in large amounts in Mallory CC bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in CC hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). CC Enriched in Rosenthal fibers of pilocytic astrocytoma CC (PubMed:11786419). In the cytoplasm, observed in both membrane-free CC ubiquitin-containing protein aggregates (sequestosomes) and membrane- CC surrounded autophagosomes (PubMed:15953362, PubMed:17580304). CC Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum CC (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies CC (PubMed:20357094). When nuclear export is blocked by treatment with CC leptomycin B, accumulates in PML bodies (PubMed:20168092). CC {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, CC ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, CC ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, CC ECO:0000269|PubMed:37802024}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13501-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13501-2; Sequence=VSP_015841; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:8650207}. CC -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in CC levels in fully differentiated myotubes compared to undifferentiated CC myoblasts. {ECO:0000269|PubMed:25101860}. CC -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at CC protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is CC directly activated by NFE2L2/NRF2; creating a positive feedback loop CC (PubMed:20452972). {ECO:0000269|PubMed:12700667, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:9762895}. CC -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin CC chains of polyubiquitinated substrates (PubMed:12857745, CC PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the CC interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains CC are necessary and sufficient for the localization into the ubiquitin- CC containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253, CC ECO:0000269|PubMed:31857589}. CC -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions CC with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, CC PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and CC UBA domains are necessary and sufficient for the localization into the CC ubiquitin-containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}. CC -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1. CC {ECO:0000269|PubMed:10747026}. CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction CC with ATG8 family proteins. {ECO:0000269|PubMed:23908376}. CC -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer CC interface and increases binding affinity to ubiquitinated proteins (By CC similarity). Phosphorylation at Ser-407 also primes for subsequent CC phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 CC by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing CC the affinity between the UBA domain and polyubiquitin chains CC (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 CC is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by CC TBK1, leading to promote relocalization of 'Lys-63'-linked CC ubiquitinated STING1 to autophagosomes (PubMed:29496741). CC Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and CC inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear CC accumulation and expression of phase II detoxifying enzymes CC (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564). CC {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165, CC ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}. CC -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 CC attracts specific vesicle-associated adapters, forming a molecular CC bridge that restrains cognate vesicles in the perinuclear region and CC organizes the endosomal pathway for efficient cargo transport CC (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 CC increases its ability to bind polyubiquitin chains by destabilizing the CC UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 CC releases target vesicles for fast transport into the cell periphery CC (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, CC increasing SQSTM1 sequestering activity and promoting its degradation CC (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked CC polyubiquitination leading to xenophagic targeting of bacteria and CC inhibition of their replication (PubMed:27880896). CC {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896, CC ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357, CC ECO:0000269|PubMed:33472082}. CC -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity CC by destabilizing the UBA dimer interface and increases binding affinity CC to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 CC (PubMed:31857589). {ECO:0000269|PubMed:31857589}. CC -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for CC efficient autophagic degradation of SQSTM1-cargo complexes by promoting CC affinity for ATG8 proteins and recruitment of p62 bodies to CC autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 CC by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}. CC -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading CC to its degradation (PubMed:24331465). Degradation by SpeB prevents CC autophagy, promoting to S.pyogenes intracellular replication CC (PubMed:24331465). {ECO:0000269|PubMed:24331465}. CC -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; CC leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1- CC positive structures. {ECO:0000269|PubMed:33509017}. CC -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of CC bone remodeling characterized by increased bone turnover affecting one CC or more sites throughout the skeleton, primarily the axial skeleton. CC Osteoclastic overactivity followed by compensatory osteoblastic CC activity leads to a structurally disorganized mosaic of bone (woven CC bone), which is mechanically weaker, larger, less compact, more CC vascular, and more susceptible to fracture than normal adult lamellar CC bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, CC ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, CC ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, CC ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to CC form a shell surrounding aggregates of mutant HTT that may protect CC cells from apoptosis, possibly by recruiting autophagosomal components CC to the polyubiquitinated protein aggregates. CC {ECO:0000269|PubMed:16286508}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 CC (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia is characterized by frontal and temporal lobe CC atrophy associated with neuronal loss, gliosis, and dementia. Patients CC exhibit progressive changes in social, behavioral, and/or language CC function. Amyotrophic lateral sclerosis is characterized by the death CC of motor neurons in the brain, brainstem, and spinal cord, resulting in CC fatal paralysis. Some FTDALS3 patients may also develop Paget disease CC of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, CC ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, CC childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder CC characterized by gait abnormalities, ataxia, dysarthria, dystonia, CC vertical gaze palsy, and cognitive decline. Disease onset is in CC childhood or adolescence. NADGP transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An CC autosomal dominant myopathy with adult onset, characterized by muscle CC weakness of the distal upper and lower limbs, walking difficulties, and CC proximal weakness of the shoulder girdle muscles. Muscle biopsy shows CC rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a CC form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) CC with NUP214. {ECO:0000269|PubMed:20851865}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U41806; AAA93299.1; -; mRNA. DR EMBL; U46751; AAC52070.1; -; mRNA. DR EMBL; AK098077; BAG53577.1; -; mRNA. DR EMBL; AK312451; BAG35358.1; -; mRNA. DR EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000951; AAH00951.1; -; mRNA. DR EMBL; BC001874; AAH01874.1; -; mRNA. DR EMBL; BC003139; AAH03139.1; -; mRNA. DR EMBL; BC017222; AAH17222.1; -; mRNA. DR EMBL; BC019111; AAH19111.1; -; mRNA. DR EMBL; AF060494; AAC64516.1; -; Genomic_DNA. DR CCDS; CCDS34317.1; -. [Q13501-1] DR CCDS; CCDS47355.1; -. [Q13501-2] DR RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2] DR RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2] DR RefSeq; NP_003891.1; NM_003900.5. [Q13501-1] DR PDB; 1Q02; NMR; -; A=387-436. DR PDB; 2JY7; NMR; -; A=387-436. DR PDB; 2JY8; NMR; -; A=387-436. DR PDB; 2K0B; NMR; -; X=387-436. DR PDB; 2KNV; NMR; -; A/B=387-436. DR PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102. DR PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102. DR PDB; 4UF9; EM; 10.30 A; A/B/D=1-122. DR PDB; 5YP7; X-ray; 1.42 A; A/D=126-180. DR PDB; 5YP8; X-ray; 1.45 A; A/B=126-180. DR PDB; 5YPA; X-ray; 2.50 A; A/B=126-180. DR PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180. DR PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180. DR PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180. DR PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180. DR PDB; 5YPG; X-ray; 2.20 A; A/B=126-180. DR PDB; 5YPH; X-ray; 1.63 A; A/B=126-180. DR PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102. DR PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169. DR PDB; 6MIU; X-ray; 1.90 A; A/B=120-171. DR PDB; 6MJ7; X-ray; 1.41 A; A=120-171. DR PDB; 6TGY; EM; 3.50 A; A=1-122. DR PDB; 6TH3; EM; 4.00 A; A/B/C=1-122. DR PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172. DR PDBsum; 1Q02; -. DR PDBsum; 2JY7; -. DR PDBsum; 2JY8; -. DR PDBsum; 2K0B; -. DR PDBsum; 2KNV; -. DR PDBsum; 4MJS; -. DR PDBsum; 4UF8; -. DR PDBsum; 4UF9; -. DR PDBsum; 5YP7; -. DR PDBsum; 5YP8; -. DR PDBsum; 5YPA; -. DR PDBsum; 5YPB; -. DR PDBsum; 5YPC; -. DR PDBsum; 5YPE; -. DR PDBsum; 5YPF; -. DR PDBsum; 5YPG; -. DR PDBsum; 5YPH; -. DR PDBsum; 6JM4; -. DR PDBsum; 6KHZ; -. DR PDBsum; 6MIU; -. DR PDBsum; 6MJ7; -. DR PDBsum; 6TGY; -. DR PDBsum; 6TH3; -. DR PDBsum; 7R1O; -. DR AlphaFoldDB; Q13501; -. DR BMRB; Q13501; -. DR EMDB; EMD-10501; -. DR EMDB; EMD-10502; -. DR EMDB; EMD-2936; -. DR EMDB; EMD-2937; -. DR SMR; Q13501; -. DR BioGRID; 114397; 1356. DR CORUM; Q13501; -. DR DIP; DIP-34443N; -. DR ELM; Q13501; -. DR FunCoup; Q13501; 2230. DR IntAct; Q13501; 311. DR MINT; Q13501; -. DR STRING; 9606.ENSP00000374455; -. DR BindingDB; Q13501; -. DR ChEMBL; CHEMBL4295816; -. DR GuidetoPHARMACOLOGY; 3213; -. DR MoonDB; Q13501; Predicted. DR GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13501; -. DR PhosphoSitePlus; Q13501; -. DR SwissPalm; Q13501; -. DR BioMuta; SQSTM1; -. DR DMDM; 74735628; -. DR jPOST; Q13501; -. DR MassIVE; Q13501; -. DR PaxDb; 9606-ENSP00000374455; -. DR PeptideAtlas; Q13501; -. DR ProteomicsDB; 59496; -. [Q13501-1] DR ProteomicsDB; 59497; -. [Q13501-2] DR Pumba; Q13501; -. DR Antibodypedia; 761; 1362 antibodies from 49 providers. DR DNASU; 8878; -. DR YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers. DR Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2] DR Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1] DR Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1] DR Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1] DR GeneID; 8878; -. DR KEGG; hsa:8878; -. DR MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1. DR UCSC; uc003mkw.5; human. [Q13501-1] DR AGR; HGNC:11280; -. DR ClinPGx; PA36109; -. DR CTD; 8878; -. DR DisGeNET; 8878; -. DR GeneCards; SQSTM1; -. DR HGNC; HGNC:11280; SQSTM1. DR HPA; ENSG00000161011; Tissue enhanced (skeletal). DR MalaCards; SQSTM1; -. DR MIM; 167250; phenotype. DR MIM; 601530; gene. DR MIM; 616437; phenotype. DR MIM; 617145; phenotype. DR MIM; 617158; phenotype. DR OpenTargets; ENSG00000161011; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 603; Distal myopathy, Welander type. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR VEuPathDB; HostDB:ENSG00000161011; -. DR eggNOG; KOG4582; Eukaryota. DR GeneTree; ENSGT00390000002781; -. DR HOGENOM; CLU_038011_1_0_1; -. DR InParanoid; Q13501; -. DR OMA; NCNGWLT; -. DR OrthoDB; 441278at2759; -. DR PAN-GO; Q13501; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13501; -. DR PathwayCommons; Q13501; -. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9664873; Pexophagy. DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; Q13501; -. DR SIGNOR; Q13501; -. DR Agora; ENSG00000161011; -. DR BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens. DR CD-CODE; 1822EB5E; Synthetic Condensate 000092. DR CD-CODE; 5D6181E1; Synthetic Condensate 000293. DR CD-CODE; 718A9EC3; P62 body. DR CD-CODE; 98C8800A; Synthetic Condensate 000338. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; EF6CBD8C; Synthetic Condensate 000070. DR CD-CODE; F17BA747; P62 cluster. DR CD-CODE; F5639AB0; Synthetic Condensate 000096. DR ChiTaRS; SQSTM1; human. DR EvolutionaryTrace; Q13501; -. DR GeneWiki; Sequestosome_1; -. DR GenomeRNAi; 8878; -. DR Pharos; Q13501; Tbio. DR PRO; PR:Q13501; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13501; protein. DR Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues. DR ExpressionAtlas; Q13501; baseline and differential. DR GO; GO:0016235; C:aggresome; IBA:GO_Central. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0097413; C:Lewy body; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000932; C:P-body; IDA:UniProtKB. DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB. DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc. DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0035973; P:aggrephagy; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0006914; P:autophagy; IDA:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0033554; P:cellular response to stress; IDA:UniProt. DR GO; GO:0016197; P:endosomal transport; TAS:UniProtKB. DR GO; GO:0007032; P:endosome organization; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IDA:UniProtKB. DR GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB. DR GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL. DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd06402; PB1_p62; 1. DR CDD; cd14320; UBA_SQSTM; 1. DR CDD; cd02340; ZZ_NBR1_like; 1. DR DisProt; DP01111; -. DR FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1. DR FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1. DR FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1. DR Gene3D; 3.30.60.90; -; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00383; -. DR InterPro; IPR052260; Autophagy_Rcpt_SigReg. DR InterPro; IPR053793; PB1-like. DR InterPro; IPR000270; PB1_dom. DR InterPro; IPR034866; PB1_p62. DR InterPro; IPR033741; SQSTM_UBA. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR000433; Znf_ZZ. DR InterPro; IPR043145; Znf_ZZ_sf. DR PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1. DR PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1. DR Pfam; PF00564; PB1; 1. DR Pfam; PF16577; UBA_5; 1. DR Pfam; PF00569; ZZ; 1. DR SMART; SM00666; PB1; 1. DR SMART; SM00165; UBA; 1. DR SMART; SM00291; ZnF_ZZ; 1. DR SUPFAM; SSF54277; CAD & PB1 domains; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51745; PB1; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS01357; ZF_ZZ_1; 1. DR PROSITE; PS50135; ZF_ZZ_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; KW Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm; KW Cytoplasmic vesicle; Differentiation; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Endosome; Immunity; KW Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration; KW Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT CHAIN 2..440 FT /note="Sequestosome-1" FT /id="PRO_0000072176" FT DOMAIN 3..102 FT /note="PB1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081" FT DOMAIN 389..434 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 123..173 FT /note="ZZ-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT REGION 2..50 FT /note="Interaction with LCK" FT /evidence="ECO:0000269|PubMed:8650207" FT REGION 43..107 FT /note="Interaction with PRKCZ and dimerization" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 50..80 FT /note="Interaction with PAWR" FT /evidence="ECO:0000269|PubMed:11755531" FT REGION 122..224 FT /note="Interaction with GABRR3" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 170..220 FT /note="LIM protein-binding (LB)" FT REGION 196..235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..390 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..440 FT /note="Interaction with NTRK1" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 321..342 FT /note="MAP1LC3B-binding" FT /evidence="ECO:0000269|PubMed:17580304" FT REGION 347..352 FT /note="Interaction with KEAP1" FT /evidence="ECO:0000269|PubMed:20452972" FT MOTIF 228..233 FT /note="TRAF6-binding" FT MOTIF 336..341 FT /note="LIR" FT COMPBIAS 283..296 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 310..324 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 337..347 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 351..373 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 154 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 160 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT SITE 252..253 FT /note="Breakpoint for translocation to form the NUP214- FT SQSTM1 fusion protein" FT /evidence="ECO:0000269|PubMed:20851865" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:24275569" FT MOD_RES 148 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 176 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:20068231" FT MOD_RES 233 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 249 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 266 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 269 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 282 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 332 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 349 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 355 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 361 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 365 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64337" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 403 FT /note="Phosphoserine; by CK2, ULK1 and TBK1" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741, FT ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101" FT MOD_RES 407 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 420 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT MOD_RES 435 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT LIPID 289 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT LIPID 290 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT CROSSLNK 91 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 189 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 420 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:28380357" FT CROSSLNK 435 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000269|PubMed:33472082, FT ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..84 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015841" FT VARIANT 16 FT /note="A -> V (in FTDALS3; dbSNP:rs1554162295)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073899" FT VARIANT 17 FT /note="A -> V (in dbSNP:rs141502868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073900" FT VARIANT 33 FT /note="A -> V (in FTDALS3; dbSNP:rs200396166)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_073901" FT VARIANT 80 FT /note="D -> E (in FTDALS3; dbSNP:rs148366738)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073902" FT VARIANT 90 FT /note="V -> M (in FTDALS3; dbSNP:rs181263868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073903" FT VARIANT 103 FT /note="K -> R (in dbSNP:rs748170760)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073904" FT VARIANT 107 FT /note="R -> Q" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073905" FT VARIANT 107 FT /note="R -> W (in FTDALS3; dbSNP:rs771903158)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073906" FT VARIANT 108 FT /note="D -> Y" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073907" FT VARIANT 110 FT /note="R -> H (in dbSNP:rs1267306593)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073908" FT VARIANT 117 FT /note="A -> V (in dbSNP:rs147810437)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:24899140" FT /id="VAR_023590" FT VARIANT 118 FT /note="P -> S (in dbSNP:rs200152247)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073909" FT VARIANT 119 FT /note="R -> G (in dbSNP:rs548787835)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073910" FT VARIANT 125 FT /note="N -> S (in dbSNP:rs769325755)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073911" FT VARIANT 129 FT /note="D -> N (in FTDALS3; dbSNP:rs753212399)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073912" FT VARIANT 139 FT /note="R -> C (in dbSNP:rs750256905)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073913" FT VARIANT 153 FT /note="V -> I (in FTDALS3; dbSNP:rs145056421)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073914" FT VARIANT 180 FT /note="S -> L (in dbSNP:rs1582008478)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073915" FT VARIANT 212 FT /note="R -> C (in FTDALS3; dbSNP:rs201263163)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073916" FT VARIANT 217 FT /note="R -> H (in dbSNP:rs761822261)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073917" FT VARIANT 219 FT /note="G -> V (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073918" FT VARIANT 226 FT /note="S -> P (in FTDALS3; dbSNP:rs765200636)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073919" FT VARIANT 228 FT /note="P -> L (in FTDALS3; dbSNP:rs151191977)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073920" FT VARIANT 232 FT /note="P -> T (in FTDALS3; dbSNP:rs1225746517)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073921" FT VARIANT 238 FT /note="K -> E (confirmed at protein level; FT dbSNP:rs11548633)" FT /evidence="ECO:0000269|PubMed:17488105, FT ECO:0000269|PubMed:24899140" FT /id="VAR_068915" FT VARIANT 238 FT /note="Missing (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083" FT /id="VAR_073922" FT VARIANT 258 FT /note="D -> N (in FTDALS3; dbSNP:rs774986849)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073923" FT VARIANT 265..266 FT /note="RS -> SR" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073924" FT VARIANT 274 FT /note="E -> D (in dbSNP:rs55793208)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_061707" FT VARIANT 274 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:11992264" FT /id="VAR_023591" FT VARIANT 278 FT /note="T -> I (in dbSNP:rs200445838)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073925" FT VARIANT 308 FT /note="A -> V (in dbSNP:rs541356917)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073926" FT VARIANT 318 FT /note="S -> P (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073927" FT VARIANT 319 FT /note="E -> K (in dbSNP:rs61748794)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073928" FT VARIANT 321 FT /note="R -> C (in FTDALS3; likely benign; FT dbSNP:rs140226523)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073929" FT VARIANT 329 FT /note="D -> G (in FTDALS3; dbSNP:rs148294622)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073930" FT VARIANT 334 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073931" FT VARIANT 348 FT /note="P -> L (in FTDALS3; dbSNP:rs772889843)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073932" FT VARIANT 349 FT /note="S -> T (in dbSNP:rs774512680)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073933" FT VARIANT 370 FT /note="S -> P (in FTDALS3; dbSNP:rs143956614)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073934" FT VARIANT 381 FT /note="A -> V (in FTDALS3; dbSNP:rs772122047)" FT /evidence="ECO:0000269|PubMed:24042580" FT /id="VAR_073935" FT VARIANT 387 FT /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)" FT /evidence="ECO:0000269|PubMed:14584883, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023592" FT VARIANT 392 FT /note="P -> L (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; dbSNP:rs104893941)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745, FT ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023593" FT VARIANT 399 FT /note="S -> P (in PDB3; dbSNP:rs1561609625)" FT /evidence="ECO:0000269|PubMed:15146436" FT /id="VAR_023594" FT VARIANT 404 FT /note="M -> T (in PDB3; decreased ability to undergo FT liquid-liquid phase separation and formation of p62 body; FT dbSNP:rs1247551175)" FT /evidence="ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:29507397" FT /id="VAR_023595" FT VARIANT 404 FT /note="M -> V (in PDB3; loss of polyubiquitin-binding; FT dbSNP:rs771966860)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15176995" FT /id="VAR_023596" FT VARIANT 411 FT /note="G -> S (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; decreased ability to undergo liquid- FT liquid phase separation and formation of p62 body; FT dbSNP:rs143511494)" FT /evidence="ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397" FT /id="VAR_023597" FT VARIANT 425 FT /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin- FT binding and increased activation of NF-kappa-B; FT dbSNP:rs757212984)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127" FT /id="VAR_023598" FT VARIANT 430 FT /note="T -> P (in FTDALS3; dbSNP:rs770118706)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073936" FT VARIANT 439 FT /note="P -> L (in dbSNP:rs199854262)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073937" FT MUTAGEN 7 FT /note="K->A: Loss of interactions with PRKCZ, PRCKI and FT NBR1. Loss of dimerization; when associated with A-69." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 9 FT /note="Y->F: No effect on interaction with LCK." FT /evidence="ECO:0000269|PubMed:8650207" FT MUTAGEN 13 FT /note="K->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 21..22 FT /note="RR->AA: Loss of interaction with PRKCI. Alters FT dimerization." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 67 FT /note="Y->A: No effect on interaction with PRKCZ." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 69 FT /note="D->A: No effect on interactions with PRKCZ, PRKCI FT and NBR1. Loss of localization in cytoplasmic inclusion FT bodies. Loss of dimerization; when associated with A-7." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508" FT MUTAGEN 71 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 73 FT /note="D->A: No effect on interactions with PRKCZ and FT PRKCI." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 80 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 82 FT /note="E->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 289..290 FT /note="CC->SS: Abolished palmitoylation." FT /evidence="ECO:0000269|PubMed:37802024" FT MUTAGEN 323..324 FT /note="EE->AA: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 332 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 335..337 FT /note="DDD->ADA: 75% decrease in MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 338 FT /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts FT interaction with GABARAP." FT /evidence="ECO:0000269|PubMed:17580304, FT ECO:0000269|PubMed:24668264" FT MUTAGEN 342 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 347 FT /note="D->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 349 FT /note="S->A: Impaired phosphorylation by ULK1, leading to FT decreased p62 body formation." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 350 FT /note="T->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972, FT ECO:0000269|PubMed:37306101" FT MUTAGEN 351 FT /note="G->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 352 FT /note="E->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 398 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 403..407 FT /note="SMGFS->EMGFE: Mimics phosphorylation; increased FT phosphorylation at S-349." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 403 FT /note="S->A: Abolished phosphorylation by CK2, leading to FT decreased affinity for ubiquitinated proteins. Abolished FT ability to promote relocalization of 'Lys-63'-linked FT ubiquitinated STING1 to autophagosomes." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29496741" FT MUTAGEN 403 FT /note="S->E: Mimmics phosphorylation; increased affinity FT for ubiquitinated proteins, leading to increased p62 body FT formation and autophagic degradation." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29507397" FT MUTAGEN 406 FT /note="F->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 409 FT /note="E->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 410 FT /note="G->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 413 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 417 FT /note="L->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 420 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-435." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 420 FT /note="K->R: Decreased ubiquitination by the BCR(KEAP1) FT complex, leading to decreased sequestering activity. FT Strongly reduced acetylation; when associated with R-435." FT /evidence="ECO:0000269|PubMed:28380357, FT ECO:0000269|PubMed:31857589" FT MUTAGEN 431 FT /note="I->V: Partial loss of polyubiquitin-binding. Loss of FT localization to cytoplasmic inclusion bodies." FT /evidence="ECO:0000269|PubMed:15340068, FT ECO:0000269|PubMed:16286508" FT MUTAGEN 435 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-420." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 435 FT /note="K->R: Strongly reduced acetylation; when associated FT with R-420." FT /evidence="ECO:0000269|PubMed:31857589" FT CONFLICT 321 FT /note="R -> A (in Ref. 1; AAA93299)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 13..15 FT /evidence="ECO:0007829|PDB:6TGY" FT STRAND 19..24 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:6TGY" FT HELIX 43..54 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4MJS" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6KHZ" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:6MJ7" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 157..162 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 165..168 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:2JY7" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 412..419 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 420..422 FT /evidence="ECO:0007829|PDB:1Q02" FT HELIX 424..431 FT /evidence="ECO:0007829|PDB:1Q02" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:2JY8" FT INIT_MET Q13501-2:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q13501-2:2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 440 AA; 47687 MW; 462D94C171F337CD CRC64; MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK NYDIGAALDT IQYSKHPPPL // ID SYUA_HUMAN Reviewed; 140 AA. AC P37840; A8K2A4; Q13701; Q4JHI3; Q6IAU6; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 28-JAN-2026, entry version 259. DE RecName: Full=Alpha-synuclein; DE AltName: Full=Non-A beta component of AD amyloid; DE AltName: Full=Non-A4 component of amyloid precursor; DE Short=NACP; GN Name=SNCA; Synonyms=NACP, PARK1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 61-95. RC TISSUE=Brain; RX PubMed=8248242; DOI=10.1073/pnas.90.23.11282; RA Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., RA Otero D.A., Kondo J., Ihara Y., Saitoh T.; RT "Molecular cloning of cDNA encoding an unrecognized component of amyloid in RT Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5). RX PubMed=7601450; DOI=10.1016/0888-7543(95)80208-4; RA Campion D., Martin C., Heilig R., Charbonnier F., Moreau V., Flaman J.-M., RA Petit J.-L., Hannequin D., Brice A., Frebourg T.; RT "The NACP/synuclein gene: chromosomal assignment and screening for RT alterations in Alzheimer disease."; RL Genomics 26:254-257(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4). RC TISSUE=Brain; RX PubMed=7802671; DOI=10.1006/bbrc.1994.2816; RA Ueda K., Saitoh T., Mori H.; RT "Tissue-dependent alternative splicing of mRNA for NACP, the precursor of RT non-A beta component of Alzheimer's disease amyloid."; RL Biochem. Biophys. Res. Commun. 205:1366-1372(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Xia Y., Silva R.D., Chen X.H., Saitoh T.; RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4). RX PubMed=11156617; DOI=10.1101/gr.165801; RA Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R., RA Orrison B.M., Polymeropoulos M.H., Nussbaum R.L.; RT "Human and mouse alpha-synuclein genes: comparative genomic sequence RT analysis and identification of a novel gene regulatory element."; RL Genome Res. 11:78-86(2001). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Hu X., Xu Y., Peng X., Yuan J., Qiang B.; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PROTEIN SEQUENCE OF 59-96, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [13] RP TISSUE SPECIFICITY. RX PubMed=8194594; DOI=10.1016/0014-5793(94)00395-5; RA Jakes R., Spillantini M.G., Goedert M.; RT "Identification of two distinct synucleins from human brain."; RL FEBS Lett. 345:27-32(1994). RN [14] RP PHOSPHORYLATION AT SER-87 AND SER-129 BY CK1 AND CK2. RX PubMed=10617630; DOI=10.1074/jbc.275.1.390; RA Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T., RA Meijer L., Kahle P.J., Haass C.; RT "Constitutive phosphorylation of the Parkinson's disease associated alpha- RT synuclein."; RL J. Biol. Chem. 275:390-397(2000). RN [15] RP PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE. RX PubMed=10852916; DOI=10.1074/jbc.m003542200; RA Pronin A.N., Morris A.J., Surguchov A., Benovic J.L.; RT "Synucleins are a novel class of substrates for G protein-coupled receptor RT kinases."; RL J. Biol. Chem. 275:26515-26522(2000). RN [16] RP PHOSPHORYLATION AT TYR-125 BY FYN. RX PubMed=11162638; DOI=10.1006/bbrc.2000.4253; RA Nakamura T., Yamashita H., Takahashi T., Nakamura S.; RT "Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125."; RL Biochem. Biophys. Res. Commun. 280:1085-1092(2001). RN [17] RP INTERACTION WITH PHOSPHOLIPASE D. RX PubMed=11821392; DOI=10.1074/jbc.m110414200; RA Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y., Wolozin B., RA Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H., Hahn S.J., RA Kim M.S., Jo Y.H., Min do S.; RT "Alpha-synuclein interacts with phospholipase D isozymes and inhibits RT pervanadate-induced phospholipase D activation in human embryonic kidney- RT 293 cells."; RL J. Biol. Chem. 277:12334-12342(2002). RN [18] RP PHOSPHORYLATION AT SER-129. RX PubMed=11813001; DOI=10.1038/ncb748; RA Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., RA Goldberg M.S., Shen J., Takio K., Iwatsubo T.; RT "alpha-Synuclein is phosphorylated in synucleinopathy lesions."; RL Nat. Cell Biol. 4:160-164(2002). RN [19] RP INTERACTION WITH HISTONES, AND SUBCELLULAR LOCATION. RX PubMed=12859192; DOI=10.1021/bi0341152; RA Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S., RA Di Monte D.A., Uversky V.N., Fink A.L.; RT "Nuclear localization of alpha-synuclein and its interaction with RT histones."; RL Biochemistry 42:8465-8471(2003). RN [20] RP ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS. RX PubMed=12859200; DOI=10.1021/bi027363r; RA Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H., RA Ischiropoulos H., Trojanowski J.Q., Lee V.M.; RT "Role of alpha-synuclein carboxy-terminus on fibril formation in vitro."; RL Biochemistry 42:8530-8540(2003). RN [21] RP REVIEW. RX PubMed=12558071; DOI=10.2174/1566524033361690; RA Alves da Costa C.; RT "Recent advances on alpha-synuclein cell biology: functions and RT dysfunctions."; RL Curr. Mol. Med. 3:17-24(2003). RN [22] RP MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION OF RP VARIANT THR-53, AND PHOSPHORYLATION AT TYR-125. RX PubMed=12893833; DOI=10.1074/jbc.m213217200; RA Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H., Avraham H., RA Avraham S., Yasuda M., Matsumoto M.; RT "Identification and characterization of a novel Pyk2/related adhesion focal RT tyrosine kinase-associated protein that inhibits alpha-synuclein RT phosphorylation."; RL J. Biol. Chem. 278:42225-42233(2003). RN [23] RP INTERACTION WITH RPH3A AND RAB3A. RX PubMed=15207266; DOI=10.1016/j.nbd.2004.01.001; RA Dalfo E., Barrachina M., Rosa J.L., Ambrosio S., Ferrer I.; RT "Abnormal alpha-synuclein interactions with rab3a and rabphilin in diffuse RT Lewy body disease."; RL Neurobiol. Dis. 16:92-97(2004). RN [24] RP SUBCELLULAR LOCATION. RX PubMed=15282274; DOI=10.1523/jneurosci.1594-04.2004; RA Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D., Edwards R.H.; RT "Lipid rafts mediate the synaptic localization of alpha-synuclein."; RL J. Neurosci. 24:6715-6723(2004). RN [25] RP FIBRILS FORMATION, DOMAIN NAC, AND MUTAGENESIS OF 67-GLY--VAL-71; RP 71-VAL--VAL-82; 76-ALA-VAL-77; VAL-77; ALA-78 AND 85-ALA--PHE-94. RX PubMed=19722699; DOI=10.1021/bi900539p; RA Waxman E.A., Mazzulli J.R., Giasson B.I.; RT "Characterization of hydrophobic residue requirements for alpha-synuclein RT fibrillization."; RL Biochemistry 48:9427-9436(2009). RN [26] RP FUNCTION, AND INTERACTION WITH VAMP2 AND SNAP25. RX PubMed=20798282; DOI=10.1126/science.1195227; RA Burre J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Suedhof T.C.; RT "Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro."; RL Science 329:1663-1667(2010). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [28] RP COPPER-BINDING, AND MUTAGENESIS OF ASP-2 AND HIS-50. RX PubMed=21319811; DOI=10.1021/bi101912q; RA Dudzik C.G., Walter E.D., Millhauser G.L.; RT "Coordination features and affinity of the Cu(2)+ site in the alpha- RT synuclein protein of Parkinson's disease."; RL Biochemistry 50:1771-1777(2011). RN [29] RP SUBUNIT. RX PubMed=21841800; DOI=10.1038/nature10324; RA Bartels T., Choi J.G., Selkoe D.J.; RT "alpha-Synuclein occurs physiologically as a helically folded tetramer that RT resists aggregation."; RL Nature 477:107-110(2011). RN [30] RP INTERACTION WITH SERF1A. RX PubMed=22854022; DOI=10.1016/j.celrep.2012.06.012; RA Falsone S.F., Meyer N.H., Schrank E., Leitinger G., Pham C.L., RA Fodero-Tavoletti M.T., Holmberg M., Dulle M., Scicluna B., Gesslbauer B., RA Rueckert H.M., Wagner G.E., Merle D.A., Nollen E.A., Kungl A.J., Hill A.F., RA Cappai R., Zangger K.; RT "SERF protein is a direct modifier of amyloid fiber assembly."; RL Cell Rep. 2:358-371(2012). RN [31] RP ACETYLATION AT MET-1. RX PubMed=22407793; DOI=10.1002/pro.2056; RA Trexler A.J., Rhoades E.; RT "N-Terminal acetylation is critical for forming alpha-helical oligomer of RT alpha-synuclein."; RL Protein Sci. 21:601-605(2012). RN [32] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC6A3. RX PubMed=26442590; DOI=10.1074/jbc.m115.691592; RA Butler B., Saha K., Rana T., Becker J.P., Sambo D., Davari P., RA Goodwin J.S., Khoshbouei H.; RT "Dopamine Transporter Activity Is Modulated by alpha-Synuclein."; RL J. Biol. Chem. 290:29542-29554(2015). RN [33] RP INTERACTION WITH STXBP1, AND SUBCELLULAR LOCATION. RX PubMed=27597756; DOI=10.1083/jcb.201512016; RA Chai Y.J., Sierecki E., Tomatis V.M., Gormal R.S., Giles N., Morrow I.C., RA Xia D., Goetz J., Parton R.G., Collins B.M., Gambin Y., Meunier F.A.; RT "Munc18-1 is a molecular chaperone for alpha-synuclein, controlling its RT self-replicating aggregation."; RL J. Cell Biol. 214:705-718(2016). RN [34] RP FUNCTION. RX PubMed=28288128; DOI=10.1038/nn.4529; RA Logan T., Bendor J., Toupin C., Thorn K., Edwards R.H.; RT "alpha-Synuclein promotes dilation of the exocytotic fusion pore."; RL Nat. Neurosci. 20:681-689(2017). RN [35] RP FUNCTION. RX PubMed=30404828; DOI=10.1242/jcs.213017; RA Huang C.C., Chiu T.Y., Lee T.Y., Hsieh H.J., Lin C.C., Kao L.S.; RT "Soluble alpha-synuclein facilitates priming and fusion by releasing Ca2+ RT from the thapsigargin-sensitive Ca2+ pool in PC12 cells."; RL J. Cell Sci. 131:0-0(2018). RN [36] RP INTERACTION WITH DDX10, AND SUBCELLULAR LOCATION. RX PubMed=33657088; DOI=10.1371/journal.pgen.1009407; RA Popova B., Wang D., Paetz C., Akkermann D., Lazaro D.F., Galka D., RA Kolog Gulko M., Bohnsack M.T., Moebius W., Bohnsack K.E., Outeiro T.F., RA Braus G.H.; RT "DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of alpha-synuclein RT toxicity and oligomerization."; RL PLoS Genet. 17:e1009407-e1009407(2021). RN [37] RP INTERACTION WITH SERF1A, AND SUBCELLULAR LOCATION. RX PubMed=31034892; DOI=10.1016/j.jmb.2019.04.031; RA Merle D.A., Witternigg A., Tam-Amersdorfer C., Hartlmueller C., RA Spreitzer E., Schrank E., Wagner-Lichtenegger S., Werzer O., Zangger K., RA Kungl A.J., Madl T., Meyer N.H., Falsone S.F.; RT "Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered RT Protein Complex."; RL J. Mol. Biol. 431:2581-2598(2019). RN [38] RP STRUCTURE BY NMR IN COMPLEX WITH DETERGENT MICELLES. RX PubMed=15615727; DOI=10.1074/jbc.m411805200; RA Ulmer T.S., Bax A., Cole N.B., Nussbaum R.L.; RT "Structure and dynamics of micelle-bound human alpha-synuclein."; RL J. Biol. Chem. 280:9595-9603(2005). RN [39] RP STRUCTURE BY NMR OF 1-12, INTERACTION WITH SNCAIP, AND SUBCELLULAR RP LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 1-57 AND 58-79. RX PubMed=21462277; DOI=10.1002/pro.630; RA Zhao M., Cascio D., Sawaya M.R., Eisenberg D.; RT "Structures of segments of alpha-synuclein fused to maltose-binding protein RT suggest intermediate states during amyloid formation."; RL Protein Sci. 20:996-1004(2011). RN [41] RP STRUCTURE BY NMR OF 1-19, AND INTERACTION WITH CALM1. RX PubMed=23607618; DOI=10.1021/bi400199p; RA Gruschus J.M., Yap T.L., Pistolesi S., Maltsev A.S., Lee J.C.; RT "NMR structure of calmodulin complexed to an N-terminally acetylated alpha- RT synuclein peptide."; RL Biochemistry 52:3436-3445(2013). RN [42] RP STRUCTURE BY ELECTRON MICROSCOPY (1.41 ANGSTROMS) OF 47-56 AND 68-78. RX PubMed=26352473; DOI=10.1038/nature15368; RA Rodriguez J.A., Ivanova M.I., Sawaya M.R., Cascio D., Reyes F.E., Shi D., RA Sangwan S., Guenther E.L., Johnson L.M., Zhang M., Jiang L., Arbing M.A., RA Nannenga B.L., Hattne J., Whitelegge J., Brewster A.S., Messerschmidt M., RA Boutet S., Sauter N.K., Gonen T., Eisenberg D.S.; RT "Structure of the toxic core of alpha-synuclein from invisible crystals."; RL Nature 525:486-490(2015). RN [43] RP STRUCTURE BY NMR. RX PubMed=27018801; DOI=10.1038/nsmb.3194; RA Tuttle M.D., Comellas G., Nieuwkoop A.J., Covell D.J., Berthold D.A., RA Kloepper K.D., Courtney J.M., Kim J.K., Barclay A.M., Kendall A., Wan W., RA Stubbs G., Schwieters C.D., Lee V.M., George J.M., Rienstra C.M.; RT "Solid-state NMR structure of a pathogenic fibril of full-length human RT alpha-synuclein."; RL Nat. Struct. Mol. Biol. 23:409-415(2016). RN [44] RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS). RX PubMed=30190461; DOI=10.1038/s41467-018-05971-2; RA Li B., Ge P., Murray K.A., Sheth P., Zhang M., Nair G., Sawaya M.R., RA Shin W.S., Boyer D.R., Ye S., Eisenberg D.S., Zhou Z.H., Jiang L.; RT "Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a RT common structural kernel."; RL Nat. Commun. 9:3609-3609(2018). RN [45] RP VARIANT PARK1 THR-53. RX PubMed=9197268; DOI=10.1126/science.276.5321.2045; RA Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., RA Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., RA Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., RA Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I., Nussbaum R.L.; RT "Mutation in the alpha-synuclein gene identified in families with RT Parkinson's disease."; RL Science 276:2045-2047(1997). RN [46] RP VARIANT PARK1 PRO-30. RX PubMed=9462735; DOI=10.1038/ng0298-106; RA Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S., RA Przuntek H., Epplen J.T., Schoels L., Riess O.; RT "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's RT disease."; RL Nat. Genet. 18:106-108(1998). RN [47] RP VARIANT PARK1/DLB LYS-46. RX PubMed=14755719; DOI=10.1002/ana.10795; RA Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., RA Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., RA Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G.; RT "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body RT dementia."; RL Ann. Neurol. 55:164-173(2004). RN [48] RP CHARACTERIZATION OF VARIANT LYS-46. RX PubMed=15498564; DOI=10.1016/j.febslet.2004.09.038; RA Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B., Crowther R.A., RA Goedert M.; RT "Mutation E46K increases phospholipid binding and assembly into filaments RT of human alpha-synuclein."; RL FEBS Lett. 576:363-368(2004). RN [49] RP VARIANT PARK1 GLN-50. RX PubMed=23457019; DOI=10.1002/mds.25421; RA Appel-Cresswell S., Vilarino-Guell C., Encarnacion M., Sherman H., Yu I., RA Shah B., Weir D., Thompson C., Szu-Tu C., Trinh J., Aasly J.O., Rajput A., RA Rajput A.H., Jon Stoessl A., Farrer M.J.; RT "Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's RT disease."; RL Mov. Disord. 28:811-813(2013). RN [50] RP VARIANT PARK1 GLN-50, AND CHARACTERIZATION OF VARIANT PARK1 GLN-50. RX PubMed=23427326; DOI=10.1212/wnl.0b013e31828727ba; RA Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M., RA Millhauser G.L., Houlden H., Schapira A.H.; RT "A novel alpha-synuclein missense mutation in Parkinson disease."; RL Neurology 80:1062-1064(2013). RN [51] RP CHARACTERIZATION OF VARIANT PARK1 GLN-50, SUBCELLULAR LOCATION, SUBUNIT, RP AND PHOSPHORYLATION AT SER-129. RX PubMed=24936070; DOI=10.1074/jbc.m114.553297; RA Khalaf O., Fauvet B., Oueslati A., Dikiy I., Mahul-Mellier A.L., RA Ruggeri F.S., Mbefo M.K., Vercruysse F., Dietler G., Lee S.J., Eliezer D., RA Lashuel H.A.; RT "The H50Q mutation enhances alpha-synuclein aggregation, secretion, and RT toxicity."; RL J. Biol. Chem. 289:21856-21876(2014). RN [52] RP CHARACTERIZATION OF VARIANTS PARK1 PRO-30; LYS-46; GLN-50 AND THR-53, RP MUTAGENESIS OF GLU-35 AND GLU-57, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=25561023; DOI=10.1021/cn500332w; RA Tsigelny I.F., Sharikov Y., Kouznetsova V.L., Greenberg J.P., Wrasidlo W., RA Overk C., Gonzalez T., Trejo M., Spencer B., Kosberg K., Masliah E.; RT "Molecular determinants of alpha-synuclein mutants' oligomerization and RT membrane interactions."; RL ACS Chem. Neurosci. 6:403-416(2015). CC -!- FUNCTION: Neuronal protein that plays several roles in synaptic CC activity such as regulation of synaptic vesicle trafficking and CC subsequent neurotransmitter release (PubMed:20798282, PubMed:26442590, CC PubMed:28288128, PubMed:30404828). Participates as a monomer in CC synaptic vesicle exocytosis by enhancing vesicle priming, fusion and CC dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). CC Mechanistically, acts by increasing local Ca(2+) release from CC microdomains which is essential for the enhancement of ATP-induced CC exocytosis (PubMed:30404828). Also acts as a molecular chaperone in its CC multimeric membrane-bound state, assisting in the folding of synaptic CC fusion components called SNAREs (Soluble NSF Attachment Protein CC REceptors) at presynaptic plasma membrane in conjunction with cysteine CC string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity CC is important to sustain normal SNARE-complex assembly during aging CC (PubMed:20798282). Also plays a role in the regulation of the dopamine CC neurotransmission by associating with the dopamine transporter (DAT1) CC and thereby modulating its activity (PubMed:26442590). CC {ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:26442590, CC ECO:0000269|PubMed:28288128, ECO:0000269|PubMed:30404828}. CC -!- SUBUNIT: Soluble monomer. Homotetramer (PubMed:21841800). A dynamic CC intracellular population of tetramers and monomers coexists normally CC and the tetramer plays an essential role in maintaining homeostasis CC (PubMed:21841800). Interacts with UCHL1 (By similarity). Interacts with CC phospholipase D and histones. Interacts (via N-terminus) with CC synphilin-1/SNCAIP; this interaction promotes formation of SNCA CC inclusions in the cytoplasm (PubMed:19762560). Interacts with CALM1 CC (PubMed:23607618). Interacts with STXBP1; this interaction controls CC SNCA self-replicating aggregation (PubMed:27597756). Interacts with CC SNARE components VAMP2 and SNAP25; these interactions allows SNARE CC complex assembly and integrity (PubMed:20798282). Interacts with RPH3A CC and RAB3A (PubMed:15207266). Interacts with SERF1A; this interaction CC promotes the aggregation of SNCA (PubMed:22854022, PubMed:31034892). CC Interacts with SEPTIN4 (By similarity). Interacts with DDX10; this CC interaction causes DDX10 mislocalization to the nucleoplasm and CC cytoplasmic inclusions (PubMed:33657088). CC {ECO:0000250|UniProtKB:O55042, ECO:0000250|UniProtKB:P37377, CC ECO:0000269|PubMed:15207266, ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:21841800, CC ECO:0000269|PubMed:22854022, ECO:0000269|PubMed:23607618, CC ECO:0000269|PubMed:27597756, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. CC -!- INTERACTION: CC P37840; Q6PCB6: ABHD17C; NbExp=3; IntAct=EBI-985879, EBI-22011868; CC P37840; P00519: ABL1; NbExp=3; IntAct=EBI-985879, EBI-375543; CC P37840; P00519-1: ABL1; NbExp=6; IntAct=EBI-985879, EBI-5278159; CC P37840; P00519-2: ABL1; NbExp=5; IntAct=EBI-985879, EBI-9254597; CC P37840; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-985879, EBI-25840993; CC P37840; P63010-2: AP2B1; NbExp=3; IntAct=EBI-985879, EBI-11529439; CC P37840; O00203: AP3B1; NbExp=3; IntAct=EBI-985879, EBI-1044383; CC P37840; P02647: APOA1; NbExp=3; IntAct=EBI-985879, EBI-701692; CC P37840; P02649: APOE; NbExp=11; IntAct=EBI-985879, EBI-1222467; CC P37840; P05067: APP; NbExp=6; IntAct=EBI-985879, EBI-77613; CC P37840; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-985879, EBI-10694449; CC P37840; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-985879, EBI-2875816; CC P37840; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-985879, EBI-10186132; CC P37840; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-985879, EBI-707573; CC P37840; P18847: ATF3; NbExp=3; IntAct=EBI-985879, EBI-712767; CC P37840; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-985879, EBI-1048913; CC P37840; P46379-2: BAG6; NbExp=3; IntAct=EBI-985879, EBI-10988864; CC P37840; Q07812: BAX; NbExp=4; IntAct=EBI-985879, EBI-516580; CC P37840; Q07817: BCL2L1; NbExp=3; IntAct=EBI-985879, EBI-78035; CC P37840; O15392: BIRC5; NbExp=3; IntAct=EBI-985879, EBI-518823; CC P37840; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-985879, EBI-2837444; CC P37840; Q5SZD1: C6orf141; NbExp=3; IntAct=EBI-985879, EBI-10697767; CC P37840; P62158: CALM3; NbExp=3; IntAct=EBI-985879, EBI-397435; CC P37840; Q8N5S9-2: CAMKK1; NbExp=3; IntAct=EBI-985879, EBI-25850646; CC P37840; P55212: CASP6; NbExp=3; IntAct=EBI-985879, EBI-718729; CC P37840; Q7Z7K6: CENPV; NbExp=4; IntAct=EBI-985879, EBI-1210604; CC P37840; Q9HD42: CHMP1A; NbExp=3; IntAct=EBI-985879, EBI-1057156; CC P37840; Q16740: CLPP; NbExp=3; IntAct=EBI-985879, EBI-1056029; CC P37840; P10909: CLU; NbExp=4; IntAct=EBI-985879, EBI-1104674; CC P37840; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-985879, EBI-350590; CC P37840; Q8IUI8: CRLF3; NbExp=3; IntAct=EBI-985879, EBI-2872414; CC P37840; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-985879, EBI-9087876; CC P37840; P99999: CYCS; NbExp=3; IntAct=EBI-985879, EBI-446479; CC P37840; O75398: DEAF1; NbExp=3; IntAct=EBI-985879, EBI-718185; CC P37840; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-985879, EBI-25842538; CC P37840; O60479: DLX3; NbExp=3; IntAct=EBI-985879, EBI-3908248; CC P37840; A0AVK6: E2F8; NbExp=3; IntAct=EBI-985879, EBI-7779316; CC P37840; O75530-2: EED; NbExp=3; IntAct=EBI-985879, EBI-11132357; CC P37840; O00472: ELL2; NbExp=3; IntAct=EBI-985879, EBI-395274; CC P37840; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-985879, EBI-9246952; CC P37840; O00471: EXOC5; NbExp=3; IntAct=EBI-985879, EBI-949824; CC P37840; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-985879, EBI-396453; CC P37840; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-985879, EBI-10226858; CC P37840; Q6PIV2: FOXR1; NbExp=3; IntAct=EBI-985879, EBI-10253815; CC P37840; P02792: FTL; NbExp=3; IntAct=EBI-985879, EBI-713279; CC P37840; P06241: FYN; NbExp=3; IntAct=EBI-985879, EBI-515315; CC P37840; P06241-3: FYN; NbExp=3; IntAct=EBI-985879, EBI-10691738; CC P37840; P62879: GNB2; NbExp=3; IntAct=EBI-985879, EBI-356942; CC P37840; P49841: GSK3B; NbExp=2; IntAct=EBI-985879, EBI-373586; CC P37840; P68431: H3C12; NbExp=3; IntAct=EBI-985879, EBI-79722; CC P37840; Q71DI3: H3C15; NbExp=3; IntAct=EBI-985879, EBI-750650; CC P37840; Q969S8: HDAC10; NbExp=3; IntAct=EBI-985879, EBI-301762; CC P37840; Q9HCC6: HES4; NbExp=3; IntAct=EBI-985879, EBI-2680288; CC P37840; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-985879, EBI-25845242; CC P37840; P09017: HOXC4; NbExp=3; IntAct=EBI-985879, EBI-3923226; CC P37840; P08107: HSPA1B; NbExp=7; IntAct=EBI-985879, EBI-629985; CC P37840; P42858: HTT; NbExp=4; IntAct=EBI-985879, EBI-466029; CC P37840; P80217-2: IFI35; NbExp=3; IntAct=EBI-985879, EBI-12823003; CC P37840; Q16352: INA; NbExp=3; IntAct=EBI-985879, EBI-366258; CC P37840; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-985879, EBI-21911304; CC P37840; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-985879, EBI-2127319; CC P37840; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-985879, EBI-2796400; CC P37840; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-985879, EBI-714379; CC P37840; Q92876: KLK6; NbExp=3; IntAct=EBI-985879, EBI-2432309; CC P37840; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-985879, EBI-1044640; CC P37840; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-985879, EBI-11985629; CC P37840; P13473-2: LAMP2; NbExp=3; IntAct=EBI-985879, EBI-21591415; CC P37840; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-985879, EBI-1108377; CC P37840; Q9H2C1: LHX5; NbExp=3; IntAct=EBI-985879, EBI-25835523; CC P37840; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-985879, EBI-10258746; CC P37840; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-985879, EBI-739832; CC P37840; Q8N448: LNX2; NbExp=3; IntAct=EBI-985879, EBI-2340947; CC P37840; A2RU56: LOC401296; NbExp=3; IntAct=EBI-985879, EBI-9088215; CC P37840; Q5S007: LRRK2; NbExp=6; IntAct=EBI-985879, EBI-5323863; CC P37840; O95777: LSM8; NbExp=3; IntAct=EBI-985879, EBI-347779; CC P37840; P07948: LYN; NbExp=3; IntAct=EBI-985879, EBI-79452; CC P37840; Q8TD91-2: MAGEC3; NbExp=3; IntAct=EBI-985879, EBI-10694180; CC P37840; P10636-6: MAPT; NbExp=3; IntAct=EBI-985879, EBI-7796455; CC P37840; P10636-8: MAPT; NbExp=12; IntAct=EBI-985879, EBI-366233; CC P37840; Q8N6F8: METTL27; NbExp=3; IntAct=EBI-985879, EBI-8487781; CC P37840; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-985879, EBI-4397720; CC P37840; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-985879, EBI-21250407; CC P37840; Q8N594: MPND; NbExp=3; IntAct=EBI-985879, EBI-2512452; CC P37840; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-985879, EBI-9092052; CC P37840; P00414: MT-CO3; NbExp=3; IntAct=EBI-985879, EBI-3932264; CC P37840; P02795: MT2A; NbExp=3; IntAct=EBI-985879, EBI-996616; CC P37840; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-985879, EBI-10698053; CC P37840; O00746: NME4; NbExp=3; IntAct=EBI-985879, EBI-744871; CC P37840; O15381-5: NVL; NbExp=3; IntAct=EBI-985879, EBI-18577082; CC P37840; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-985879, EBI-25888682; CC P37840; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-985879, EBI-1058491; CC P37840; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-985879, EBI-25830200; CC P37840; Q6VY07: PACS1; NbExp=3; IntAct=EBI-985879, EBI-2555014; CC P37840; O96013-2: PAK4; NbExp=3; IntAct=EBI-985879, EBI-21659863; CC P37840; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-985879, EBI-17159452; CC P37840; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-985879, EBI-6309018; CC P37840; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-985879, EBI-716063; CC P37840; O75925: PIAS1; NbExp=3; IntAct=EBI-985879, EBI-629434; CC P37840; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-985879, EBI-12891828; CC P37840; P17252: PRKCA; NbExp=3; IntAct=EBI-985879, EBI-1383528; CC P37840; Q02156: PRKCE; NbExp=3; IntAct=EBI-985879, EBI-706254; CC P37840; O60260-5: PRKN; NbExp=8; IntAct=EBI-985879, EBI-21251460; CC P37840; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-985879, EBI-5280197; CC P37840; P62191: PSMC1; NbExp=3; IntAct=EBI-985879, EBI-357598; CC P37840; P17980: PSMC3; NbExp=6; IntAct=EBI-985879, EBI-359720; CC P37840; Q9UI14: RABAC1; NbExp=4; IntAct=EBI-985879, EBI-712367; CC P37840; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-985879, EBI-14093916; CC P37840; P62826: RAN; NbExp=3; IntAct=EBI-985879, EBI-286642; CC P37840; Q13702-2: RAPSN; NbExp=3; IntAct=EBI-985879, EBI-22012855; CC P37840; P57052: RBM11; NbExp=3; IntAct=EBI-985879, EBI-741332; CC P37840; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-985879, EBI-714023; CC P37840; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-985879, EBI-21535400; CC P37840; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-985879, EBI-25829984; CC P37840; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-985879, EBI-749039; CC P37840; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-985879, EBI-914207; CC P37840; Q96D59: RNF183; NbExp=3; IntAct=EBI-985879, EBI-743938; CC P37840; Q8N488: RYBP; NbExp=3; IntAct=EBI-985879, EBI-752324; CC P37840; O75446: SAP30; NbExp=3; IntAct=EBI-985879, EBI-632609; CC P37840; O00560: SDCBP; NbExp=3; IntAct=EBI-985879, EBI-727004; CC P37840; O43236: SEPTIN4; NbExp=3; IntAct=EBI-985879, EBI-1047513; CC P37840; O75920-2: SERF1B; NbExp=4; IntAct=EBI-985879, EBI-21283682; CC P37840; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-985879, EBI-10182463; CC P37840; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-985879, EBI-358545; CC P37840; Q01959: SLC6A3; NbExp=3; IntAct=EBI-985879, EBI-6661445; CC P37840; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-985879, EBI-9845742; CC P37840; P37840: SNCA; NbExp=51; IntAct=EBI-985879, EBI-985879; CC P37840; Q9Y6H5: SNCAIP; NbExp=22; IntAct=EBI-985879, EBI-717182; CC P37840; Q9Y6H5-2: SNCAIP; NbExp=2; IntAct=EBI-985879, EBI-15577909; CC P37840; Q16143: SNCB; NbExp=3; IntAct=EBI-985879, EBI-727106; CC P37840; P00441: SOD1; NbExp=9; IntAct=EBI-985879, EBI-990792; CC P37840; P23497-2: SP100; NbExp=3; IntAct=EBI-985879, EBI-6589365; CC P37840; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-985879, EBI-11959123; CC P37840; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-985879, EBI-7067260; CC P37840; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-985879, EBI-8345366; CC P37840; Q13501: SQSTM1; NbExp=3; IntAct=EBI-985879, EBI-307104; CC P37840; O75886: STAM2; NbExp=3; IntAct=EBI-985879, EBI-373258; CC P37840; Q16623: STX1A; NbExp=2; IntAct=EBI-985879, EBI-712466; CC P37840; Q9BR01-2: SULT4A1; NbExp=3; IntAct=EBI-985879, EBI-25831443; CC P37840; Q92797-2: SYMPK; NbExp=3; IntAct=EBI-985879, EBI-21560407; CC P37840; Q16650: TBR1; NbExp=3; IntAct=EBI-985879, EBI-1047158; CC P37840; Q13569: TDG; NbExp=3; IntAct=EBI-985879, EBI-348333; CC P37840; P28347-2: TEAD1; NbExp=3; IntAct=EBI-985879, EBI-12151837; CC P37840; Q15554-4: TERF2; NbExp=3; IntAct=EBI-985879, EBI-25840535; CC P37840; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-985879, EBI-74615; CC P37840; O94811: TPPP; NbExp=8; IntAct=EBI-985879, EBI-3927802; CC P37840; P19474: TRIM21; NbExp=3; IntAct=EBI-985879, EBI-81290; CC P37840; P68363: TUBA1B; NbExp=3; IntAct=EBI-985879, EBI-487083; CC P37840; P07437: TUBB; NbExp=3; IntAct=EBI-985879, EBI-350864; CC P37840; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-985879, EBI-1797313; CC P37840; P62987: UBA52; NbExp=3; IntAct=EBI-985879, EBI-357304; CC P37840; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-985879, EBI-749370; CC P37840; O15205: UBD; NbExp=3; IntAct=EBI-985879, EBI-6657186; CC P37840; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-985879, EBI-11530712; CC P37840; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-985879, EBI-17761788; CC P37840; O75604-3: USP2; NbExp=3; IntAct=EBI-985879, EBI-10696113; CC P37840; P63027: VAMP2; NbExp=5; IntAct=EBI-985879, EBI-520113; CC P37840; P40337-2: VHL; NbExp=3; IntAct=EBI-985879, EBI-12157263; CC P37840; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-985879, EBI-11141397; CC P37840; O00308: WWP2; NbExp=3; IntAct=EBI-985879, EBI-743923; CC P37840; Q04917: YWHAH; NbExp=4; IntAct=EBI-985879, EBI-306940; CC P37840; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-985879, EBI-25842419; CC P37840; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-985879, EBI-2682299; CC P37840; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-985879, EBI-8834821; CC P37840; Q8N895: ZNF366; NbExp=3; IntAct=EBI-985879, EBI-2813661; CC P37840; Q8N988-2: ZNF557; NbExp=3; IntAct=EBI-985879, EBI-10699005; CC P37840; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-985879, EBI-8490788; CC P37840; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-985879, EBI-12021938; CC P37840; A8K878; NbExp=3; IntAct=EBI-985879, EBI-25831303; CC P37840; P0DTC9: N; Xeno; NbExp=2; IntAct=EBI-985879, EBI-25475856; CC P37840; Q61327: Slc6a3; Xeno; NbExp=5; IntAct=EBI-985879, EBI-7839708; CC P37840-1; P37840-1: SNCA; NbExp=21; IntAct=EBI-9684465, EBI-9684465; CC P37840-1; Q04917: YWHAH; NbExp=9; IntAct=EBI-9684465, EBI-306940; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:26442590, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. Membrane {ECO:0000269|PubMed:24936070}. CC Nucleus {ECO:0000269|PubMed:12859192, ECO:0000269|PubMed:24936070}. CC Synapse {ECO:0000269|PubMed:15282274}. Secreted CC {ECO:0000269|PubMed:24936070}. Cell projection, axon CC {ECO:0000250|UniProtKB:O55042}. Note=Membrane-bound in dopaminergic CC neurons (PubMed:15282274). Expressed and colocalized with SEPTIN4 in CC dopaminergic axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:O55042, CC ECO:0000269|PubMed:15282274}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=NACP140; CC IsoId=P37840-1; Sequence=Displayed; CC Name=2-4; Synonyms=NACP112; CC IsoId=P37840-2; Sequence=VSP_006364; CC Name=2-5; CC IsoId=P37840-3; Sequence=VSP_006363; CC -!- TISSUE SPECIFICITY: Highly expressed in presynaptic terminals in the CC central nervous system. Expressed principally in brain. CC {ECO:0000269|PubMed:8194594}. CC -!- DOMAIN: The 'non A-beta component of Alzheimer disease amyloid plaque' CC domain (NAC domain) is involved in fibrils formation. The middle CC hydrophobic region forms the core of the filaments. The C-terminus may CC regulate aggregation and determine the diameter of the filaments. CC {ECO:0000269|PubMed:19722699}. CC -!- PTM: Phosphorylated, predominantly on serine residues. Phosphorylation CC by CK1 appears to occur on residues distinct from the residue CC phosphorylated by other kinases. Phosphorylation of Ser-129 is CC selective and extensive in synucleinopathy lesions. In vitro, CC phosphorylation at Ser-129 promoted insoluble fibril formation. CC Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic CC stress. {ECO:0000269|PubMed:10617630, ECO:0000269|PubMed:10852916, CC ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11813001, CC ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:24936070}. CC -!- PTM: Hallmark lesions of neurodegenerative synucleinopathies contain CC alpha-synuclein that is modified by nitration of tyrosine residues and CC possibly by dityrosine cross-linking to generated stable oligomers. CC -!- PTM: Ubiquitinated. The predominant conjugate is the diubiquitinated CC form. {ECO:0000250|UniProtKB:P37377}. CC -!- PTM: Acetylation at Met-1 seems to be important for proper folding and CC native oligomeric structure. {ECO:0000269|PubMed:22407793}. CC -!- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant CC polymerization into fibrils, are associated with several CC neurodegenerative diseases (synucleinopathies). SNCA fibrillar CC aggregates represent the major non A-beta component of Alzheimer CC disease amyloid plaque, and a major component of Lewy body inclusions. CC They are also found within Lewy body (LB)-like intraneuronal CC inclusions, glial inclusions and axonal spheroids in neurodegeneration CC with brain iron accumulation type 1. CC -!- DISEASE: Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601]: CC A complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability. Additional CC features are characteristic postural abnormalities, dysautonomia, CC dystonic cramps, and dementia. The pathology of Parkinson disease CC involves the loss of dopaminergic neurons in the substantia nigra and CC the presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. The CC disease is progressive and usually manifests after the age of 50 years, CC although early-onset cases (before 50 years) are known. The majority of CC the cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:14755719, CC ECO:0000269|PubMed:23427326, ECO:0000269|PubMed:23457019, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:9197268, ECO:0000269|PubMed:9462735}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543]: CC A complex neurodegenerative disorder with manifestations ranging from CC typical Parkinson disease to dementia with Lewy bodies. Clinical CC features include parkinsonian symptoms (resting tremor, rigidity, CC postural instability and bradykinesia), dementia, diffuse Lewy body CC pathology, autonomic dysfunction, hallucinations and paranoia. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Dementia, Lewy body (DLB) [MIM:127750]: A neurodegenerative CC disorder characterized by mental impairment leading to dementia, CC parkinsonism, fluctuating cognitive function, visual hallucinations, CC falls, syncopal episodes, and sensitivity to neuroleptic medication. CC Brainstem or cortical intraneuronal accumulations of aggregated CC proteins (Lewy bodies) are the only essential pathologic features. CC Patients may also have hippocampal and neocortical senile plaques, CC sometimes in sufficient number to fulfill the diagnostic criteria for CC Alzheimer disease. {ECO:0000269|PubMed:14755719}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the synuclein family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L08850; AAA16117.1; -; mRNA. DR EMBL; L36674; AAA98493.1; -; mRNA. DR EMBL; L36675; AAA98487.1; -; mRNA. DR EMBL; D31839; BAA06625.1; -; mRNA. DR EMBL; U46901; AAC02114.1; -; Genomic_DNA. DR EMBL; U46897; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46898; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46899; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; AF163864; AAG30302.1; -; Genomic_DNA. DR EMBL; AF163864; AAG30303.1; -; Genomic_DNA. DR EMBL; AY049786; AAL15443.1; -; mRNA. DR EMBL; AK290169; BAF82858.1; -; mRNA. DR EMBL; CR457058; CAG33339.1; -; mRNA. DR EMBL; DQ088379; AAY88735.1; -; Genomic_DNA. DR EMBL; CH471057; EAX06036.1; -; Genomic_DNA. DR EMBL; BC013293; AAH13293.1; -; mRNA. DR EMBL; BC108275; AAI08276.1; -; mRNA. DR CCDS; CCDS3634.1; -. [P37840-1] DR CCDS; CCDS43252.1; -. [P37840-2] DR PIR; A49669; A49669. DR PIR; S56746; S56746. DR RefSeq; NP_000336.1; NM_000345.4. [P37840-1] DR RefSeq; NP_001139526.1; NM_001146054.2. [P37840-1] DR RefSeq; NP_001139527.1; NM_001146055.2. [P37840-1] DR RefSeq; NP_001362214.1; NM_001375285.1. [P37840-1] DR RefSeq; NP_001362215.1; NM_001375286.1. [P37840-1] DR RefSeq; NP_001362216.1; NM_001375287.1. [P37840-1] DR RefSeq; NP_001362217.1; NM_001375288.1. [P37840-1] DR RefSeq; NP_009292.1; NM_007308.3. [P37840-2] DR PDB; 1XQ8; NMR; -; A=1-140. DR PDB; 2JN5; NMR; -; A=1-12. DR PDB; 2KKW; NMR; -; A=1-140. DR PDB; 2M55; NMR; -; B=1-19. DR PDB; 2N0A; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 2X6M; X-ray; 1.62 A; B=132-140. DR PDB; 3Q25; X-ray; 1.90 A; A=1-19. DR PDB; 3Q26; X-ray; 1.54 A; A=10-42. DR PDB; 3Q27; X-ray; 1.30 A; A=32-57. DR PDB; 3Q28; X-ray; 1.60 A; A=58-79. DR PDB; 3Q29; X-ray; 2.30 A; A/C=1-19. DR PDB; 4BXL; NMR; -; C=35-56. DR PDB; 4R0U; X-ray; 1.38 A; A=72-78. DR PDB; 4R0W; X-ray; 1.50 A; A=70-76. DR PDB; 4RIK; X-ray; 1.85 A; A=69-77. DR PDB; 4RIL; EM; 1.43 A; A=68-78. DR PDB; 4ZNN; EM; 1.41 A; A=47-56. DR PDB; 5CRW; X-ray; 1.60 A; B=31-41. DR PDB; 6A6B; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J/K/L=37-99. DR PDB; 6CT7; X-ray; 1.90 A; S/T=1-10. DR PDB; 6CU7; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6CU8; EM; 3.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6H6B; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-121. DR PDB; 6I42; X-ray; 1.38 A; B=48-60. DR PDB; 6L1T; EM; 3.22 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6L1U; EM; 3.37 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-140. DR PDB; 6L4S; EM; 3.37 A; A/B/C/D/E/F=45-99. DR PDB; 6LRQ; EM; 3.49 A; A/B/C/D/E/F=1-140. DR PDB; 6OSJ; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSL; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSM; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6PEO; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 6PES; EM; 3.60 A; A/B/C/D/E/V/W/X/Y/Z=1-140. DR PDB; 6RT0; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6RTB; EM; 3.46 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SST; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SSX; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6UFR; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYO; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYP; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYQ; EM; 3.09 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7C1D; EM; 3.80 A; A/B/C/D/E/F=1-140. DR PDB; 7E0F; EM; 3.02 A; A/B/C/D/E/F=1-140. DR PDB; 7L7H; EM; 4.00 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7LC9; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L=41-140. DR PDB; 7NCA; EM; 3.47 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCG; EM; 3.43 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCH; EM; 3.84 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCI; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCJ; EM; 4.23 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCK; EM; 3.18 A; A/B/C/D/E/F=1-140. DR PDB; 7OZG; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7OZH; EM; 3.02 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7STX; EM; 3.14 A; C=1-5. DR PDB; 7UAK; EM; 3.38 A; A/B/C/D/E/F=1-140. DR PDB; 7V47; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7V48; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7V49; EM; 3.40 A; A/B/C=1-140. DR PDB; 7V4A; EM; 3.20 A; A/B/C=1-140. DR PDB; 7V4B; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7V4C; EM; 3.30 A; A/B/F=1-140. DR PDB; 7V4D; EM; 3.50 A; A/B/C/D/E/F=1-140. DR PDB; 7WMM; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7WNZ; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=36-100. DR PDB; 7WO0; EM; 2.70 A; A/B/C/D/E/F/G/O/P/Q/R/S/T/U=35-99. DR PDB; 7XJX; EM; 2.70 A; A/B/C/D/E/F=1-140. DR PDB; 7XO0; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO1; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO2; EM; 3.00 A; A/B/C/D/E/I=1-140. DR PDB; 7XO3; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7YK2; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YK8; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7YNF; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 7YNG; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7YNL; EM; 2.60 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7YNM; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNN; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNO; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNP; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNQ; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNR; EM; 2.90 A; A/B/C/D/E/F=1-140. DR PDB; 7YNS; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7YNT; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8A4L; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J/K/L/M/O/P=1-140. DR PDB; 8A9L; EM; 2.16 A; A=1-140. DR PDB; 8ADS; EM; 3.05 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADU; EM; 3.24 A; A/B/C/D/E=1-140. DR PDB; 8ADV; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADW; EM; 2.95 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8AEX; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8B9V; X-ray; 2.16 A; A=110-119. DR PDB; 8BQV; EM; 2.00 A; A=1-140. DR PDB; 8BQW; EM; 2.30 A; A/C=1-140. DR PDB; 8CE7; EM; 2.70 A; A/C=1-140. DR PDB; 8CEB; EM; 2.70 A; A/C=1-140. DR PDB; 8CYR; EM; 4.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYS; EM; 3.10 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYT; EM; 3.00 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYV; EM; 3.50 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYW; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYX; EM; 3.00 A; A/B/C/D/E/I/J/K/L/M=1-140. DR PDB; 8CYY; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ0; EM; 2.90 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ1; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ2; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ3; EM; 3.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ6; EM; 3.20 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8FPT; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8G0L; EM; 3.39 A; C=1-5. DR PDB; 8GF7; EM; 4.80 A; A/B/C/D/E/F=7-96. DR PDB; 8H03; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8H04; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8H05; EM; 3.40 A; A/B/C=1-140. DR PDB; 8HZB; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZC; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZS; EM; 3.30 A; A/B/C/D/E/F=1-140. DR PDB; 8JEX; EM; 3.10 A; A/B/G/H/K/P=1-140. DR PDB; 8JEY; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 8JJV; X-ray; 1.23 A; B=43-56. DR PDB; 8JLY; X-ray; 1.29 A; B=43-56. DR PDB; 8OG0; X-ray; 1.71 A; P=136-140. DR PDB; 8OJR; NMR; -; A=1-25. DR PDB; 8OL8; NMR; -; A=2-12. DR PDB; 8OQI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PIX; EM; 3.41 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PJO; EM; 2.31 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PK2; EM; 3.26 A; A/B/C/D/E=1-140. DR PDB; 8PK4; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8QPZ; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J/K/L=8-140. DR PDB; 8RI9; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 8RQM; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8RRR; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8UKA; EM; 3.90 A; A/B/C/D/E/a/b/c/d/e=1-140. DR PDB; 8X7B; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7M; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7P; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7Q; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7R; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8XWD; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2P; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2Q; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8ZLI; EM; 3.40 A; A/B/C/D/E/F/I/J/K/L=45-99. DR PDB; 8ZLO; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/O/T=45-99. DR PDB; 8ZLP; EM; 3.50 A; A/B/C/F/G/H=1-98. DR PDB; 8ZMY; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-98. DR PDB; 8ZVY; X-ray; 1.72 A; C/D=121-140. DR PDB; 8ZWH; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWI; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWJ; EM; 3.10 A; A/B/C/D/E/G=1-140. DR PDB; 8ZWK; EM; 3.40 A; A/B/C/D/E/F=1-140. DR PDB; 9C5R; EM; 2.61 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 9CD9; EM; 3.20 A; E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z=1-140. DR PDB; 9CDA; EM; 3.30 A; K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b=1-140. DR PDB; 9CK3; EM; 2.04 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 9CX6; EM; 3.20 A; G/H=1-140. DR PDB; 9D5C; EM; 4.80 A; A/B/C/F/G/H=1-96. DR PDB; 9EUU; EM; 1.93 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9FYP; EM; 2.23 A; I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9HGR; EM; 2.70 A; A/B=1-140. DR PDB; 9HGS; EM; 3.00 A; C=1-140. DR PDB; 9HXA; EM; 3.70 A; A/C=1-140. DR PDB; 9IJP; EM; 3.10 A; B/C/E/G/I/L=1-140. DR PDB; 9O4B; EM; 2.59 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDBsum; 1XQ8; -. DR PDBsum; 2JN5; -. DR PDBsum; 2KKW; -. DR PDBsum; 2M55; -. DR PDBsum; 2N0A; -. DR PDBsum; 2X6M; -. DR PDBsum; 3Q25; -. DR PDBsum; 3Q26; -. DR PDBsum; 3Q27; -. DR PDBsum; 3Q28; -. DR PDBsum; 3Q29; -. DR PDBsum; 4BXL; -. DR PDBsum; 4R0U; -. DR PDBsum; 4R0W; -. DR PDBsum; 4RIK; -. DR PDBsum; 4RIL; -. DR PDBsum; 4ZNN; -. DR PDBsum; 5CRW; -. DR PDBsum; 6A6B; -. DR PDBsum; 6CT7; -. DR PDBsum; 6CU7; -. DR PDBsum; 6CU8; -. DR PDBsum; 6H6B; -. DR PDBsum; 6I42; -. DR PDBsum; 6L1T; -. DR PDBsum; 6L1U; -. DR PDBsum; 6L4S; -. DR PDBsum; 6LRQ; -. DR PDBsum; 6OSJ; -. DR PDBsum; 6OSL; -. DR PDBsum; 6OSM; -. DR PDBsum; 6PEO; -. DR PDBsum; 6PES; -. DR PDBsum; 6RT0; -. DR PDBsum; 6RTB; -. DR PDBsum; 6SST; -. DR PDBsum; 6SSX; -. DR PDBsum; 6UFR; -. DR PDBsum; 6XYO; -. DR PDBsum; 6XYP; -. DR PDBsum; 6XYQ; -. DR PDBsum; 7C1D; -. DR PDBsum; 7E0F; -. DR PDBsum; 7L7H; -. DR PDBsum; 7LC9; -. DR PDBsum; 7NCA; -. DR PDBsum; 7NCG; -. DR PDBsum; 7NCH; -. DR PDBsum; 7NCI; -. DR PDBsum; 7NCJ; -. DR PDBsum; 7NCK; -. DR PDBsum; 7OZG; -. DR PDBsum; 7OZH; -. DR PDBsum; 7STX; -. DR PDBsum; 7UAK; -. DR PDBsum; 7V47; -. DR PDBsum; 7V48; -. DR PDBsum; 7V49; -. DR PDBsum; 7V4A; -. DR PDBsum; 7V4B; -. DR PDBsum; 7V4C; -. DR PDBsum; 7V4D; -. DR PDBsum; 7WMM; -. DR PDBsum; 7WNZ; -. DR PDBsum; 7WO0; -. DR PDBsum; 7XJX; -. DR PDBsum; 7XO0; -. DR PDBsum; 7XO1; -. DR PDBsum; 7XO2; -. DR PDBsum; 7XO3; -. DR PDBsum; 7YK2; -. DR PDBsum; 7YK8; -. DR PDBsum; 7YNF; -. DR PDBsum; 7YNG; -. DR PDBsum; 7YNL; -. DR PDBsum; 7YNM; -. DR PDBsum; 7YNN; -. DR PDBsum; 7YNO; -. DR PDBsum; 7YNP; -. DR PDBsum; 7YNQ; -. DR PDBsum; 7YNR; -. DR PDBsum; 7YNS; -. DR PDBsum; 7YNT; -. DR PDBsum; 8A4L; -. DR PDBsum; 8A9L; -. DR PDBsum; 8ADS; -. DR PDBsum; 8ADU; -. DR PDBsum; 8ADV; -. DR PDBsum; 8ADW; -. DR PDBsum; 8AEX; -. DR PDBsum; 8B9V; -. DR PDBsum; 8BQV; -. DR PDBsum; 8BQW; -. DR PDBsum; 8CE7; -. DR PDBsum; 8CEB; -. DR PDBsum; 8CYR; -. DR PDBsum; 8CYS; -. DR PDBsum; 8CYT; -. DR PDBsum; 8CYV; -. DR PDBsum; 8CYW; -. DR PDBsum; 8CYX; -. DR PDBsum; 8CYY; -. DR PDBsum; 8CZ0; -. DR PDBsum; 8CZ1; -. DR PDBsum; 8CZ2; -. DR PDBsum; 8CZ3; -. DR PDBsum; 8CZ6; -. DR PDBsum; 8FPT; -. DR PDBsum; 8G0L; -. DR PDBsum; 8GF7; -. DR PDBsum; 8H03; -. DR PDBsum; 8H04; -. DR PDBsum; 8H05; -. DR PDBsum; 8HZB; -. DR PDBsum; 8HZC; -. DR PDBsum; 8HZS; -. DR PDBsum; 8JEX; -. DR PDBsum; 8JEY; -. DR PDBsum; 8JJV; -. DR PDBsum; 8JLY; -. DR PDBsum; 8OG0; -. DR PDBsum; 8OJR; -. DR PDBsum; 8OL8; -. DR PDBsum; 8OQI; -. DR PDBsum; 8PIX; -. DR PDBsum; 8PJO; -. DR PDBsum; 8PK2; -. DR PDBsum; 8PK4; -. DR PDBsum; 8QPZ; -. DR PDBsum; 8RI9; -. DR PDBsum; 8RQM; -. DR PDBsum; 8RRR; -. DR PDBsum; 8UKA; -. DR PDBsum; 8X7B; -. DR PDBsum; 8X7L; -. DR PDBsum; 8X7M; -. DR PDBsum; 8X7O; -. DR PDBsum; 8X7P; -. DR PDBsum; 8X7Q; -. DR PDBsum; 8X7R; -. DR PDBsum; 8XWD; -. DR PDBsum; 8Y2P; -. DR PDBsum; 8Y2Q; -. DR PDBsum; 8ZLI; -. DR PDBsum; 8ZLO; -. DR PDBsum; 8ZLP; -. DR PDBsum; 8ZMY; -. DR PDBsum; 8ZVY; -. DR PDBsum; 8ZWH; -. DR PDBsum; 8ZWI; -. DR PDBsum; 8ZWJ; -. DR PDBsum; 8ZWK; -. DR PDBsum; 9C5R; -. DR PDBsum; 9CD9; -. DR PDBsum; 9CDA; -. DR PDBsum; 9CK3; -. DR PDBsum; 9CX6; -. DR PDBsum; 9D5C; -. DR PDBsum; 9EUU; -. DR PDBsum; 9FYP; -. DR PDBsum; 9HGR; -. DR PDBsum; 9HGS; -. DR PDBsum; 9HXA; -. DR PDBsum; 9IJP; -. DR PDBsum; 9O4B; -. DR AlphaFoldDB; P37840; -. DR BMRB; P37840; -. DR EMDB; EMD-0148; -. DR EMDB; EMD-0801; -. DR EMDB; EMD-0803; -. DR EMDB; EMD-0833; -. DR EMDB; EMD-0958; -. DR EMDB; EMD-10305; -. DR EMDB; EMD-10307; -. DR EMDB; EMD-10650; -. DR EMDB; EMD-10651; -. DR EMDB; EMD-10652; -. DR EMDB; EMD-12264; -. DR EMDB; EMD-12265; -. DR EMDB; EMD-12266; -. DR EMDB; EMD-12267; -. DR EMDB; EMD-12268; -. DR EMDB; EMD-12269; -. DR EMDB; EMD-13123; -. DR EMDB; EMD-13124; -. DR EMDB; EMD-15148; -. DR EMDB; EMD-15285; -. DR EMDB; EMD-15369; -. DR EMDB; EMD-15370; -. DR EMDB; EMD-15371; -. DR EMDB; EMD-15372; -. DR EMDB; EMD-15388; -. DR EMDB; EMD-16188; -. DR EMDB; EMD-16189; -. DR EMDB; EMD-16600; -. DR EMDB; EMD-16603; -. DR EMDB; EMD-17111; -. DR EMDB; EMD-17693; -. DR EMDB; EMD-17714; -. DR EMDB; EMD-17723; -. DR EMDB; EMD-17726; -. DR EMDB; EMD-18570; -. DR EMDB; EMD-19184; -. DR EMDB; EMD-19446; -. DR EMDB; EMD-19462; -. DR EMDB; EMD-19986; -. DR EMDB; EMD-20183; -. DR EMDB; EMD-20185; -. DR EMDB; EMD-20186; -. DR EMDB; EMD-20328; -. DR EMDB; EMD-20331; -. DR EMDB; EMD-20759; -. DR EMDB; EMD-23212; -. DR EMDB; EMD-23270; -. DR EMDB; EMD-25438; -. DR EMDB; EMD-26427; -. DR EMDB; EMD-27082; -. DR EMDB; EMD-27083; -. DR EMDB; EMD-27084; -. DR EMDB; EMD-27085; -. DR EMDB; EMD-27086; -. DR EMDB; EMD-27087; -. DR EMDB; EMD-27088; -. DR EMDB; EMD-27089; -. DR EMDB; EMD-27090; -. DR EMDB; EMD-27091; -. DR EMDB; EMD-27092; -. DR EMDB; EMD-27093; -. DR EMDB; EMD-29657; -. DR EMDB; EMD-29980; -. DR EMDB; EMD-30269; -. DR EMDB; EMD-30931; -. DR EMDB; EMD-3094; -. DR EMDB; EMD-3095; -. DR EMDB; EMD-31702; -. DR EMDB; EMD-31703; -. DR EMDB; EMD-31704; -. DR EMDB; EMD-31705; -. DR EMDB; EMD-31706; -. DR EMDB; EMD-31707; -. DR EMDB; EMD-31708; -. DR EMDB; EMD-32615; -. DR EMDB; EMD-32636; -. DR EMDB; EMD-32637; -. DR EMDB; EMD-33236; -. DR EMDB; EMD-33332; -. DR EMDB; EMD-33333; -. DR EMDB; EMD-33334; -. DR EMDB; EMD-33335; -. DR EMDB; EMD-33884; -. DR EMDB; EMD-33890; -. DR EMDB; EMD-33960; -. DR EMDB; EMD-33961; -. DR EMDB; EMD-33965; -. DR EMDB; EMD-33966; -. DR EMDB; EMD-33967; -. DR EMDB; EMD-33968; -. DR EMDB; EMD-33969; -. DR EMDB; EMD-33970; -. DR EMDB; EMD-33971; -. DR EMDB; EMD-35087; -. DR EMDB; EMD-35088; -. DR EMDB; EMD-35090; -. DR EMDB; EMD-36202; -. DR EMDB; EMD-36203; -. DR EMDB; EMD-38097; -. DR EMDB; EMD-38103; -. DR EMDB; EMD-38104; -. DR EMDB; EMD-38105; -. DR EMDB; EMD-38106; -. DR EMDB; EMD-38107; -. DR EMDB; EMD-38108; -. DR EMDB; EMD-38733; -. DR EMDB; EMD-38862; -. DR EMDB; EMD-38863; -. DR EMDB; EMD-42350; -. DR EMDB; EMD-45221; -. DR EMDB; EMD-45464; -. DR EMDB; EMD-45465; -. DR EMDB; EMD-45639; -. DR EMDB; EMD-45650; -. DR EMDB; EMD-45651; -. DR EMDB; EMD-45979; -. DR EMDB; EMD-47820; -. DR EMDB; EMD-4994; -. DR EMDB; EMD-4996; -. DR EMDB; EMD-50077; -. DR EMDB; EMD-50860; -. DR EMDB; EMD-50888; -. DR EMDB; EMD-52165; -. DR EMDB; EMD-52166; -. DR EMDB; EMD-52458; -. DR EMDB; EMD-54402; -. DR EMDB; EMD-60226; -. DR EMDB; EMD-60231; -. DR EMDB; EMD-60232; -. DR EMDB; EMD-60262; -. DR EMDB; EMD-60527; -. DR EMDB; EMD-60528; -. DR EMDB; EMD-60529; -. DR EMDB; EMD-60530; -. DR EMDB; EMD-60637; -. DR EMDB; EMD-61330; -. DR EMDB; EMD-61355; -. DR EMDB; EMD-61356; -. DR EMDB; EMD-61357; -. DR EMDB; EMD-61383; -. DR EMDB; EMD-61384; -. DR EMDB; EMD-61394; -. DR EMDB; EMD-6482; -. DR EMDB; EMD-6988; -. DR EMDB; EMD-70093; -. DR EMDB; EMD-70295; -. DR EMDB; EMD-7618; -. DR EMDB; EMD-7619; -. DR PCDDB; P37840; -. DR SMR; P37840; -. DR BioGRID; 112506; 1553. DR CORUM; P37840; -. DR DIP; DIP-35354N; -. DR FunCoup; P37840; 336. DR IntAct; P37840; 474. DR MINT; P37840; -. DR STRING; 9606.ENSP00000500990; -. DR BindingDB; P37840; -. DR ChEMBL; CHEMBL6152; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB04209; Dequalinium. DR DrugBank; DB02709; Resveratrol. DR DrugCentral; P37840; -. DR GuidetoPHARMACOLOGY; 3285; -. DR TCDB; 1.C.77.1.1; the synuclein (synuclein) family. DR GlyConnect; 2893; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; P37840; 5 sites, 1 glycan. DR GlyGen; P37840; 7 sites, 2 O-linked glycans (7 sites). DR iPTMnet; P37840; -. DR MetOSite; P37840; -. DR PhosphoSitePlus; P37840; -. DR SwissPalm; P37840; -. DR BioMuta; SNCA; -. DR DMDM; 586067; -. DR jPOST; P37840; -. DR MassIVE; P37840; -. DR PaxDb; 9606-ENSP00000338345; -. DR PeptideAtlas; P37840; -. DR ProteomicsDB; 55279; -. [P37840-1] DR ProteomicsDB; 55280; -. [P37840-2] DR ProteomicsDB; 55281; -. [P37840-3] DR Pumba; P37840; -. DR TopDownProteomics; P37840-1; -. [P37840-1] DR ABCD; P37840; 22 sequenced antibodies. DR Antibodypedia; 14688; 3097 antibodies from 56 providers. DR DNASU; 6622; -. DR Ensembl; ENST00000336904.7; ENSP00000338345.3; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000345009.8; ENSP00000343683.4; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000394986.5; ENSP00000378437.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000394989.6; ENSP00000378440.2; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000394991.8; ENSP00000378442.4; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000420646.6; ENSP00000396241.2; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000505199.5; ENSP00000421485.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000506244.5; ENSP00000422238.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000508895.5; ENSP00000426955.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000618500.4; ENSP00000484044.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000673718.1; ENSP00000500990.1; ENSG00000145335.18. [P37840-1] DR GeneID; 6622; -. DR KEGG; hsa:6622; -. DR MANE-Select; ENST00000394991.8; ENSP00000378442.4; NM_000345.4; NP_000336.1. DR UCSC; uc003hso.3; human. [P37840-1] DR AGR; HGNC:11138; -. DR ClinPGx; PA35986; -. DR CTD; 6622; -. DR DisGeNET; 6622; -. DR GeneCards; SNCA; -. DR GeneReviews; SNCA; -. DR HGNC; HGNC:11138; SNCA. DR HPA; ENSG00000145335; Group enriched (bone marrow, brain). DR MalaCards; SNCA; -. DR MIM; 127750; phenotype. DR MIM; 163890; gene. DR MIM; 168600; phenotype. DR MIM; 168601; phenotype. DR MIM; 605543; phenotype. DR OpenTargets; ENSG00000145335; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 171695; Parkinsonian-pyramidal syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000145335; -. DR eggNOG; ENOG502S0Q7; Eukaryota. DR GeneTree; ENSGT00950000183175; -. DR HOGENOM; CLU_129378_1_0_1; -. DR InParanoid; P37840; -. DR OMA; LPQEGMM; -. DR OrthoDB; 9900372at2759; -. DR PAN-GO; P37840; 8 GO annotations based on evolutionary models. DR PhylomeDB; P37840; -. DR PathwayCommons; P37840; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P37840; -. DR SIGNOR; P37840; -. DR Agora; ENSG00000145335; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 6622; 12 hits in 1150 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SNCA; human. DR EvolutionaryTrace; P37840; -. DR GeneWiki; Alpha-synuclein; -. DR GenomeRNAi; 6622; -. DR Pharos; P37840; Tchem. DR PRO; PR:P37840; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P37840; protein. DR Bgee; ENSG00000145335; Expressed in trabecular bone tissue and 205 other cell types or tissues. DR ExpressionAtlas; P37840; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ParkinsonsUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central. DR GO; GO:0005640; C:nuclear outer membrane; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0032991; C:protein-containing complex; IMP:UniProtKB. DR GO; GO:0005840; C:ribosome; IEA:Ensembl. DR GO; GO:0099512; C:supramolecular fiber; IDA:UniProtKB. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IPI:ARUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IPI:UniProtKB. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0070840; F:dynein complex binding; IPI:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:BHF-UCL. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0019894; F:kinesin binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; EXP:DisProt. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IEA:Ensembl. DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB. DR GO; GO:0043274; F:phospholipase binding; IEA:Ensembl. DR GO; GO:0005543; F:phospholipid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051219; F:phosphoprotein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl. DR GO; GO:0004860; F:protein kinase inhibitor activity; TAS:ARUK-UCL. DR GO; GO:0140311; F:protein sequestering activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0000149; F:SNARE binding; IDA:UniProtKB. DR GO; GO:0048156; F:tau protein binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0141108; F:transporter regulator activity; IGI:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; EXP:DisProt. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:1990000; P:amyloid fibril formation; EXP:DisProt. DR GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl. DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB. DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IEA:Ensembl. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0042416; P:dopamine biosynthetic process; TAS:UniProtKB. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0006749; P:glutathione metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0042775; P:mitochondrial ATP synthesis coupled electron transport; IEA:Ensembl. DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:1904715; P:negative regulation of chaperone-mediated autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl. DR GO; GO:0051585; P:negative regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB. DR GO; GO:0045920; P:negative regulation of exocytosis; IMP:UniProtKB. DR GO; GO:0031115; P:negative regulation of microtubule polymerization; IDA:BHF-UCL. DR GO; GO:1902957; P:negative regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051622; P:negative regulation of norepinephrine uptake; IDA:UniProtKB. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0051612; P:negative regulation of serotonin uptake; IDA:UniProtKB. DR GO; GO:0070495; P:negative regulation of thrombin-activated receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ParkinsonsUK-UCL. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0006638; P:neutral lipid metabolic process; IEA:Ensembl. DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB. DR GO; GO:0045921; P:positive regulation of exocytosis; IMP:UniProtKB. DR GO; GO:1903285; P:positive regulation of hydrogen peroxide catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:ParkinsonsUK-UCL. DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0001921; P:positive regulation of receptor recycling; IDA:UniProtKB. DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:UniProtKB. DR GO; GO:0035543; P:positive regulation of SNARE complex assembly; IDA:CACAO. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB. DR GO; GO:0050812; P:regulation of acyl-CoA biosynthetic process; IEA:Ensembl. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:UniProtKB. DR GO; GO:0014048; P:regulation of glutamate secretion; IEA:Ensembl. DR GO; GO:0040012; P:regulation of locomotion; IEA:Ensembl. DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl. DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:BHF-UCL. DR GO; GO:0051621; P:regulation of norepinephrine uptake; IGI:ARUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1903421; P:regulation of synaptic vesicle recycling; TAS:ParkinsonsUK-UCL. DR GO; GO:1904307; P:response to desipramine; IEA:Ensembl. DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB. DR GO; GO:0010040; P:response to iron(II) ion; IDA:UniProtKB. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0032026; P:response to magnesium ion; IDA:UniProtKB. DR GO; GO:0034341; P:response to type II interferon; IDA:UniProtKB. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0035493; P:SNARE complex assembly; IDA:UniProtKB. DR GO; GO:0097435; P:supramolecular fiber organization; TAS:UniProtKB. DR GO; GO:0050808; P:synapse organization; IBA:GO_Central. DR GO; GO:0048488; P:synaptic vesicle endocytosis; ISS:UniProtKB. DR GO; GO:0016079; P:synaptic vesicle exocytosis; IDA:UniProtKB. DR GO; GO:0016082; P:synaptic vesicle priming; IMP:UniProtKB. DR GO; GO:0048489; P:synaptic vesicle transport; IEA:Ensembl. DR DisProt; DP00070; -. DR FunFam; 1.10.287.700:FF:000001; Alpha-synuclein; 1. DR Gene3D; 1.10.287.700; Helix hairpin bin; 1. DR IDEAL; IID00302; -. DR InterPro; IPR001058; Synuclein. DR InterPro; IPR002460; Synuclein_alpha. DR PANTHER; PTHR13820:SF5; ALPHA-SYNUCLEIN; 1. DR PANTHER; PTHR13820; SYNUCLEIN; 1. DR Pfam; PF01387; Synuclein; 1. DR PRINTS; PR01212; ASYNUCLEIN. DR PRINTS; PR01211; SYNUCLEIN. DR SUPFAM; SSF118375; Synuclein; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Amyloid; Cell projection; Copper; Cytoplasm; Direct protein sequencing; KW Disease variant; Membrane; Metal-binding; Neurodegeneration; Nucleus; KW Parkinson disease; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Synapse; Ubl conjugation. FT CHAIN 1..140 FT /note="Alpha-synuclein" FT /id="PRO_0000184022" FT REPEAT 20..30 FT /note="1" FT REPEAT 31..41 FT /note="2" FT REPEAT 42..56 FT /note="3; approximate" FT REPEAT 57..67 FT /note="4" FT REGION 20..67 FT /note="4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V- FT X(4)" FT REGION 100..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 111..140 FT /note="Interaction with SERF1A" FT /evidence="ECO:0000269|PubMed:22854022" FT COMPBIAS 112..140 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 2 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT BINDING 50 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:22407793" FT MOD_RES 87 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:10617630" FT MOD_RES 125 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:11162638, FT ECO:0000269|PubMed:12893833" FT MOD_RES 129 FT /note="Phosphoserine; by BARK1, PLK2, CK2, CK1 and GRK5" FT /evidence="ECO:0000269|PubMed:10617630, FT ECO:0000269|PubMed:11813001, ECO:0000269|PubMed:24936070" FT VAR_SEQ 41..54 FT /note="Missing (in isoform 2-5)" FT /evidence="ECO:0000303|PubMed:7601450" FT /id="VSP_006363" FT VAR_SEQ 103..130 FT /note="Missing (in isoform 2-4)" FT /evidence="ECO:0000303|PubMed:7601450, FT ECO:0000303|PubMed:7802671" FT /id="VSP_006364" FT VARIANT 30 FT /note="A -> P (in PARK1; no effect on oligomerization; FT dbSNP:rs104893878)" FT /evidence="ECO:0000269|PubMed:25561023, FT ECO:0000269|PubMed:9462735" FT /id="VAR_007957" FT VARIANT 46 FT /note="E -> K (in PARK1 and DLB; significant increase in FT binding to negatively charged phospholipid liposomes; FT increases oligomerization; dbSNP:rs104893875)" FT /evidence="ECO:0000269|PubMed:14755719, FT ECO:0000269|PubMed:15498564, ECO:0000269|PubMed:25561023" FT /id="VAR_022703" FT VARIANT 50 FT /note="H -> Q (in PARK1; no effect on protein structure; no FT effect on phosphorylation of the protein; no effect on FT membrane- and lipid-binding; increases oligomerization; FT increases fibril formation; increases secretion of the FT protein; impairs copper-binding; dbSNP:rs201106962)" FT /evidence="ECO:0000269|PubMed:23427326, FT ECO:0000269|PubMed:23457019, ECO:0000269|PubMed:24936070, FT ECO:0000269|PubMed:25561023" FT /id="VAR_070171" FT VARIANT 53 FT /note="A -> T (in PARK1; no effect on osmotic stress- FT induced phosphorylation; increases oligomerization; FT dbSNP:rs104893877)" FT /evidence="ECO:0000269|PubMed:12893833, FT ECO:0000269|PubMed:25561023, ECO:0000269|PubMed:9197268" FT /id="VAR_007454" FT MUTAGEN 2 FT /note="D->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 35 FT /note="E->K: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 39 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 50 FT /note="H->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 57 FT /note="E->K: Increases oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 67..71 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 71..82 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76..77 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT MUTAGEN 77 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 78 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 85..94 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 125 FT /note="Y->F: Abolishes osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 133 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 136 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT HELIX 3..11 FT /evidence="ECO:0007829|PDB:3Q25" FT STRAND 16..18 FT /evidence="ECO:0007829|PDB:7YK8" FT HELIX 21..32 FT /evidence="ECO:0007829|PDB:3Q26" FT STRAND 34..36 FT /evidence="ECO:0007829|PDB:8A4L" FT STRAND 38..40 FT /evidence="ECO:0007829|PDB:7V48" FT HELIX 41..44 FT /evidence="ECO:0007829|PDB:3Q27" FT STRAND 45..49 FT /evidence="ECO:0007829|PDB:8PJO" FT STRAND 52..55 FT /evidence="ECO:0007829|PDB:8JJV" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:8RQM" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:9FYP" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:3Q28" FT STRAND 70..72 FT /evidence="ECO:0007829|PDB:7YNP" FT STRAND 73..83 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:8AEX" FT STRAND 88..96 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 110..113 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 120..122 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 124..126 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 133..136 FT /evidence="ECO:0007829|PDB:2N0A" SQ SEQUENCE 140 AA; 14460 MW; 6BB2F12128931663 CRC64; MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP DNEAYEMPSE EGYQDYEPEA // ID T106B_HUMAN Reviewed; 274 AA. AC Q9NUM4; A4D108; Q53FL9; Q8N4L0; DT 27-JUN-2006, integrated into UniProtKB/Swiss-Prot. DT 27-JUN-2006, sequence version 2. DT 28-JAN-2026, entry version 162. DE RecName: Full=Transmembrane protein 106B {ECO:0000305}; GN Name=TMEM106B {ECO:0000312|HGNC:HGNC:22407}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-185. RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Gastric mucosa; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [8] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-183. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [9] RP INVOLVEMENT IN FTD2. RX PubMed=20154673; DOI=10.1038/ng.536; RA Van Deerlin V.M., Sleiman P.M., Martinez-Lage M., Chen-Plotkin A., RA Wang L.S., Graff-Radford N.R., Dickson D.W., Rademakers R., Boeve B.F., RA Grossman M., Arnold S.E., Mann D.M., Pickering-Brown S.M., Seelaar H., RA Heutink P., van Swieten J.C., Murrell J.R., Ghetti B., Spina S., RA Grafman J., Hodges J., Spillantini M.G., Gilman S., Lieberman A.P., RA Kaye J.A., Woltjer R.L., Bigio E.H., Mesulam M., Al-Sarraj S., Troakes C., RA Rosenberg R.N., White C.L. III, Ferrer I., Llado A., Neumann M., RA Kretzschmar H.A., Hulette C.M., Welsh-Bohmer K.A., Miller B.L., RA Alzualde A., de Munain A.L., McKee A.C., Gearing M., Levey A.I., Lah J.J., RA Hardy J., Rohrer J.D., Lashley T., Mackenzie I.R., Feldman H.H., RA Hamilton R.L., Dekosky S.T., van der Zee J., Kumar-Singh S., RA Van Broeckhoven C., Mayeux R., Vonsattel J.P., Troncoso J.C., Kril J.J., RA Kwok J.B., Halliday G.M., Bird T.D., Ince P.G., Shaw P.J., Cairns N.J., RA Morris J.C., McLean C.A., DeCarli C., Ellis W.G., Freeman S.H., RA Frosch M.P., Growdon J.H., Perl D.P., Sano M., Bennett D.A., RA Schneider J.A., Beach T.G., Reiman E.M., Woodruff B.K., Cummings J., RA Vinters H.V., Miller C.A., Chui H.C., Alafuzoff I., Hartikainen P., RA Seilhean D., Galasko D., Masliah E., Cotman C.W., Tunon M.T., RA Martinez M.C., Munoz D.G., Carroll S.L., Marson D., Riederer P.F., RA Bogdanovic N., Schellenberg G.D., Hakonarson H., Trojanowski J.Q., RA Lee V.M.; RT "Common variants at 7p21 are associated with frontotemporal lobar RT degeneration with TDP-43 inclusions."; RL Nat. Genet. 42:234-239(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP INVOLVEMENT IN FTD2. RX PubMed=21178100; DOI=10.1212/wnl.0b013e31820a0e3b; RA Finch N., Carrasquillo M.M., Baker M., Rutherford N.J., Coppola G., RA Dejesus-Hernandez M., Crook R., Hunter T., Ghidoni R., Benussi L., RA Crook J., Finger E., Hantanpaa K.J., Karydas A.M., Sengdy P., Gonzalez J., RA Seeley W.W., Johnson N., Beach T.G., Mesulam M., Forloni G., Kertesz A., RA Knopman D.S., Uitti R., White C.L. III, Caselli R., Lippa C., Bigio E.H., RA Wszolek Z.K., Binetti G., Mackenzie I.R., Miller B.L., Boeve B.F., RA Younkin S.G., Dickson D.W., Petersen R.C., Graff-Radford N.R., RA Geschwind D.H., Rademakers R.; RT "TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN RT mutation carriers."; RL Neurology 76:467-474(2011). RN [12] RP SUBCELLULAR LOCATION, TOPOLOGY, AND GLYCOSYLATION AT ASN-145; ASN-151; RP ASN-164; ASN-183 AND ASN-256. RX PubMed=22511793; DOI=10.1074/jbc.m112.365098; RA Lang C.M., Fellerer K., Schwenk B.M., Kuhn P.H., Kremmer E., Edbauer D., RA Capell A., Haass C.; RT "Membrane orientation and subcellular localization of transmembrane protein RT 106B (TMEM106B), a major risk factor for frontotemporal lobar RT degeneration."; RL J. Biol. Chem. 287:19355-19365(2012). RN [13] RP INVOLVEMENT IN FTD2. RX PubMed=22895706; DOI=10.1523/jneurosci.0521-12.2012; RA Chen-Plotkin A.S., Unger T.L., Gallagher M.D., Bill E., Kwong L.K., RA Volpicelli-Daley L., Busch J.I., Akle S., Grossman M., Van Deerlin V., RA Trojanowski J.Q., Lee V.M.; RT "TMEM106B, the risk gene for frontotemporal dementia, is regulated by the RT microRNA-132/212 cluster and affects progranulin pathways."; RL J. Neurosci. 32:11213-11227(2012). RN [14] RP SUBCELLULAR LOCATION, TOPOLOGY, AND HOMOMERIZATION. RX PubMed=23136129; DOI=10.1093/hmg/dds475; RA Brady O.A., Zheng Y., Murphy K., Huang M., Hu F.; RT "The frontotemporal lobar degeneration risk factor, TMEM106B, regulates RT lysosomal morphology and function."; RL Hum. Mol. Genet. 22:685-695(2013). RN [15] RP INVOLVEMENT IN FTD2, VARIANT SER-185, SUBCELLULAR LOCATION, AND RP GLYCOSYLATION AT ASN-183. RX PubMed=23742080; DOI=10.1111/jnc.12329; RA Nicholson A.M., Finch N.A., Wojtas A., Baker M.C., Perkerson R.B., RA Castanedes-Casey M., Rousseau L., Benussi L., Binetti G., Ghidoni R., RA Hsiung G.Y., Mackenzie I.R., Finger E., Boeve B.F., Ertekin-Taner N., RA Graff-Radford N.R., Dickson D.W., Rademakers R.; RT "TMEM106B p.T185S regulates TMEM106B protein levels: implications for RT frontotemporal dementia."; RL J. Neurochem. 126:781-791(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [17] RP INVOLVEMENT IN FTDALS1. RX PubMed=24488309; DOI=10.1007/s00401-014-1249-3; RA Deming Y., Cruchaga C.; RT "TMEM106B: a strong FTLD disease modifier."; RL Acta Neuropathol. 127:419-422(2014). RN [18] RP INVOLVEMENT IN FTDALS1. RX PubMed=24442578; DOI=10.1007/s00401-013-1239-x; RA Gallagher M.D., Suh E., Grossman M., Elman L., McCluskey L., RA Van Swieten J.C., Al-Sarraj S., Neumann M., Gelpi E., Ghetti B., RA Rohrer J.D., Halliday G., Van Broeckhoven C., Seilhean D., Shaw P.J., RA Frosch M.P., Alafuzoff I., Antonell A., Bogdanovic N., Brooks W., RA Cairns N.J., Cooper-Knock J., Cotman C., Cras P., Cruts M., De Deyn P.P., RA Decarli C., Dobson-Stone C., Engelborghs S., Fox N., Galasko D., RA Gearing M., Gijselinck I., Grafman J., Hartikainen P., Hatanpaa K.J., RA Highley J.R., Hodges J., Hulette C., Ince P.G., Jin L.W., Kirby J., RA Kofler J., Kril J., Kwok J.B., Levey A., Lieberman A., Llado A., RA Martin J.J., Masliah E., McDermott C.J., McKee A., McLean C., Mead S., RA Miller C.A., Miller J., Munoz D.G., Murrell J., Paulson H., Piguet O., RA Rossor M., Sanchez-Valle R., Sano M., Schneider J., Silbert L.C., Spina S., RA van der Zee J., Van Langenhove T., Warren J., Wharton S.B., White Iii C.L., RA Woltjer R.L., Trojanowski J.Q., Lee V.M., Van Deerlin V., RA Chen-Plotkin A.S.; RT "TMEM106B is a genetic modifier of frontotemporal lobar degeneration with RT C9orf72 hexanucleotide repeat expansions."; RL Acta Neuropathol. 127:407-418(2014). RN [19] RP INVOLVEMENT IN FTDALS1. RX PubMed=24385136; DOI=10.1007/s00401-013-1240-4; RA van Blitterswijk M., Mullen B., Nicholson A.M., Bieniek K.F., Heckman M.G., RA Baker M.C., Dejesus-Hernandez M., Finch N.A., Brown P.H., Murray M.E., RA Hsiung G.Y., Stewart H., Karydas A.M., Finger E., Kertesz A., Bigio E.H., RA Weintraub S., Mesulam M., Hatanpaa K.J., White Iii C.L., Strong M.J., RA Beach T.G., Wszolek Z.K., Lippa C., Caselli R., Petrucelli L., RA Josephs K.A., Parisi J.E., Knopman D.S., Petersen R.C., Mackenzie I.R., RA Seeley W.W., Grinberg L.T., Miller B.L., Boylan K.B., Graff-Radford N.R., RA Boeve B.F., Dickson D.W., Rademakers R.; RT "TMEM106B protects C9ORF72 expansion carriers against frontotemporal RT dementia."; RL Acta Neuropathol. 127:397-406(2014). RN [20] RP INTERACTION WITH MAP6. RX PubMed=24357581; DOI=10.1002/embj.201385857; RA Schwenk B.M., Lang C.M., Hogl S., Tahirovic S., Orozco D., Rentzsch K., RA Lichtenthaler S.F., Hoogenraad C.C., Capell A., Haass C., Edbauer D.; RT "The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of RT lysosomes."; RL EMBO J. 33:450-467(2014). RN [21] RP FUNCTION, INTERACTION WITH AP2M1; CLTC AND TMEM106C, HOMOMERIZATION, RP SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=25066864; DOI=10.1016/j.mcn.2014.07.006; RA Stagi M., Klein Z.A., Gould T.J., Bewersdorf J., Strittmatter S.M.; RT "Lysosome size, motility and stress response regulated by fronto-temporal RT dementia modifier TMEM106B."; RL Mol. Cell. Neurosci. 61:226-240(2014). RN [22] RP MYRISTOYLATION AT GLY-2, CLEAVAGE OF INITIATOR METHIONINE, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=25255805; DOI=10.1038/ncomms5919; RA Thinon E., Serwa R.A., Broncel M., Brannigan J.A., Brassat U., Wright M.H., RA Heal W.P., Wilkinson A.J., Mann D.J., Tate E.W.; RT "Global profiling of co- and post-translationally N-myristoylated proteomes RT in human cells."; RL Nat. Commun. 5:4919-4919(2014). RN [23] RP INTERACTION WITH ATP6AP1. RX PubMed=28728022; DOI=10.1016/j.neuron.2017.06.026; RA Klein Z.A., Takahashi H., Ma M., Stagi M., Zhou M., Lam T.T., RA Strittmatter S.M.; RT "Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related RT phenotypes in progranulin-deficient mice."; RL Neuron 95:281-296(2017). RN [24] RP FUNCTION (MICROBIAL INFECTION). RX PubMed=33333024; DOI=10.1016/j.cell.2020.12.004; RA Wang R., Simoneau C.R., Kulsuptrakul J., Bouhaddou M., Travisano K.A., RA Hayashi J.M., Carlson-Stevermer J., Zengel J.R., Richards C.M., Fozouni P., RA Oki J., Rodriguez L., Joehnk B., Walcott K., Holden K., Sil A., RA Carette J.E., Krogan N.J., Ott M., Puschnik A.S.; RT "Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold RT Coronaviruses."; RL Cell 184:106-119(2021). RN [25] RP FUNCTION (MICROBIAL INFECTION), AND TISSUE SPECIFICITY. RX PubMed=33686287; DOI=10.1038/s41588-021-00805-2; RA Baggen J., Persoons L., Vanstreels E., Jansen S., Van Looveren D., RA Boeckx B., Geudens V., De Man J., Jochmans D., Wauters J., Wauters E., RA Vanaudenaerde B.M., Lambrechts D., Neyts J., Dallmeier K., Thibaut H.J., RA Jacquemyn M., Maes P., Daelemans D.; RT "Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor RT for SARS-CoV-2."; RL Nat. Genet. 53:435-444(2021). RN [26] {ECO:0007744|PDB:7U10, ECO:0007744|PDB:7U11, ECO:0007744|PDB:7U12, ECO:0007744|PDB:7U13, ECO:0007744|PDB:7U14, ECO:0007744|PDB:7U15, ECO:0007744|PDB:7U16, ECO:0007744|PDB:7U17} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF 120-254, AGGREGATION RP IN NEURODEGENERATIVE DISEASES, AND TISSUE SPECIFICITY. RX PubMed=35247328; DOI=10.1016/j.cell.2022.02.026; RA Chang A., Xiang X., Wang J., Lee C., Arakhamia T., Simjanoska M., Wang C., RA Carlomagno Y., Zhang G., Dhingra S., Thierry M., Perneel J., Heeman B., RA Forgrave L.M., DeTure M., DeMarco M.L., Cook C.N., Rademakers R., RA Dickson D.W., Petrucelli L., Stowell M.H.B., Mackenzie I.R.A., RA Fitzpatrick A.W.P.; RT "Homotypic fibrillization of TMEM106B across diverse neurodegenerative RT diseases."; RL Cell 185:1346-1355(2022). RN [27] {ECO:0007744|PDB:7SAQ, ECO:0007744|PDB:7SAR, ECO:0007744|PDB:7SAS} RP STRUCTURE BY ELECTRON MICROSCOPY (2.90 ANGSTROMS) OF 120-254, AND RP AGGREGATION IN NEURODEGENERATIVE DISEASES. RX PubMed=35344984; DOI=10.1038/s41586-022-04670-9; RA Jiang Y.X., Cao Q., Sawaya M.R., Abskharon R., Ge P., DeTure M., RA Dickson D.W., Fu J.Y., Ogorzalek Loo R.R., Loo J.A., Loo J.A., RA Eisenberg D.S.; RT "Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43."; RL Nature 605:304-309(2022). RN [28] {ECO:0007744|PDB:7QVC, ECO:0007744|PDB:7QVF, ECO:0007744|PDB:7QWG, ECO:0007744|PDB:7QWL, ECO:0007744|PDB:7QWM} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS) OF 120-254, AGGREGATION RP IN NEURODEGENERATIVE DISEASES, AND TISSUE SPECIFICITY. RX PubMed=35344985; DOI=10.1038/s41586-022-04650-z; RA Schweighauser M., Arseni D., Bacioglu M., Huang M., Lovestam S., Shi Y., RA Yang Y., Zhang W., Kotecha A., Garringer H.J., Vidal R., Hallinan G.I., RA Newell K.L., Tarutani A., Murayama S., Miyazaki M., Saito Y., Yoshida M., RA Hasegawa K., Lashley T., Revesz T., Kovacs G.G., van Swieten J., Takao M., RA Hasegawa M., Ghetti B., Spillantini M.G., Ryskeldi-Falcon B., Murzin A.G., RA Goedert M., Scheres S.H.W.; RT "Age-dependent formation of TMEM106B amyloid filaments in human brains."; RL Nature 605:310-314(2022). RN [29] RP STRUCTURE BY ELECTRON MICROSCOPY (2.59 ANGSTROMS) OF 118-261, FUNCTION RP (MICROBIAL INFECTION), INTERACTION WITH SARS-COV-2 SPIKE GLYCOPROTEIN RP (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 210-MET--PHE-213; MET-210 AND PHE-213. RX PubMed=37421949; DOI=10.1016/j.cell.2023.06.005; RA Baggen J., Jacquemyn M., Persoons L., Vanstreels E., Pye V.E., Wrobel A.G., RA Calvaresi V., Martin S.R., Roustan C., Cronin N.B., Reading E., RA Thibaut H.J., Vercruysse T., Maes P., De Smet F., Yee A., Nivitchanyong T., RA Roell M., Franco-Hernandez N., Rhinn H., Mamchak A.A., Ah Young-Chapon M., RA Brown E., Cherepanov P., Daelemans D.; RT "TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry."; RL Cell 186:1-16(2023). RN [30] RP INVOLVEMENT IN HLD16, AND VARIANT HLD16 ASN-252. RX PubMed=29186371; DOI=10.1093/brain/awx314; RA Simons C., Dyment D., Bent S.J., Crawford J., D'Hooghe M., RA Kohlschuetter A., Venkateswaran S., Helman G., Poll-The B.T., RA Makowski C.C., Ito Y., Kernohan K., Hartley T., Waisfisz Q., Taft R.J., RA van der Knaap M.S., Wolf N.I.; RT "A recurrent de novo mutation in TMEM106B causes hypomyelinating RT leukodystrophy."; RL Brain 140:3105-3111(2017). RN [31] RP INVOLVEMENT IN HLD16, AND VARIANT HLD16 ASN-252. RX PubMed=29444210; DOI=10.1093/brain/awy029; RA Yan H., Kubisiak T., Ji H., Xiao J., Wang J., Burmeister M.; RT "The recurrent mutation in TMEM106B also causes hypomyelinating RT leukodystrophy in China and is a CpG hotspot."; RL Brain 141:E36-E36(2018). CC -!- FUNCTION: In neurons, involved in the transport of late CC endosomes/lysosomes (PubMed:25066864). May be involved in dendrite CC morphogenesis and maintenance by regulating lysosomal trafficking CC (PubMed:25066864). May act as a molecular brake for retrograde CC transport of late endosomes/lysosomes, possibly via its interaction CC with MAP6 (By similarity). In motoneurons, may mediate the axonal CC transport of lysosomes and axonal sorting at the initial segment (By CC similarity). It remains unclear whether TMEM106B affects the transport CC of moving lysosomes in the anterograde or retrograde direction in CC neurites and whether it is important in the sorting of lysosomes in CC axons or in dendrites (By similarity). In neurons, may also play a role CC in the regulation of lysosomal size and responsiveness to stress CC (PubMed:25066864). Required for proper lysosomal acidification (By CC similarity). {ECO:0000250|UniProtKB:Q6AYA5, CC ECO:0000250|UniProtKB:Q80X71, ECO:0000269|PubMed:25066864}. CC -!- FUNCTION: (Microbial infection) Plays a role in human coronavirus SARS- CC CoV-2 infection, but not in common cold coronaviruses HCoV-229E and CC HCoV-OC43 infections. Involved in ACE2-independent SARS-CoV-2 cell CC entry. Required for post-endocytic stage of virus entry, facilitates CC spike-mediated membrane fusion. Virus attachment and endocytosis can CC also be mediated by other cell surface receptors. CC {ECO:0000269|PubMed:33333024, ECO:0000269|PubMed:33686287, CC ECO:0000269|PubMed:37421949}. CC -!- SUBUNIT: Can form homomers (PubMed:23136129, PubMed:25066864). CC Interacts (via N-terminus) with MAP6 (via C-terminus) CC (PubMed:24357581). Interacts (via C-terminus) with the vacuolar-type CC ATPase subunit ATP6AP1 (PubMed:28728022). Interacts (via N-terminus) CC with AP2M1 and CLTC (PubMed:25066864). Interacts with TMEM106C CC (PubMed:25066864). {ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:24357581, ECO:0000269|PubMed:25066864, CC ECO:0000269|PubMed:28728022}. CC -!- SUBUNIT: (Microbial infection) Interacts with SARS coronavirus-2/SARS- CC CoV-2 spike protein (via RBD domain). {ECO:0000269|PubMed:37421949}. CC -!- INTERACTION: CC Q9NUM4; P42858: HTT; NbExp=3; IntAct=EBI-10490807, EBI-466029; CC Q9NUM4; Q9BVX2: TMEM106C; NbExp=4; IntAct=EBI-10490807, EBI-2821497; CC -!- SUBCELLULAR LOCATION: Late endosome membrane CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}; Single-pass type II membrane protein CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}. Lysosome membrane CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:25066864, CC ECO:0000269|PubMed:37421949}; Single-pass type II membrane protein CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}. Cell membrane CC {ECO:0000269|PubMed:37421949}; Single-pass type II membrane protein CC {ECO:0000255}. Note=Colocalizes with LAMP1. A small fraction resides on CC the cell surface (PubMed:37421949). {ECO:0000269|PubMed:22511793, CC ECO:0000269|PubMed:25066864, ECO:0000269|PubMed:37421949}. CC -!- TISSUE SPECIFICITY: Expressed in the brain, including in the frontal CC cortex (at protein level) (PubMed:35247328, PubMed:35344985). Expressed CC in lung epithelial cells (PubMed:33686287). CC {ECO:0000269|PubMed:33686287, ECO:0000269|PubMed:35247328, CC ECO:0000269|PubMed:35344985}. CC -!- DISEASE: Frontotemporal dementia 2 (FTD2) [MIM:607485]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. Gestural apraxia, CC parkinsonism, visual loss, and visual hallucinations are present in 25 CC to 40% of patients. {ECO:0000269|PubMed:20154673, CC ECO:0000269|PubMed:21178100, ECO:0000269|PubMed:22895706, CC ECO:0000269|PubMed:23742080}. Note=The gene represented in this entry CC may act as a disease modifier. Risk alleles confer genetic CC susceptibility by increasing gene expression (PubMed:20154673, CC PubMed:21178100). Increased expression may be the result of down- CC regulation of microRNA miR-132 and miR-212, that repress TMEM106B CC expression (PubMed:22895706). Thr-185 is a risk allele associated with CC lower GRN protein levels and early age at onset in GRN FTD2 mutation CC carriers: it presents slower protein degradation that leads to higher CC steady-state TMEM106B levels, leading to alterations in the CC intracellular versus extracellular partitioning of GRN CC (PubMed:23742080). {ECO:0000269|PubMed:20154673, CC ECO:0000269|PubMed:21178100, ECO:0000269|PubMed:22895706, CC ECO:0000269|PubMed:23742080}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 CC (FTDALS1) [MIM:105550]: An autosomal dominant neurodegenerative CC disorder characterized by adult onset of frontotemporal dementia and/or CC amyotrophic lateral sclerosis in an affected individual. There is high CC intrafamilial variation. Frontotemporal dementia is characterized by CC frontal and temporal lobe atrophy associated with neuronal loss, CC gliosis, and dementia. Patients exhibit progressive changes in social, CC behavioral, and/or language function. Amyotrophic lateral sclerosis is CC characterized by the death of motor neurons in the brain, brainstem, CC and spinal cord, resulting in fatal paralysis. CC {ECO:0000269|PubMed:24385136, ECO:0000269|PubMed:24442578, CC ECO:0000303|PubMed:24488309}. Note=The gene represented in this entry CC acts as a disease modifier. CC -!- DISEASE: Leukodystrophy, hypomyelinating, 16 (HLD16) [MIM:617964]: An CC autosomal dominant disorder characterized by hypomyelination, CC leukodystrophy, and thin corpus callosum observed on brain imaging. CC Clinical features include hypotonia, nystagmus, and mildly delayed CC motor development with onset in infancy, ataxic or broad-based gait, CC hyperreflexia, intention tremor, dysmetria, and a mild pyramidal CC syndrome. Some patients have cognitive impairment, whereas others may CC have normal cognition or mild intellectual disability with speech CC difficulties. {ECO:0000269|PubMed:29186371, CC ECO:0000269|PubMed:29444210}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A TMEM106B truncated C-terminal fragment (residues 120 CC through 254) was found to aggregate into stable amyloid fibrils in the CC brain of patients suffering from diverse genetic and sporadic CC tauopathies, amyloid-beta amyloidoses, synucleinopathies and TDP-43 CC proteinopathies. It is currently unclear whether TMEM106B fibrils are CC associated with a pathogenic process or represents a non-specific CC secondary phenomenon, a general downstream marker of lysosomal stress CC for instance (PubMed:35247328, PubMed:35344984, PubMed:35344985). CC TMEM106B amyloid filaments form in an age-dependent manner in human CC brains, however fibrillization of TMEM106B seems substantially greater CC in patients with known neurodegeneration compared to age-matched CC unaffected individuals (PubMed:35344985). {ECO:0000269|PubMed:35247328, CC ECO:0000269|PubMed:35344984, ECO:0000269|PubMed:35344985}. CC -!- SIMILARITY: Belongs to the TMEM106 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK002135; BAA92099.1; -; mRNA. DR EMBL; AK223263; BAD96983.1; -; mRNA. DR EMBL; AC007321; AAQ96840.1; -; Genomic_DNA. DR EMBL; CH236948; EAL24296.1; -; Genomic_DNA. DR EMBL; CH471073; EAW93638.1; -; Genomic_DNA. DR EMBL; BC033901; AAH33901.1; -; mRNA. DR EMBL; BC039741; AAH39741.1; -; mRNA. DR CCDS; CCDS5358.1; -. DR RefSeq; NP_001127704.1; NM_001134232.2. DR RefSeq; NP_060844.2; NM_018374.3. DR PDB; 7QVC; EM; 2.64 A; A/B/C=120-254. DR PDB; 7QVF; EM; 3.64 A; A/B/C/D/E/F=120-254. DR PDB; 7QWG; EM; 3.38 A; A/B/C=120-254. DR PDB; 7QWL; EM; 3.47 A; A/B/C=120-254. DR PDB; 7QWM; EM; 2.76 A; A/B/C=120-254. DR PDB; 7SAQ; EM; 2.90 A; A/B/C/D/E=120-254. DR PDB; 7SAR; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J=120-254. DR PDB; 7SAS; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J=120-254. DR PDB; 7TMC; EM; 3.25 A; A/B/C=1-274. DR PDB; 7U10; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U11; EM; 3.20 A; A/B/C=120-254. DR PDB; 7U12; EM; 3.50 A; A/B/C=120-254. DR PDB; 7U13; EM; 2.90 A; A/B/C=120-254. DR PDB; 7U14; EM; 4.50 A; A/B/C=120-254. DR PDB; 7U15; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U16; EM; 2.70 A; A/B/C=120-254. DR PDB; 7U17; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U18; EM; 2.70 A; A/B/C=120-254. DR PDB; 7X83; EM; 3.40 A; A/B/C=1-274. DR PDB; 7X84; EM; 3.00 A; A/B/C=120-254. DR PDB; 8B7D; X-ray; 2.59 A; A=118-274. DR PDB; 8F9K; EM; 3.40 A; A/B/C/D/E/F=1-274. DR PDB; 8J7N; EM; 3.00 A; A/B/C=1-274. DR PDB; 8J7P; EM; 3.40 A; A/B/C=1-274. DR PDB; 8OTD; EM; 2.60 A; A/B/C/D=1-274. DR PDB; 8OTE; EM; 3.60 A; A/B/C/D/E/F/G/H=1-274. DR PDB; 8X5H; EM; 3.47 A; A/B/C=1-274. DR PDB; 9FNB; EM; 2.64 A; A/B/C/D=120-254. DR PDBsum; 7QVC; -. DR PDBsum; 7QVF; -. DR PDBsum; 7QWG; -. DR PDBsum; 7QWL; -. DR PDBsum; 7QWM; -. DR PDBsum; 7SAQ; -. DR PDBsum; 7SAR; -. DR PDBsum; 7SAS; -. DR PDBsum; 7TMC; -. DR PDBsum; 7U10; -. DR PDBsum; 7U11; -. DR PDBsum; 7U12; -. DR PDBsum; 7U13; -. DR PDBsum; 7U14; -. DR PDBsum; 7U15; -. DR PDBsum; 7U16; -. DR PDBsum; 7U17; -. DR PDBsum; 7U18; -. DR PDBsum; 7X83; -. DR PDBsum; 7X84; -. DR PDBsum; 8B7D; -. DR PDBsum; 8F9K; -. DR PDBsum; 8J7N; -. DR PDBsum; 8J7P; -. DR PDBsum; 8OTD; -. DR PDBsum; 8OTE; -. DR PDBsum; 8X5H; -. DR PDBsum; 9FNB; -. DR AlphaFoldDB; Q9NUM4; -. DR EMDB; EMD-14174; -. DR EMDB; EMD-14176; -. DR EMDB; EMD-14187; -. DR EMDB; EMD-14188; -. DR EMDB; EMD-14189; -. DR EMDB; EMD-17170; -. DR EMDB; EMD-17175; -. DR EMDB; EMD-17176; -. DR EMDB; EMD-24953; -. DR EMDB; EMD-24954; -. DR EMDB; EMD-24955; -. DR EMDB; EMD-25995; -. DR EMDB; EMD-26273; -. DR EMDB; EMD-26274; -. DR EMDB; EMD-26275; -. DR EMDB; EMD-26276; -. DR EMDB; EMD-26277; -. DR EMDB; EMD-26278; -. DR EMDB; EMD-26279; -. DR EMDB; EMD-28943; -. DR EMDB; EMD-33054; -. DR EMDB; EMD-33055; -. DR EMDB; EMD-36043; -. DR EMDB; EMD-36045; -. DR EMDB; EMD-38069; -. DR EMDB; EMD-50587; -. DR SMR; Q9NUM4; -. DR BioGRID; 120093; 371. DR FunCoup; Q9NUM4; 1015. DR IntAct; Q9NUM4; 76. DR MINT; Q9NUM4; -. DR STRING; 9606.ENSP00000379901; -. DR TCDB; 9.B.23.1.1; the tmem106 (tmem106) family. DR GlyConnect; 1849; 19 N-Linked glycans (2 sites). DR GlyCosmos; Q9NUM4; 6 sites, 20 glycans. DR GlyGen; Q9NUM4; 8 sites, 28 N-linked glycans (3 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q9NUM4; -. DR PhosphoSitePlus; Q9NUM4; -. DR SwissPalm; Q9NUM4; -. DR BioMuta; TMEM106B; -. DR DMDM; 109895058; -. DR jPOST; Q9NUM4; -. DR MassIVE; Q9NUM4; -. DR PaxDb; 9606-ENSP00000379901; -. DR PeptideAtlas; Q9NUM4; -. DR ProteomicsDB; 82695; -. DR Pumba; Q9NUM4; -. DR Antibodypedia; 43908; 126 antibodies from 30 providers. DR DNASU; 54664; -. DR YCharOS; Q9NUM4; Tested 6 antibodies from 5 manufacturers. DR Ensembl; ENST00000396667.7; ENSP00000379901.2; ENSG00000106460.21. DR Ensembl; ENST00000396668.8; ENSP00000379902.3; ENSG00000106460.21. DR Ensembl; ENST00000444443.6; ENSP00000401302.2; ENSG00000106460.21. DR Ensembl; ENST00000704455.1; ENSP00000515905.1; ENSG00000106460.21. DR GeneID; 54664; -. DR KEGG; hsa:54664; -. DR MANE-Select; ENST00000396668.8; ENSP00000379902.3; NM_001134232.2; NP_001127704.1. DR UCSC; uc003ssh.4; human. DR AGR; HGNC:22407; -. DR ClinPGx; PA142670756; -. DR CTD; 54664; -. DR DisGeNET; 54664; -. DR GeneCards; TMEM106B; -. DR HGNC; HGNC:22407; TMEM106B. DR HPA; ENSG00000106460; Low tissue specificity. DR MalaCards; TMEM106B; -. DR MIM; 105550; phenotype. DR MIM; 607485; phenotype. DR MIM; 613413; gene. DR MIM; 617964; phenotype. DR NIAGADS; ENSG00000106460; -. DR OpenTargets; ENSG00000106460; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000106460; -. DR eggNOG; ENOG502QQRZ; Eukaryota. DR GeneTree; ENSGT00940000158360; -. DR HOGENOM; CLU_089337_2_0_1; -. DR InParanoid; Q9NUM4; -. DR OMA; FGHSEQT; -. DR OrthoDB; 508875at2759; -. DR PAN-GO; Q9NUM4; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q9NUM4; -. DR PathwayCommons; Q9NUM4; -. DR SignaLink; Q9NUM4; -. DR Agora; ENSG00000106460; -. DR BioGRID-ORCS; 54664; 25 hits in 1169 CRISPR screens. DR ChiTaRS; TMEM106B; human. DR GeneWiki; TMEM106B; -. DR GenomeRNAi; 54664; -. DR Pharos; Q9NUM4; Tbio. DR PRO; PR:Q9NUM4; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q9NUM4; protein. DR Bgee; ENSG00000106460; Expressed in cauda epididymis and 213 other cell types or tissues. DR ExpressionAtlas; Q9NUM4; baseline and differential. DR GO; GO:0005768; C:endosome; IDA:HPA. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0051117; F:ATPase binding; IPI:MGI. DR GO; GO:0048813; P:dendrite morphogenesis; IMP:UniProtKB. DR GO; GO:0007042; P:lysosomal lumen acidification; IEA:Ensembl. DR GO; GO:1905146; P:lysosomal protein catabolic process; IEA:Ensembl. DR GO; GO:0007041; P:lysosomal transport; IBA:GO_Central. DR GO; GO:0032418; P:lysosome localization; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; IBA:GO_Central. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:1900006; P:positive regulation of dendrite development; IEA:Ensembl. DR GO; GO:1905671; P:regulation of lysosome organization; IEA:Ensembl. DR DisProt; DP02543; -. DR InterPro; IPR009790; TMEM106. DR InterPro; IPR048509; TMEM106_C. DR InterPro; IPR048511; TMEM106_N. DR PANTHER; PTHR28556; TRANSMEMBRANE PROTEIN 106B; 1. DR PANTHER; PTHR28556:SF1; TRANSMEMBRANE PROTEIN 106B; 1. DR Pfam; PF07092; TMEM106; 1. DR Pfam; PF21002; TMEM106_N; 1. DR SUPFAM; SSF117070; LEA14-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Amyotrophic lateral sclerosis; Cell membrane; KW Disease variant; Disulfide bond; Endosome; Glycoprotein; Leukodystrophy; KW Lipoprotein; Lysosome; Membrane; Myristate; Neurodegeneration; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Signal-anchor; Transmembrane; Transmembrane helix; Transport. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:25255805" FT CHAIN 2..274 FT /note="Transmembrane protein 106B" FT /id="PRO_0000242650" FT TOPO_DOM 2..96 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:22511793, FT ECO:0000269|PubMed:23136129, ECO:0000269|PubMed:25066864" FT TRANSMEM 97..117 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 118..274 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:22511793, FT ECO:0000269|PubMed:23136129, ECO:0000269|PubMed:25066864" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..11 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 33 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT LIPID 2 FT /note="N-myristoyl glycine" FT /evidence="ECO:0000269|PubMed:25255805" FT CARBOHYD 145 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 151 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 164 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 183 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23742080" FT CARBOHYD 256 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT DISULFID 214..253 FT /evidence="ECO:0000269|PubMed:35344984" FT VARIANT 185 FT /note="T -> S (in dbSNP:rs3173615)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:23742080" FT /id="VAR_026849" FT VARIANT 252 FT /note="D -> N (in HLD16; dbSNP:rs1554310600)" FT /evidence="ECO:0000269|PubMed:29186371, FT ECO:0000269|PubMed:29444210" FT /id="VAR_081068" FT MUTAGEN 210..213 FT /note="MYDF->AYDA: Highly decreased number of infected FT cells by SARS-CoV-2. No effect on infection with HCoV- FT 229E." FT /evidence="ECO:0000269|PubMed:37421949" FT MUTAGEN 210 FT /note="M->A: Decreased number of infected cells by SARS- FT CoV-2. No effect on infection with HCoV-229E." FT /evidence="ECO:0000269|PubMed:37421949" FT MUTAGEN 213 FT /note="F->A: Decreased number of infected cells by SARS- FT CoV-2. No effect on infection with HCoV-229E." FT /evidence="ECO:0000269|PubMed:37421949" FT CONFLICT 50 FT /note="Y -> C (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT CONFLICT 106 FT /note="L -> P (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT CONFLICT 197 FT /note="Y -> N (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT STRAND 122..136 FT /evidence="ECO:0007829|PDB:8B7D" FT TURN 137..140 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 141..153 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 160..171 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 174..183 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 184..187 FT /evidence="ECO:0007829|PDB:7QWM" FT STRAND 192..203 FT /evidence="ECO:0007829|PDB:8B7D" FT HELIX 205..208 FT /evidence="ECO:0007829|PDB:8B7D" FT HELIX 209..214 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 216..220 FT /evidence="ECO:0007829|PDB:7QVC" FT STRAND 223..236 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 239..252 FT /evidence="ECO:0007829|PDB:8B7D" SQ SEQUENCE 274 AA; 31127 MW; 906C923986DC04E6 CRC64; MGKSLSHLPL HSSKEDAYDG VTSENMRNGL VNSEVHNEDG RNGDVSQFPY VEFTGRDSVT CPTCQGTGRI PRGQENQLVA LIPYSDQRLR PRRTKLYVMA SVFVCLLLSG LAVFFLFPRS IDVKYIGVKS AYVSYDVQKR TIYLNITNTL NITNNNYYSV EVENITAQVQ FSKTVIGKAR LNNITIIGPL DMKQIDYTVP TVIAEEMSYM YDFCTLISIK VHNIVLMMQV TVTTTYFGHS EQISQERYQY VDCGRNTTYQ LGQSEYLNVL QPQQ // ID TAU_HUMAN Reviewed; 758 AA. AC P10636; P18518; Q14799; Q15549; Q15550; Q15551; Q1RMF6; Q53YB1; Q5CZI7; AC Q5XWF0; Q6QT54; Q9UDJ3; Q9UMH0; Q9UQ96; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 31-MAY-2011, sequence version 5. DT 28-JAN-2026, entry version 293. DE RecName: Full=Microtubule-associated protein tau {ECO:0000305}; DE AltName: Full=Neurofibrillary tangle protein; DE AltName: Full=Paired helical filament-tau; DE Short=PHF-tau; GN Name=MAPT {ECO:0000312|HGNC:HGNC:6893}; Synonyms=MAPTL, MTBT1, TAU; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FETAL-TAU). RC TISSUE=Brain; RX PubMed=3131773; DOI=10.1073/pnas.85.11.4051; RA Goedert M., Wischik C., Crowther R., Walker J., Klug A.; RT "Cloning and sequencing of the cDNA encoding a core protein of the paired RT helical filament of Alzheimer disease: identification as the microtubule- RT associated protein tau."; RL Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-D). RC TISSUE=Brain; RX PubMed=2498079; DOI=10.1002/j.1460-2075.1989.tb03390.x; RA Goedert M., Spillantini M.G., Potier M.-C., Ulrich J., Crowther R.A.; RT "Cloning and sequencing of the cDNA encoding an isoform of microtubule- RT associated protein tau containing four tandem repeats: differential RT expression of tau protein mRNAs in human brain."; RL EMBO J. 8:393-399(1989). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-A AND FETAL-TAU). RC TISSUE=Fetal brain; RX PubMed=2516729; DOI=10.1016/0896-6273(89)90050-0; RA Lee G., Neve R.L., Kosik K.S.; RT "The microtubule binding domain of tau protein."; RL Neuron 2:1615-1624(1989). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-B; TAU-C; TAU-E AND TAU-F), AND RP ASSOCIATION WITH ALZHEIMER DISEASE. RC TISSUE=Brain; RX PubMed=2484340; DOI=10.1016/0896-6273(89)90210-9; RA Goedert M., Spillantini M.G., Jakes R., Rutherford D., Crowther R.A.; RT "Multiple isoforms of human microtubule-associated protein tau: sequences RT and localization in neurofibrillary tangles of Alzheimer's disease."; RL Neuron 3:519-526(1989). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS PNS-TAU; FETAL-TAU AND TAU-F), RP ALTERNATIVE SPLICING, AND VARIANT HIS-441. RX PubMed=1420178; DOI=10.1021/bi00158a027; RA Andreadis A., Brown W.M., Kosik K.S.; RT "Structure and novel exons of the human tau gene."; RL Biochemistry 31:10626-10633(1992). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-E). RA Chun J., Kwon T., Lee E.-J., Hyun S.-H., Kang S.S.; RT "Cloning of tau-related genes."; RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM FETAL-TAU). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS FETAL-TAU AND TAU-D). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP PROTEIN SEQUENCE OF 2-73; 103-381; 468-497; 508-571; 577-583; 592-607; RP 616-634; 639-657; 661-664; 671-700 AND 703-758, CLEAVAGE OF INITIATOR RP METHIONINE, ACETYLATION AT ALA-2, AND DEAMIDATION AT ASN-484 AND ASN-596. RC TISSUE=Brain; RX PubMed=1512244; DOI=10.1016/s0021-9258(18)41890-x; RA Hasegawa M., Morishima-Kawashima M., Takio K., Suzuki M., Titani K., RA Ihara Y.; RT "Protein sequence and mass spectrometric analyses of tau in the Alzheimer's RT disease brain."; RL J. Biol. Chem. 267:17047-17054(1992). RN [11] RP PROTEIN SEQUENCE OF 25-44; 529-538; 560-571 AND 671-686, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 466-740 (ISOFORMS RP TAU-A/TAU-B/TAU-C/FETAL-TAU). RA Han J., Zhang J., Dong X.-P.; RT "Molecular interactions of recombinant neural protein tau with recombinant RT and native PrP proteins in vitro."; RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases. RN [13] RP PROTEIN SEQUENCE OF 543-551; 560-574; 576-584 AND 623-634, PHOSPHORYLATION RP AT SER-531; THR-534; THR-548; SER-552; SER-554; SER-579; SER-713 AND RP SER-739, UBIQUITINATION AT LYS-571; LYS-628 AND LYS-670, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RX PubMed=16443603; DOI=10.1074/jbc.m512786200; RA Cripps D., Thomas S.N., Jeng Y., Yang F., Davies P., Yang A.J.; RT "Alzheimer disease-specific conformation of hyperphosphorylated paired RT helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 RT ubiquitin conjugation."; RL J. Biol. Chem. 281:10825-10838(2006). RN [14] RP PROTEIN SEQUENCE OF 577-584; 608-611; 616-628; 639-648 AND 671-686, RP PHOSPHORYLATION AT SER-579; SER-610; SER-622; SER-641 AND SER-673, RP MUTAGENESIS, AND DOMAIN. RX PubMed=7706316; DOI=10.1074/jbc.270.13.7679; RA Drewes G., Trinczek B., Illenberger S., Biernat J., Schmitt-Ulms G., RA Meyer H.E., Mandelkow E.-M., Mandelkow E.; RT "Microtubule-associated protein/microtubule affinity-regulating kinase RT (p110mark). A novel protein kinase that regulates tau-microtubule RT interactions and dynamic instability by phosphorylation at the Alzheimer- RT specific site serine 262."; RL J. Biol. Chem. 270:7679-7688(1995). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 592-622 (ISOFORMS PNS-TAU/TAU-D/TAU-E/TAU-F). RC TISSUE=Brain; RX PubMed=2495000; DOI=10.1016/0006-291x(89)92240-7; RA Mori H., Hamada Y., Kawaguchi M., Honda T., Kondo J., Ihara Y.; RT "A distinct form of tau is selectively incorporated into Alzheimer's paired RT helical filaments."; RL Biochem. Biophys. Res. Commun. 159:1221-1226(1989). RN [16] RP PROTEIN SEQUENCE OF 379-392 AND 568-581, AND PHOSPHORYLATION AT SER-713. RX PubMed=1899488; DOI=10.1126/science.1899488; RA Lee V.M., Balin B.J., Otvos L. Jr., Trojanowski J.Q.; RT "A68: a major subunit of paired helical filaments and derivatized forms of RT normal Tau."; RL Science 251:675-678(1991). RN [17] RP PROTEIN SEQUENCE OF 616-712. RX PubMed=1915258; DOI=10.1002/j.1460-2075.1991.tb07820.x; RA Jakes R., Novak M., Davison M., Wischik C.M.; RT "Identification of 3- and 4-repeat tau isoforms within the PHF in RT Alzheimer's disease."; RL EMBO J. 10:2725-2729(1991). RN [18] RP IDENTIFICATION (ISOFORM TAU-G), AND VARIANT HIS-441. RX PubMed=15365985; DOI=10.1002/humu.20086; RA Rademakers R., Cruts M., van Broeckhoven C.; RT "The role of tau (MAPT) in frontotemporal dementia and related RT tauopathies."; RL Hum. Mutat. 24:277-295(2004). RN [19] RP REVIEW. RX PubMed=1713721; DOI=10.1016/0166-2236(91)90105-4; RA Goedert M., Crowther R.A., Garner C.C.; RT "Molecular characterization of microtubule-associated proteins tau and RT MAP2."; RL Trends Neurosci. 14:193-199(1991). RN [20] RP PHOSPHORYLATION AT SER-554; SER-579; SER-602; SER-622 AND SER-669. RX PubMed=8999860; DOI=10.1016/s0021-9258(19)67481-8; RA Paudel H.K.; RT "The regulatory Ser262 of microtubule-associated protein tau is RT phosphorylated by phosphorylase kinase."; RL J. Biol. Chem. 272:1777-1785(1997). RN [21] RP GLYCATION AT LYS-87; LYS-383; LYS-467; LYS-480; LYS-491; LYS-542; LYS-551; RP LYS-576; LYS-597; LYS-598; LYS-664; LYS-670 AND LYS-686, AND LACK OF RP GLYCATION AT LYS-24; LYS-44; LYS-67; LYS-381; LYS-391; LYS-392; LYS-394; RP LYS-465; LYS-497; LYS-507; LYS-541; LYS-557; LYS-571; LYS-574; LYS-584; RP LYS-591; LYS-607; LYS-611; LYS-615; LYS-628; LYS-634; LYS-638; LYS-648; RP LYS-657; LYS-660; LYS-687; LYS-692; LYS-700; LYS-702; LYS-712 AND LYS-755. RX PubMed=9326300; DOI=10.1046/j.1471-4159.1997.69041709.x; RA Nacharaju P., Ko L., Yen S.H.; RT "Characterization of in vitro glycation sites of tau."; RL J. Neurochem. 69:1709-1719(1997). RN [22] RP PHOSPHORYLATION, AND MUTAGENESIS. RX PubMed=9735171; DOI=10.1006/abbi.1998.0813; RA Sengupta A., Kabat J., Novak M., Wu Q., Grundke-Iqbal I., Iqbal K.; RT "Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal RT inhibition of its binding to microtubules."; RL Arch. Biochem. Biophys. 357:299-309(1998). RN [23] RP PHOSPHORYLATION AT THR-470; SER-516; SER-519; THR-529; SER-531; SER-552; RP SER-579; SER-713; SER-721 AND SER-739, AND MUTAGENESIS. RX PubMed=9614189; DOI=10.1091/mbc.9.6.1495; RA Illenberger S., Zheng-Fischhofer Q., Preuss U., Stamer K., Baumann K., RA Trinczek B., Biernat J., Godemann R., Mandelkow E.-M., Mandelkow E.; RT "The endogenous and cell cycle-dependent phosphorylation of tau protein in RT living cells: implications for Alzheimer's disease."; RL Mol. Biol. Cell 9:1495-1512(1998). RN [24] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION. RX PubMed=10747907; DOI=10.1074/jbc.m000389200; RA Maas T., Eidenmueller J., Brandt R.; RT "Interaction of tau with the neural membrane cortex is regulated by RT phosphorylation at sites that are modified in paired helical filaments."; RL J. Biol. Chem. 275:15733-15740(2000). RN [25] RP PHOSPHORYLATION AT SER-519; THR-522; SER-713 AND SER-721 BY CSNK1D/CK1, AND RP INTERACTION WITH CSNK1D. RX PubMed=14761950; DOI=10.1074/jbc.m314116200; RA Li G., Yin H., Kuret J.; RT "Casein kinase 1 delta phosphorylates tau and disrupts its binding to RT microtubules."; RL J. Biol. Chem. 279:15938-15945(2004). RN [26] RP PHOSPHORYLATION AT THR-548 BY GSK3B. RX PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x; RA Cho J.H., Johnson G.V.; RT "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta RT (GSK3beta) plays a critical role in regulating tau's ability to bind and RT stabilize microtubules."; RL J. Neurochem. 88:349-358(2004). RN [27] RP PHOSPHORYLATION AT TYR-18 BY FYN. RX PubMed=14999081; DOI=10.1523/jneurosci.4162-03.2004; RA Lee G., Thangavel R., Sharma V.M., Litersky J.M., Bhaskar K., Fang S.M., RA Do L.H., Andreadis A., Van Hoesen G., Ksiezak-Reding H.; RT "Phosphorylation of tau by fyn: implications for Alzheimer's disease."; RL J. Neurosci. 24:2304-2312(2004). RN [28] RP INTERACTION WITH SQSTM1, UBIQUITINATION, AND PROTEASOMAL DEGRADATION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [29] RP PHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531; RP THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726, AND RP DEPHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531; RP THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726 BY PPP5C. RX PubMed=15546861; DOI=10.1074/jbc.m410775200; RA Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X.; RT "Dephosphorylation of tau by protein phosphatase 5: impairment in RT Alzheimer's disease."; RL J. Biol. Chem. 280:1790-1796(2005). RN [30] RP PHOSPHORYLATION AT TYR-514; SER-515; SER-516; SER-519; SER-733; SER-739 AND RP THR-744. RX PubMed=16923168; DOI=10.1111/j.1471-4159.2006.04059.x; RA Sato S., Cerny R.L., Buescher J.L., Ikezu T.; RT "Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is RT involved in tau phosphorylation and aggregation."; RL J. Neurochem. 98:1573-1584(2006). RN [31] RP PHOSPHORYLATION AT SER-214 BY SGK1, AND INTERACTION WITH SGK1. RX PubMed=16982696; DOI=10.1128/mcb.01017-06; RA Yang Y.C., Lin C.H., Lee E.H.; RT "Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite RT formation through microtubule depolymerization by SGK1 and by SGK1 RT phosphorylation of tau."; RL Mol. Cell. Biol. 26:8357-8370(2006). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [33] RP PHOSPHORYLATION BY CSNK1D/CK1. RX PubMed=17562708; DOI=10.1074/jbc.m703269200; RA Hanger D.P., Byers H.L., Wray S., Leung K.-Y., Saxton M.J., Seereeram A., RA Reynolds C.H., Ward M.A., Anderton B.H.; RT "Novel phosphorylation sites in tau from Alzheimer brain support a role for RT casein kinase 1 in disease pathogenesis."; RL J. Biol. Chem. 282:23645-23654(2007). RN [34] RP PHOSPHORYLATION AT THR-529 BY DYRK2. RX PubMed=18599021; DOI=10.1016/j.bcp.2008.05.021; RA Yoshida K.; RT "Role for DYRK family kinases on regulation of apoptosis."; RL Biochem. Pharmacol. 76:1389-1394(2008). RN [35] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [36] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [37] RP GLYCOSYLATION, PHOSPHORYLATION AT SER-516; SER-519; THR-522; THR-529; RP SER-531; THR-534; SER-579; SER-713; SER-721 AND SER-739, AND ASSOCIATION RP WITH ALZHEIMER DISEASE. RX PubMed=19451179; DOI=10.1093/brain/awp099; RA Liu F., Shi J., Tanimukai H., Gu J., Gu J., Grundke-Iqbal I., Iqbal K., RA Gong C.X.; RT "Reduced O-GlcNAcylation links lower brain glucose metabolism and tau RT pathology in Alzheimer's disease."; RL Brain 132:1820-1832(2009). RN [38] RP INTERACTION WITH EPM2A. RX PubMed=19542233; DOI=10.1074/jbc.m109.009688; RA Puri R., Suzuki T., Yamakawa K., Ganesh S.; RT "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an RT animal model for Lafora disease."; RL J. Biol. Chem. 284:22657-22663(2009). RN [39] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-713; SER-717; SER-721 AND RP SER-726, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [41] RP GLYCOSYLATION AT SER-525; SER-555 AND SER-717, PHOSPHORYLATION AT SER-519; RP SER-713 SER-717 AND SER-721, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=21327254; DOI=10.1039/c0mb00337a; RA Smet-Nocca C., Broncel M., Wieruszeski J.M., Tokarski C., Hanoulle X., RA Leroy A., Landrieu I., Rolando C., Lippens G., Hackenberger C.P.; RT "Identification of O-GlcNAc sites within peptides of the Tau protein and RT their impact on phosphorylation."; RL Mol. Biosyst. 7:1420-1429(2011). RN [42] RP FUNCTION, AND PHOSPHORYLATION AT THR-529 AND SER-579. RX PubMed=21985311; DOI=10.1111/j.1471-4159.2011.07523.x; RA Yoshida H., Goedert M.; RT "Phosphorylation of microtubule-associated protein tau by AMPK-related RT kinases."; RL J. Neurochem. 120:165-176(2012). RN [43] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519; THR-548; SER-552; RP SER-713 AND SER-721, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [44] RP INTERACTION WITH MARK1; MARK2; MARK3 AND MARK4, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT SER-579. RX PubMed=23666762; DOI=10.1007/s12017-013-8232-3; RA Gu G.J., Lund H., Wu D., Blokzijl A., Classon C., von Euler G., RA Landegren U., Sunnemark D., Kamali-Moghaddam M.; RT "Role of individual MARK isoforms in phosphorylation of tau at Ser262 in RT Alzheimer's disease."; RL NeuroMolecular Med. 15:458-469(2013). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [46] RP INTERACTION WITH LRRK2, AND SUBCELLULAR LOCATION. RX PubMed=26014385; DOI=10.1007/s12035-015-9209-z; RA Guerreiro P.S., Gerhardt E., Lopes da Fonseca T., Baehr M., Outeiro T.F., RA Eckermann K.; RT "LRRK2 Promotes Tau Accumulation, Aggregation and Release."; RL Mol. Neurobiol. 53:3124-3135(2016). RN [47] RP INTERACTION WITH LRP1. RX PubMed=32296178; DOI=10.1038/s41586-020-2156-5; RA Rauch J.N., Luna G., Guzman E., Challis C., Sibih Y.E., Leshuk C., RA Hernandez I., Wegmann S., Hyman B.T., Gradinaru V., Kampmann M., RA Kosik K.S.; RT "LRP1 is a master regulator of tau uptake and spread."; RL Nature 580:381-385(2020). RN [48] RP STRUCTURE BY NMR OF 542-554 IN COMPLEX WITH PIN1. RX PubMed=11313338; DOI=10.1074/jbc.m010327200; RA Wintjens R., Wieruszeski J.-M., Drobecq H., Rousselot-Pailley P., Buee L., RA Lippens G., Landrieu I.; RT "1H NMR study on the binding of Pin1 Trp-Trp domain with phosphothreonine RT peptides."; RL J. Biol. Chem. 276:25150-25156(2001). RN [49] RP SUBCELLULAR LOCATION. RX PubMed=32272059; DOI=10.1016/j.cell.2020.03.031; RA Zhang M., Liu L., Lin X., Wang Y., Li Y., Guo Q., Li S., Sun Y., Tao X., RA Zhang D., Lv X., Zheng L., Ge L.; RT "A Translocation Pathway for Vesicle-Mediated Unconventional Protein RT Secretion."; RL Cell 181:637-652(2020). RN [50] RP REVIEW ON VARIANTS. RX PubMed=10899436; DOI=10.1016/s0925-4439(00)00037-5; RA Goedert M., Spillantini M.G.; RT "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for RT Alzheimer's disease."; RL Biochim. Biophys. Acta 1502:110-121(2000). RN [51] RP VARIANT FTD1 MET-654, VARIANTS ASN-285; ALA-289; HIS-441 AND PRO-447, AND RP INVOLVEMENT IN FTD1. RX PubMed=9629852; DOI=10.1002/ana.410430617; RA Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L., RA Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.; RT "Tau is a candidate gene for chromosome 17 frontotemporal dementia."; RL Ann. Neurol. 43:815-825(1998). RN [52] RP ERRATUM OF PUBMED:9629852. RA Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L., RA Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.; RL Ann. Neurol. 44:428-428(1998). RN [53] RP VARIANT FTD1 LEU-618. RX PubMed=9736786; DOI=10.1093/hmg/7.11.1825; RA Dumanchin C., Camuzat A., Campion D., Verpillat P., Hannequin D., RA Dubois B., Saugier-Veber P., Martin C., Penet C., Charbonnier F., Agid Y., RA Frebourg T., Brice A.; RT "Segregation of a missense mutation in the microtubule-associated protein RT tau gene with familial frontotemporal dementia and parkinsonism."; RL Hum. Mol. Genet. 7:1825-1829(1998). RN [54] RP VARIANTS FTD1 VAL-589; LEU-618 AND TRP-723. RX PubMed=9641683; DOI=10.1038/31508; RA Hutton M., Lendon C.L., Rizzu P., Baker M., Froelich S., Houlden H., RA Pickering-Brown S., Chakraverty S., Isaacs A., Grover A., Hackett J., RA Adamson J., Lincoln S., Dickson D., Davies P., Petersen R.C., Stevens M., RA de Graaff E., Wauters E., van Baren J., Hillebrand M., Joosse M., RA Kwon J.M., Nowotny P., Che L.K., Norton J., Morris J.C., Reed L.A., RA Trojanowski J., Basun H., Lannfelt L., Neystat M., Fahn S., Dark F., RA Tannenberg T., Dodd P.R., Hayward N., Kwok J.B.J., Schofield P.R., RA Andreadis A., Snowden J., Craufurd D., Neary D., Owen F., Oostra B.A., RA Hardy J., Goate A., van Swieten J., Mann D., Lynch T., Heutink P.; RT "Association of missense and 5'-splice-site mutations in tau with the RT inherited dementia FTDP-17."; RL Nature 393:702-705(1998). RN [55] RP VARIANTS FTD1 LYS-596 AND LEU-618. RX PubMed=9789048; DOI=10.1073/pnas.95.22.13103; RA Clark L.N., Poorkaj P., Wszolek Z., Geschwind D.H., Nasreddine Z.S., RA Miller B., Li D., Payami H., Awert F., Markopoulou K., Andreadis A., RA D'Souza I., Lee V.M.-Y., Reed L., Trojanowski J.Q., Zhukareva V., Bird T., RA Schellenberg G., Wilhelmsen K.C.; RT "Pathogenic implications of mutations in the tau gene in pallido-ponto- RT nigral degeneration and related neurodegenerative disorders linked to RT chromosome 17."; RL Proc. Natl. Acad. Sci. U.S.A. 95:13103-13107(1998). RN [56] RP VARIANT PPND LYS-596. RX PubMed=10412802; DOI=10.1007/s004010051052; RA Delisle M.-B., Murrell J.R., Richardson R., Trofatter J.A., Rascol O., RA Soulages X., Mohr M., Calvas P., Ghetti B.; RT "A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a RT tauopathy with dementia and supranuclear palsy."; RL Acta Neuropathol. 98:62-77(1999). RN [57] RP VARIANTS FTD1 VAL-589; LYS-597 DEL; LEU-618 AND TRP-723. RX PubMed=9973279; DOI=10.1086/302256; RA Rizzu P., Van Swieten J.C., Joosse M., Hasegawa M., Stevens M., Tibben A., RA Niermeijer M.F., Hillebrand M., Ravid R., Oostra B.A., Goedert M., RA van Duijn C.M., Heutink P.; RT "High prevalence of mutations in the microtubule-associated protein tau in RT a population study of frontotemporal dementia in the Netherlands."; RL Am. J. Hum. Genet. 64:414-421(1999). RN [58] RP VARIANT FTD1 SER-618. RX PubMed=10553987; RX DOI=10.1002/1531-8249(199911)46:5<708::aid-ana5>3.0.co;2-k; RA Sperfeld A.D., Collatz M.B., Baier H., Palmbach M., Storch A., Schwarz J., RA Tatsch K., Reske S., Joosse M., Heutink P., Ludolph A.C.; RT "FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures RT caused by a novel mutation."; RL Ann. Neurol. 46:708-715(1999). RN [59] RP VARIANTS FTD1 LEU-618; MET-654 AND TRP-723. RX PubMed=10214944; DOI=10.1016/s0014-5793(99)00294-x; RA Nacharaju P., Lewis J., Easson C., Yen S., Hackett J., Hutton M., Yen S.H.; RT "Accelerated filament formation from tau protein with specific FTDP-17 RT missense mutations."; RL FEBS Lett. 447:195-199(1999). RN [60] RP VARIANT FTD1/CBD SER-618. RX PubMed=10374757; DOI=10.1097/00005072-199906000-00011; RA Bugiani O., Murrell J.R., Giaccone G., Hasegawa M., Ghigo G., Tabaton M., RA Morbin M., Primavera A., Carella F., Solaro C., Grisoli M., Savoiardo M., RA Spillantini M.G., Tagliavini F., Goedert M., Ghetti B.; RT "Frontotemporal dementia and corticobasal degeneration in a family with a RT P301S mutation in tau."; RL J. Neuropathol. Exp. Neurol. 58:667-677(1999). RN [61] RP VARIANT PIDB ARG-706. RX PubMed=10604746; DOI=10.1097/00005072-199912000-00002; RA Murrell J.R., Spillantini M.G., Zolo P., Guazzelli M., Smith M.J., RA Hasegawa M., Redi F., Crowther R.A., Pietrini P., Ghetti B., Goedert M.; RT "Tau gene mutation G389R causes a tauopathy with abundant pick body-like RT inclusions and axonal deposits."; RL J. Neuropathol. Exp. Neurol. 58:1207-1226(1999). RN [62] RP VARIANT FTD1 LYS-596. RX PubMed=10489057; DOI=10.1212/wnl.53.4.864; RA Yasuda M., Kawamata T., Komure O., Kuno S., D'Souza I., Poorkaj P., RA Kawai J., Tanimukai S., Yamamoto Y., Hasegawa H., Sasahara M., Hazama F., RA Schellenberg G.D., Tanaka C.; RT "A mutation in the microtubule-associated protein tau in pallido-nigro- RT luysian degeneration."; RL Neurology 53:864-868(1999). RN [63] RP VARIANTS PSNP1 ASN-285 AND ALA-289. RX PubMed=10534245; DOI=10.1212/wnl.53.7.1421; RA Higgins J.J., Adler R.L., Loveless J.M.; RT "Mutational analysis of the tau gene in progressive supranuclear palsy."; RL Neurology 53:1421-1424(1999). RN [64] RP VARIANT FTD1 ASN-622. RX PubMed=10208578; DOI=10.1097/00001756-199902250-00010; RA Iijima M., Tabira T., Poorkaj P., Schellenberg G.D., Trojanowski J.Q., RA Lee V.M.-Y., Schmidt M.L., Takahashi K., Nabika T., Matsumoto T., RA Yamashita Y., Yoshioka S., Ishino H.; RT "A distinct familial presenile dementia with a novel missense mutation in RT the tau gene."; RL NeuroReport 10:497-501(1999). RN [65] RP VARIANT FTD1 VAL-659. RX PubMed=11117541; RX DOI=10.1002/1531-8249(200012)48:6<850::aid-ana5>3.3.co;2-m; RA Lippa C.F., Zhukareva V., Kawarai T., Uryu K., Shafiq M., Nee L.E., RA Grafman J., Liang Y., St George-Hyslop P.H., Trojanowski J.Q., Lee V.M.-Y.; RT "Frontotemporal dementia with novel tau pathology and a Glu342Val tau RT mutation."; RL Ann. Neurol. 48:850-858(2000). RN [66] RP VARIANTS PIDB THR-574 AND ARG-706, AND CHARACTERIZATION OF VARIANTS PIDB RP THR-574 AND ARG-706. RX PubMed=11117542; RX DOI=10.1002/1531-8249(200012)48:6<859::aid-ana6>3.3.co;2-t; RA Pickering-Brown S., Baker M., Yen S.-H., Liu W.-K., Hasegawa M., Cairns N., RA Lantos P.L., Rossor M., Iwatsubo T., Davies Y., Allsop D., Furlong R., RA Owen F., Hardy J., Mann D., Hutton M.; RT "Pick's disease is associated with mutations in the tau gene."; RL Ann. Neurol. 48:859-867(2000). RN [67] RP VARIANT PIDB THR-574. RX PubMed=11089577; DOI=10.1093/jnen/59.11.990; RA Rizzini C., Goedert M., Hodges J.R., Smith M.J., Jakes R., Hills R., RA Xuereb J.H., Crowther R.A., Spillantini M.G.; RT "Tau gene mutation K257T causes a tauopathy similar to Pick's disease."; RL J. Neuropathol. Exp. Neurol. 59:990-1001(2000). RN [68] RP VARIANT FTD1 LYS-596. RX PubMed=10802785; DOI=10.1212/wnl.54.9.1787; RA Arima K., Kowalska A., Hasegawa M., Mukoyama M., Watanabe R., Kawai M., RA Takahashi K., Iwatsubo T., Tabira T., Sunohara N.; RT "Two brothers with frontotemporal dementia and parkinsonism with an N279K RT mutation of the tau gene."; RL Neurology 54:1787-1795(2000). RN [69] RP VARIANT FTD1 SER-618. RX PubMed=11071507; DOI=10.1212/wnl.55.8.1224; RA Yasuda M., Yokoyama K., Nakayasu T., Nishimura Y., Matsui M., Yokoyama T., RA Miyoshi K., Tanaka C.; RT "A Japanese patient with frontotemporal dementia and parkinsonism by a tau RT P301S mutation."; RL Neurology 55:1224-1227(2000). RN [70] RP VARIANT FTD1 HIS-613. RX PubMed=11585254; DOI=10.1007/s004010000333; RA Iseki E., Matsumura T., Marui W., Hino H., Odawara T., Sugiyama N., RA Suzuki K., Sawada H., Arai T., Kosaka K.; RT "Familial frontotemporal dementia and parkinsonism with a novel N296H RT mutation in exon 10 of the tau gene and a widespread tau accumulation in RT the glial cells."; RL Acta Neuropathol. 102:285-292(2001). RN [71] RP VARIANT PSNP1 ASN-613 DEL. RX PubMed=11220749; RX DOI=10.1002/1531-8249(20010201)49:2<263::aid-ana50>3.0.co;2-k; RA Pastor P., Pastor E., Carnero C., Vela R., Garcia T., Amer G., Tolosa E., RA Oliva R.; RT "Familial atypical progressive supranuclear palsy associated with RT homozygosity for the delN296 mutation in the tau gene."; RL Ann. Neurol. 49:263-267(2001). RN [72] RP VARIANT PIDB ILE-686, AND CHARACTERIZATION OF VARIANT PIDB ILE-686. RX PubMed=11601501; DOI=10.1002/ana.1223; RA Neumann M., Schulz-Schaeffer W., Crowther R.A., Smith M.J., RA Spillantini M.G., Goedert M., Kretzschmar H.A.; RT "Pick's disease associated with the novel Tau gene mutation K369I."; RL Ann. Neurol. 50:503-513(2001). RN [73] RP CHARACTERIZATION OF VARIANT FTD1 TRP-723. RX PubMed=11278002; DOI=10.1016/s0014-5793(01)02267-0; RA Connell J.W., Gibb G.M., Betts J.C., Blackstock W.P., Gallo J.-M., RA Lovestone S., Hutton M., Anderton B.H.; RT "Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by RT glycogen synthase kinase 3beta identified by mass spectrometry demonstrate RT certain mutations exert long-range conformational changes."; RL FEBS Lett. 493:40-44(2001). RN [74] RP VARIANT FTD1 LYS-596. RX PubMed=12473774; DOI=10.1212/01.wnl.0000038909.49164.4b; RA Tsuboi Y., Baker M., Hutton M.L., Uitti R.J., Rascol O., Delisle M.-B., RA Soulages X., Murrell J.R., Ghetti B., Yasuda M., Komure O., Kuno S., RA Arima K., Sunohara N., Kobayashi T., Mizuno Y., Wszolek Z.K.; RT "Clinical and genetic studies of families with the tau N279K mutation RT (FTDP-17)."; RL Neurology 59:1791-1793(2002). RN [75] RP VARIANT PIDB PHE-637, AND CHARACTERIZATION OF VARIANT PIDB PHE-637. RX PubMed=11891833; DOI=10.1002/ana.10140; RA Rosso S.M., Van Herpen E., Deelen W., Kamphorst W., Severijnen L.-A., RA Willemsen R., Ravid R., Niermeijer M.F., Dooijes D., Smith M.J., RA Goedert M., Heutink P., Van Swieten J.C.; RT "A novel tau mutation, S320F, causes a tauopathy with inclusions similar to RT those in Pick's disease."; RL Ann. Neurol. 51:373-376(2002). RN [76] RP VARIANT FTD1 HIS-5, AND CHARACTERIZATION OF VARIANT FTD1 HIS-5. RX PubMed=11921059; DOI=10.1002/ana.10163; RA Hayashi S., Toyoshima Y., Hasegawa M., Umeda Y., Wakabayashi K., RA Tokiguchi S., Iwatsubo T., Takahashi H.; RT "Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene RT mutation."; RL Ann. Neurol. 51:525-530(2002). RN [77] RP VARIANT PSNP1 LEU-5, AND CHARACTERIZATION OF VARIANT PSNP1 LEU-5. RX PubMed=12325083; DOI=10.1002/ana.10340; RA Poorkaj P., Muma N.A., Zhukareva V., Cochran E.J., Shannon K.M., Hurtig H., RA Koller W.C., Bird T.D., Trojanowski J.Q., Lee V.M.-Y., Schellenberg G.D.; RT "An R5L tau mutation in a subject with a progressive supranuclear palsy RT phenotype."; RL Ann. Neurol. 52:511-516(2002). RN [78] RP CHARACTERIZATION OF VARIANTS FTD1 ASN-613 DEL AND HIS-613. RX PubMed=11906000; DOI=10.1046/j.0022-3042.2001.00729.x; RA Yoshida H., Crowther R.A., Goedert M.; RT "Functional effects of tau gene mutations deltaN296 and N296H."; RL J. Neurochem. 80:548-551(2002). RN [79] RP VARIANT FTD1 TRP-723. RX PubMed=11889249; DOI=10.1212/wnl.58.5.811; RA Saito Y., Geyer A., Sasaki R., Kuzuhara S., Nanba E., Miyasaka T., RA Suzuki K., Murayama S.; RT "Early-onset, rapidly progressive familial tauopathy with R406W mutation."; RL Neurology 58:811-813(2002). RN [80] RP VARIANT FTD1 VAL-583, AND CHARACTERIZATION OF VARIANT FTD1 VAL-583. RX PubMed=12509859; DOI=10.1002/ana.10447; RA Kobayashi T., Ota S., Tanaka K., Ito Y., Hasegawa M., Umeda Y., Motoi Y., RA Takanashi M., Yasuhara M., Anno M., Mizuno Y., Mori H.; RT "A novel L266V mutation of the tau gene causes frontotemporal dementia with RT a unique tau pathology."; RL Ann. Neurol. 53:133-137(2003). RN [81] RP VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669, AND CHARACTERIZATION OF RP VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669. RX PubMed=14595660; DOI=10.1002/ana.10747; RA Nicholl D.J., Greenstone M.A., Clarke C.E., Rizzu P., Crooks D., Crowe A., RA Trojanowski J.Q., Lee V.M.-Y., Heutink P.; RT "An English kindred with a novel recessive tauopathy and respiratory RT failure."; RL Ann. Neurol. 54:682-686(2003). RN [82] RP VARIANT FTD1/ALZHEIMER DISEASE TRP-723, AND INVOLVEMENT IN ALZHEIMER RP DISEASE. RX PubMed=14517953; DOI=10.1002/humu.10269; RA Rademakers R., Dermaut B., Peeters K., Cruts M., Heutink P., Goate A., RA Van Broeckhoven C.; RT "Tau (MAPT) mutation arg406trp presenting clinically with Alzheimer disease RT does not share a common founder in western Europe."; RL Hum. Mutat. 22:409-411(2003). RN [83] RP VARIANT ATYPICAL PSNP1 ASN-613 DEL. RX PubMed=14991829; DOI=10.1002/ana.20006; RA Rossi G., Gasparoli E., Pasquali C., Di Fede G., Testa D., Albanese A., RA Bracco F., Tagliavini F.; RT "Progressive supranuclear palsy and Parkinson's disease in a family with a RT new mutation in the tau gene."; RL Ann. Neurol. 55:448-448(2004). RN [84] RP VARIANT PSNP1/ATYPICAL PSNP1 ASN-613 DEL. RX PubMed=14991828; DOI=10.1002/ana.20025; RA Oliva R., Pastor P.; RT "Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear RT palsy."; RL Ann. Neurol. 55:448-449(2004). RN [85] RP VARIANT FTD1 SER-618. RX PubMed=16240366; DOI=10.1002/ana.20668; RA Yasuda M., Nakamura Y., Kawamata T., Kaneyuki H., Maeda K., Komure O.; RT "Phenotypic heterogeneity within a new family with the MAPT P301S RT mutation."; RL Ann. Neurol. 58:920-928(2005). RN [86] RP VARIANT PSNP1 VAL-620. RX PubMed=16157753; DOI=10.1001/archneur.62.9.1444; RA Ros R., Thobois S., Streichenberger N., Kopp N., Sanchez M.P., Perez M., RA Hoenicka J., Avila J., Honnorat J., de Yebenes J.G.; RT "A new mutation of the tau gene, G303V, in early-onset familial progressive RT supranuclear palsy."; RL Arch. Neurol. 62:1444-1450(2005). RN [87] RP VARIANT FTD1 MET-634. RX PubMed=15883319; DOI=10.1212/01.wnl.0000160116.65034.12; RA Zarranz J.J., Ferrer I., Lezcano E., Forcadas M.I., Eizaguirre B., RA Atares B., Puig B., Gomez-Esteban J.C., Fernandez-Maiztegui C., Rouco I., RA Perez-Concha T., Fernandez M., Rodriguez O., Rodriguez-Martinez A.B., RA de Pancorbo M.M., Pastor P., Perez-Tur J.; RT "A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron RT disease."; RL Neurology 64:1578-1585(2005). RN [88] RP VARIANTS MET-17; ALA-30 AND ILE-617. RX PubMed=20020531; DOI=10.1002/humu.21152; RA Guerreiro R.J., Washecka N., Hardy J., Singleton A.; RT "A thorough assessment of benign genetic variability in GRN and MAPT."; RL Hum. Mutat. 31:E1126-E1140(2010). RN [89] RP VARIANT FTD1/ALZHEIMER DISEASE TRP-723. RX PubMed=26086902; DOI=10.1016/j.gene.2015.06.033; RA Behnam M., Ghorbani F., Shin J.H., Kim D.S., Jang H., Nouri N., Sedghi M., RA Salehi M., Ansari B., Basiri K.; RT "Homozygous MAPT R406W mutation causing FTDP phenotype: A unique instance RT of a unique mutation."; RL Gene 570:150-152(2015). RN [90] RP VARIANT FTD1 ARG-590, CHARACTERIZATION OF VARIANT FTD1 ARG-590, AND RP FUNCTION. RX PubMed=32961270; DOI=10.1016/j.nbd.2020.105079; RA Sandberg A., Ling H., Gearing M., Dombroski B., Cantwell L., R'Bibo L., RA Levey A., Schellenberg G.D., Hardy J., Wood N., Fernius J., Nystroem S., RA Svensson S., Thor S., Hammarstroem P., Revesz T., Mok K.Y.; RT "Fibrillation and molecular characteristics are coherent with clinical and RT pathological features of 4-repeat tauopathy caused by MAPT variant G273R."; RL Neurobiol. Dis. 146:105079-105079(2020). CC -!- FUNCTION: Promotes microtubule assembly and stability, and might be CC involved in the establishment and maintenance of neuronal polarity CC (PubMed:21985311). The C-terminus binds axonal microtubules while the CC N-terminus binds neural plasma membrane components, suggesting that tau CC functions as a linker protein between both (PubMed:21985311, CC PubMed:32961270). Axonal polarity is predetermined by TAU/MAPT CC localization (in the neuronal cell) in the domain of the cell body CC defined by the centrosome. The short isoforms allow plasticity of the CC cytoskeleton whereas the longer isoforms may preferentially play a role CC in its stabilization. {ECO:0000269|PubMed:21985311, CC ECO:0000269|PubMed:32961270}. CC -!- SUBUNIT: Interacts with MARK1, MARK2, MARK3 and MARK4 CC (PubMed:23666762). Interacts with PSMC2 through SQSTM1 (By similarity). CC Interacts with SQSTM1 when polyubiquitinated (PubMed:15953362). CC Interacts with FKBP4 (By similarity). Binds to CSNK1D CC (PubMed:14761950). Interacts with SGK1 (PubMed:16982696). Interacts CC with EPM2A; the interaction dephosphorylates MAPT at Ser-396 CC (PubMed:19542233). Interacts with PIN1 (PubMed:11313338). Interacts CC with LRRK2 (PubMed:26014385). Interacts with LRP1, leading to CC endocytosis; this interaction is reduced in the presence of LRPAP1/RAP CC (PubMed:32296178). {ECO:0000250|UniProtKB:P10637, CC ECO:0000250|UniProtKB:P19332, ECO:0000269|PubMed:11313338, CC ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19542233, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385, CC ECO:0000269|PubMed:32296178}. CC -!- INTERACTION: CC P10636; P31749: AKT1; NbExp=2; IntAct=EBI-366182, EBI-296087; CC P10636; PRO_0000001987 [P02649]: APOE; NbExp=3; IntAct=EBI-366182, EBI-9209835; CC P10636; P05067: APP; NbExp=8; IntAct=EBI-366182, EBI-77613; CC P10636; PRO_0000000092 [P05067]: APP; NbExp=5; IntAct=EBI-366182, EBI-821758; CC P10636; Q9HC96: CAPN10; NbExp=3; IntAct=EBI-366182, EBI-3915761; CC P10636; Q9NR30: DDX21; NbExp=3; IntAct=EBI-366182, EBI-357942; CC P10636; O43583: DENR; NbExp=2; IntAct=EBI-366182, EBI-716083; CC P10636; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-366182, EBI-25875570; CC P10636; P06241: FYN; NbExp=3; IntAct=EBI-366182, EBI-515315; CC P10636; P49841: GSK3B; NbExp=4; IntAct=EBI-366182, EBI-373586; CC P10636; P11142: HSPA8; NbExp=6; IntAct=EBI-366182, EBI-351896; CC P10636; Q8TCE9: LGALS14; NbExp=3; IntAct=EBI-366182, EBI-10274069; CC P10636; Q9UPY8: MAPRE3; NbExp=3; IntAct=EBI-366182, EBI-726739; CC P10636; P10636: MAPT; NbExp=3; IntAct=EBI-366182, EBI-366182; CC P10636; P04156: PRNP; NbExp=2; IntAct=EBI-366182, EBI-977302; CC P10636; P46779: RPL28; NbExp=4; IntAct=EBI-366182, EBI-366357; CC P10636; P43004: SLC1A2; NbExp=4; IntAct=EBI-366182, EBI-3440986; CC P10636; Q9UNE7: STUB1; NbExp=2; IntAct=EBI-366182, EBI-357085; CC P10636; Q9UNE7-1: STUB1; NbExp=5; IntAct=EBI-366182, EBI-15687717; CC P10636; O15195-2: VILL; NbExp=3; IntAct=EBI-366182, EBI-21845957; CC P10636; P63104: YWHAZ; NbExp=8; IntAct=EBI-366182, EBI-347088; CC P10636; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-366182, EBI-25850811; CC P10636-2; P06241: FYN; NbExp=2; IntAct=EBI-7796412, EBI-515315; CC P10636-2; Q5S007: LRRK2; NbExp=3; IntAct=EBI-7796412, EBI-5323863; CC P10636-2; P31947: SFN; NbExp=2; IntAct=EBI-7796412, EBI-476295; CC P10636-2; P63104: YWHAZ; NbExp=2; IntAct=EBI-7796412, EBI-347088; CC P10636-3; P63104: YWHAZ; NbExp=9; IntAct=EBI-7145070, EBI-347088; CC P10636-5; P06241: FYN; NbExp=2; IntAct=EBI-21313635, EBI-515315; CC P10636-6; P02649: APOE; NbExp=3; IntAct=EBI-7796455, EBI-1222467; CC P10636-6; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-7796455, EBI-25840379; CC P10636-6; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-7796455, EBI-25875570; CC P10636-6; P06241: FYN; NbExp=3; IntAct=EBI-7796455, EBI-515315; CC P10636-6; P11142: HSPA8; NbExp=3; IntAct=EBI-7796455, EBI-351896; CC P10636-6; O60260-5: PRKN; NbExp=3; IntAct=EBI-7796455, EBI-21251460; CC P10636-6; P37840: SNCA; NbExp=3; IntAct=EBI-7796455, EBI-985879; CC P10636-6; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-7796455, EBI-25850811; CC P10636-7; O00499-1: BIN1; NbExp=5; IntAct=EBI-6926270, EBI-6926280; CC P10636-8; P07355: ANXA2; NbExp=10; IntAct=EBI-366233, EBI-352622; CC P10636-8; P08133: ANXA6; NbExp=5; IntAct=EBI-366233, EBI-352541; CC P10636-8; P05067: APP; NbExp=4; IntAct=EBI-366233, EBI-77613; CC P10636-8; O00499-1: BIN1; NbExp=6; IntAct=EBI-366233, EBI-6926280; CC P10636-8; Q14203: DCTN1; NbExp=9; IntAct=EBI-366233, EBI-724352; CC P10636-8; P26196: DDX6; NbExp=10; IntAct=EBI-366233, EBI-351257; CC P10636-8; Q02790: FKBP4; NbExp=7; IntAct=EBI-366233, EBI-1047444; CC P10636-8; Q13451: FKBP5; NbExp=8; IntAct=EBI-366233, EBI-306914; CC P10636-8; P06241: FYN; NbExp=9; IntAct=EBI-366233, EBI-515315; CC P10636-8; P49840: GSK3A; NbExp=2; IntAct=EBI-366233, EBI-1044067; CC P10636-8; P49841: GSK3B; NbExp=12; IntAct=EBI-366233, EBI-373586; CC P10636-8; P08238: HSP90AB1; NbExp=18; IntAct=EBI-366233, EBI-352572; CC P10636-8; P14625: HSP90B1; NbExp=5; IntAct=EBI-366233, EBI-359129; CC P10636-8; Q92743: HTRA1; NbExp=9; IntAct=EBI-366233, EBI-352256; CC P10636-8; Q5S007: LRRK2; NbExp=9; IntAct=EBI-366233, EBI-5323863; CC P10636-8; P10636-8: MAPT; NbExp=6; IntAct=EBI-366233, EBI-366233; CC P10636-8; O43347: MSI1; NbExp=2; IntAct=EBI-366233, EBI-726515; CC P10636-8; Q96DH6: MSI2; NbExp=4; IntAct=EBI-366233, EBI-2462339; CC P10636-8; P07237: P4HB; NbExp=6; IntAct=EBI-366233, EBI-395883; CC P10636-8; Q12765: SCRN1; NbExp=5; IntAct=EBI-366233, EBI-2690712; CC P10636-8; P31947: SFN; NbExp=10; IntAct=EBI-366233, EBI-476295; CC P10636-8; P37840: SNCA; NbExp=12; IntAct=EBI-366233, EBI-985879; CC P10636-8; Q71U36: TUBA1A; NbExp=7; IntAct=EBI-366233, EBI-302552; CC P10636-8; P07437: TUBB; NbExp=4; IntAct=EBI-366233, EBI-350864; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10747907, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385}. Cell CC membrane {ECO:0000269|PubMed:10747907}; Peripheral membrane protein CC {ECO:0000269|PubMed:10747907}; Cytoplasmic side CC {ECO:0000269|PubMed:10747907}. Cytoplasm, cytoskeleton CC {ECO:0000269|PubMed:10747907}. Cell projection, axon CC {ECO:0000269|PubMed:10747907}. Cell projection, dendrite CC {ECO:0000269|PubMed:23666762}. Secreted {ECO:0000269|PubMed:32272059}. CC Note=Mostly found in the axons of neurons, in the cytosol and in CC association with plasma membrane components (PubMed:10747907). Can be CC secreted; the secretion is dependent on protein unfolding and CC facilitated by the cargo receptor TMED10; it results in protein CC translocation from the cytoplasm into the ERGIC (endoplasmic reticulum- CC Golgi intermediate compartment) followed by vesicle entry and secretion CC (PubMed:32272059). {ECO:0000269|PubMed:10747907, CC ECO:0000269|PubMed:32272059}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=9; CC Comment=Additional isoforms seem to exist. Isoforms differ from each CC other by the presence or absence of up to 5 of the 15 exons. One of CC these optional exons contains the additional tau/MAP repeat.; CC Name=PNS-tau; CC IsoId=P10636-1; Sequence=Displayed; CC Name=Fetal-tau; Synonyms=0N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-2; Sequence=VSP_003176, VSP_003177, VSP_003179, CC VSP_003180, VSP_003181; CC Name=Tau-A; CC IsoId=P10636-3; Sequence=VSP_003175, VSP_003176, VSP_003177, CC VSP_003178, VSP_003179, VSP_003180, CC VSP_003181; CC Name=Tau-B; Synonyms=1N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-4; Sequence=VSP_003177, VSP_003179, VSP_003180, CC VSP_003181; CC Name=Tau-C; Synonyms=Tau-3, 2N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-5; Sequence=VSP_003179, VSP_003180, VSP_003181; CC Name=Tau-D; Synonyms=0N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-6; Sequence=VSP_003176, VSP_003177, VSP_003179, CC VSP_003180; CC Name=Tau-E; Synonyms=1N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-7; Sequence=VSP_003177, VSP_003179, VSP_003180; CC Name=Tau-F; Synonyms=Tau-4, 2N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-8; Sequence=VSP_003179, VSP_003180; CC Name=Tau-G; CC IsoId=P10636-9; Sequence=VSP_026780; CC -!- TISSUE SPECIFICITY: Expressed in neurons. Isoform PNS-tau is expressed CC in the peripheral nervous system while the others are expressed in the CC central nervous system. CC -!- DEVELOPMENTAL STAGE: Four-repeat (type II) TAU/MAPT is expressed in an CC adult-specific manner and is not found in fetal brain, whereas three- CC repeat (type I) TAU/MAPT is found in both adult and fetal brain. CC -!- DOMAIN: The tau/MAP repeat binds to tubulin. Type I isoforms contain 3 CC repeats while type II isoforms contain 4 repeats. CC -!- PTM: Phosphorylation at serine and threonine residues in S-P or T-P CC motifs by proline-directed protein kinases (PDPK1, CDK1, CDK5, GSK3, CC MAPK) (only 2-3 sites per protein in interphase, seven-fold increase in CC mitosis, and in the form associated with paired helical filaments (PHF- CC tau)), and at serine residues in K-X-G-S motifs by MAP/microtubule CC affinity-regulating kinase (MARK1, MARK2, MARK3 or MARK4), causing CC detachment from microtubules, and their disassembly (PubMed:23666762, CC PubMed:7706316). Phosphorylation decreases with age. Phosphorylation CC within tau/MAP's repeat domain or in flanking regions seems to reduce CC tau/MAP's interaction with, respectively, microtubules or plasma CC membrane components (PubMed:7706316). Phosphorylation on Ser-610, Ser- CC 622, Ser-641 and Ser-673 in several isoforms during mitosis. CC Phosphorylation at Ser-548 by GSK3B reduces ability to bind and CC stabilize microtubules. Phosphorylation at Ser-579 by BRSK1 and BRSK2 CC in neurons affects ability to bind microtubules and plays a role in CC neuron polarization. Phosphorylated at Ser-554, Ser-579, Ser-602, Ser- CC 606 and Ser-669 by PHK. Phosphorylation at Ser-214 by SGK1 mediates CC microtubule depolymerization and neurite formation in hippocampal CC neurons. There is a reciprocal down-regulation of phosphorylation and CC O-GlcNAcylation. Phosphorylation on Ser-717 completely abolishes the O- CC GlcNAcylation on this site, while phosphorylation on Ser-713 and Ser- CC 721 reduces glycosylation by a factor of 2 and 4 respectively. CC Phosphorylation on Ser-721 is reduced by about 41.5% by GlcNAcylation CC on Ser-717. Dephosphorylated at several serine and threonine residues CC by the serine/threonine phosphatase PPP5C. CC {ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, CC ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19451179, CC ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:21985311, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:7706316, CC ECO:0000269|PubMed:8999860, ECO:0000269|PubMed:9614189}. CC -!- PTM: Polyubiquitinated. Requires functional TRAF6 and may provoke CC SQSTM1-dependent degradation by the proteasome (By similarity). PHF-tau CC can be modified by three different forms of polyubiquitination. 'Lys- CC 48'-linked polyubiquitination is the major form, 'Lys-6'-linked and CC 'Lys-11'-linked polyubiquitination also occur. {ECO:0000250, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16443603}. CC -!- PTM: O-glycosylated. O-GlcNAcylation content is around 8.2%. There is CC reciprocal down-regulation of phosphorylation and O-GlcNAcylation. CC Phosphorylation on Ser-717 completely abolishes the O-GlcNAcylation on CC this site, while phosphorylation on Ser-713 and Ser-721 reduces O- CC GlcNAcylation by a factor of 2 and 4 respectively. O-GlcNAcylation on CC Ser-717 decreases the phosphorylation on Ser-721 by about 41.5%. CC {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15546861, CC ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, CC ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189}. CC -!- PTM: Glycation of PHF-tau, but not normal brain TAU/MAPT. Glycation is CC a non-enzymatic post-translational modification that involves a CC covalent linkage between a sugar and an amino group of a protein CC molecule forming ketoamine. Subsequent oxidation, fragmentation and/or CC cross-linking of ketoamine leads to the production of advanced CC glycation endproducts (AGES). Glycation may play a role in stabilizing CC PHF aggregation leading to tangle formation in AD. CC -!- DISEASE: Note=In Alzheimer disease, the neuronal cytoskeleton in the CC brain is progressively disrupted and replaced by tangles of paired CC helical filaments (PHF) and straight filaments, mainly composed of CC hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation CC is greatly reduced in Alzheimer disease brain cerebral cortex leading CC to an increase in TAU/MAPT phosphorylations. CC {ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902}. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:10208578, ECO:0000269|PubMed:10214944, CC ECO:0000269|PubMed:10374757, ECO:0000269|PubMed:10489057, CC ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:10802785, CC ECO:0000269|PubMed:11071507, ECO:0000269|PubMed:11117541, CC ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11585254, CC ECO:0000269|PubMed:11889249, ECO:0000269|PubMed:11906000, CC ECO:0000269|PubMed:11921059, ECO:0000269|PubMed:12473774, CC ECO:0000269|PubMed:12509859, ECO:0000269|PubMed:14517953, CC ECO:0000269|PubMed:15883319, ECO:0000269|PubMed:16240366, CC ECO:0000269|PubMed:26086902, ECO:0000269|PubMed:32961270, CC ECO:0000269|PubMed:9629852, ECO:0000269|PubMed:9641683, CC ECO:0000269|PubMed:9736786, ECO:0000269|PubMed:9789048, CC ECO:0000269|PubMed:9973279}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:10604746, CC ECO:0000269|PubMed:11089577, ECO:0000269|PubMed:11117542, CC ECO:0000269|PubMed:11601501, ECO:0000269|PubMed:11891833}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Note=Defects in MAPT are a cause of corticobasal degeneration CC (CBD). It is marked by extrapyramidal signs and apraxia and can be CC associated with memory loss. Neuropathologic features may overlap CC Alzheimer disease, progressive supranuclear palsy, and Parkinson CC disease. CC -!- DISEASE: Progressive supranuclear palsy 1 (PSNP1) [MIM:601104]: CC Characterized by akinetic-rigid syndrome, supranuclear gaze palsy, CC pyramidal tract dysfunction, pseudobulbar signs and cognitive CC capacities deterioration. Neurofibrillary tangles and gliosis but no CC amyloid plaques are found in diseased brains. Most cases appear to be CC sporadic, with a significant association with a common haplotype CC including the MAPT gene and the flanking regions. Familial cases show CC an autosomal dominant pattern of transmission with incomplete CC penetrance; genetic analysis of a few cases showed the occurrence of CC tau mutations, including a deletion of Asn-613. CC {ECO:0000269|PubMed:10534245, ECO:0000269|PubMed:11220749, CC ECO:0000269|PubMed:12325083, ECO:0000269|PubMed:14991828, CC ECO:0000269|PubMed:14991829, ECO:0000269|PubMed:16157753}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson-dementia syndrome (PARDE) [MIM:260540]: A syndrome CC characterized by parkinsonism, tremor, rigidity, dementia, CC ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration CC occurs in the hippocampus, basal ganglia and brainstem nuclei. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- WEB RESOURCE: Name=Alzforum; Note=MAPT mutations; CC URL="https://www.alzforum.org/mutations/mapt"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Vita minima - Issue 68 of CC March 2006; CC URL="https://www.proteinspotlight.org/back_issues/068"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tau protein entry; CC URL="https://en.wikipedia.org/wiki/Tau_protein"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J03778; AAA60615.1; -; mRNA. DR EMBL; X14474; CAA32636.1; -; mRNA. DR EMBL; AF047863; AAC04277.1; -; Genomic_DNA. DR EMBL; AF027491; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047856; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047857; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027492; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047858; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047859; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027494; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027491; AAC04278.1; -; Genomic_DNA. DR EMBL; AF027492; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047863; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027491; AAC04279.1; -; Genomic_DNA. DR EMBL; AF047856; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047857; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027492; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027494; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047863; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047861; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AY730549; AAU45390.1; -; mRNA. DR EMBL; BT006772; AAP35418.1; -; mRNA. DR EMBL; AC004139; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC010792; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC217771; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC217779; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000558; AAH00558.1; -; mRNA. DR EMBL; BC098281; AAH98281.1; -; mRNA. DR EMBL; BC099721; AAH99721.1; -; mRNA. DR EMBL; BC101936; AAI01937.1; -; mRNA. DR EMBL; BC114504; AAI14505.1; -; mRNA. DR EMBL; BC114948; AAI14949.1; -; mRNA. DR EMBL; AY526356; AAS17881.1; -; mRNA. DR EMBL; M25298; AAA57264.1; -; mRNA. DR EMBL; BN000503; CAG26750.1; -; mRNA. DR CCDS; CCDS11499.1; -. [P10636-8] DR CCDS; CCDS11500.1; -. [P10636-6] DR CCDS; CCDS11501.1; -. [P10636-1] DR CCDS; CCDS11502.1; -. [P10636-2] DR CCDS; CCDS45715.1; -. [P10636-9] DR CCDS; CCDS45716.1; -. [P10636-7] DR CCDS; CCDS56033.1; -. [P10636-5] DR CCDS; CCDS92347.1; -. [P10636-4] DR PIR; I52232; I52232. DR PIR; JS0370; QRHUT1. DR PIR; PN0001; QRHUT2. DR PIR; S26663; S26663. DR RefSeq; NP_001116538.2; NM_001123066.4. [P10636-9] DR RefSeq; NP_001116539.1; NM_001123067.4. [P10636-7] DR RefSeq; NP_001190180.1; NM_001203251.2. [P10636-4] DR RefSeq; NP_001190181.1; NM_001203252.2. [P10636-5] DR RefSeq; NP_001364197.1; NM_001377268.1. [P10636-2] DR RefSeq; NP_005901.2; NM_005910.5. [P10636-8] DR RefSeq; NP_058518.1; NM_016834.5. [P10636-6] DR RefSeq; NP_058519.3; NM_016835.5. [P10636-1] DR RefSeq; NP_058525.1; NM_016841.5. [P10636-2] DR PDB; 1I8H; NMR; -; A=542-554. DR PDB; 2MZ7; NMR; -; A=584-629. DR PDB; 2ON9; X-ray; 1.51 A; A/B=623-628. DR PDB; 3OVL; X-ray; 1.81 A; A=623-628. DR PDB; 4E0M; X-ray; 1.75 A; A/B/C/D=622-634. DR PDB; 4E0N; X-ray; 1.65 A; A/B/C/D=622-634. DR PDB; 4E0O; X-ray; 1.82 A; A/B/C/D=622-634. DR PDB; 4FL5; X-ray; 1.90 A; P/Q=527-536. DR PDB; 4GLR; X-ray; 1.90 A; A/B=541-557. DR PDB; 4NP8; X-ray; 1.51 A; A=623-628. DR PDB; 4TQE; X-ray; 1.60 A; A=532-547. DR PDB; 4Y32; X-ray; 1.70 A; C/D=528-534. DR PDB; 4Y5I; X-ray; 1.40 A; F/G=528-534. DR PDB; 5DMG; X-ray; 2.50 A; P/X/Z=733-747. DR PDB; 5E2V; X-ray; 1.64 A; P=511-528. DR PDB; 5E2W; X-ray; 1.50 A; P=511-528. DR PDB; 5HF3; X-ray; 1.80 A; B=528-534. DR PDB; 5K7N; EM; 1.10 A; Z=623-628. DR PDB; 5MO3; X-ray; 1.69 A; A=615-628. DR PDB; 5MP1; X-ray; 3.10 A; A/B/E/I=615-628. DR PDB; 5MP3; X-ray; 2.75 A; C/D=609-638. DR PDB; 5MP5; X-ray; 2.31 A; I/J/K=615-628. DR PDB; 5N5A; NMR; -; A=571-607. DR PDB; 5N5B; NMR; -; A=609-636. DR PDB; 5NVB; NMR; -; A=571-585. DR PDB; 5O3L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5O3O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5O3T; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5V5B; EM; 1.50 A; A=591-600. DR PDB; 5V5C; EM; 1.25 A; A=592-597. DR PDB; 5ZIA; X-ray; 2.60 A; C/F/J/N/Q/R=552-560. DR PDB; 5ZV3; X-ray; 2.09 A; A=52-71. DR PDB; 6BB4; X-ray; 2.10 A; P/Q/R=703-725. DR PDB; 6CVJ; EM; 3.20 A; D=514-717. DR PDB; 6CVN; EM; 3.90 A; D=514-717. DR PDB; 6DC8; X-ray; 1.80 A; P=696-725. DR PDB; 6DC9; X-ray; 3.00 A; P/Q=696-725. DR PDB; 6DCA; X-ray; 2.60 A; P/Q/R/S=696-725. DR PDB; 6FBW; X-ray; 1.45 A; B/D=528-533. DR PDB; 6FI5; X-ray; 1.70 A; B=529-533. DR PDB; 6GK7; X-ray; 2.95 A; A=625-635. DR PDB; 6GK8; X-ray; 2.85 A; I=52-71. DR PDB; 6GX5; EM; 3.20 A; A/B/C=602-695. DR PDB; 6H06; X-ray; 2.63 A; G/I/J/K=721-746. DR PDB; 6HRE; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 6HRF; EM; 3.30 A; A/B/C/D/E/F=1-758. DR PDB; 6LRA; X-ray; 1.90 A; C=592-597. DR PDB; 6N4P; X-ray; 1.85 A; A/C=5-10. DR PDB; 6NK4; EM; 1.99 A; A=591-599. DR PDB; 6NWP; EM; 2.30 A; A/B/C/D/E/F=1-758. DR PDB; 6NWQ; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 6ODG; X-ray; 1.00 A; A/B=622-627. DR PDB; 6PXR; X-ray; 1.56 A; A=15-22. DR PDB; 6QJH; EM; 3.30 A; A/B/C=589-647. DR PDB; 6QJM; EM; 3.30 A; A/B/C=591-638. DR PDB; 6QJP; EM; 3.50 A; A/B/C=591-638. DR PDB; 6QJQ; EM; 3.70 A; A/B/C/D/E/F=620-647. DR PDB; 6TJO; EM; 3.20 A; A/B/C=1-758. DR PDB; 6TJX; EM; 3.00 A; A/B/C/D/E/F=1-758. DR PDB; 6VH7; EM; 3.80 A; A/B/C/E/F/G=591-697. DR PDB; 6VHA; EM; 4.30 A; E/F/G=591-697. DR PDB; 6VHL; EM; 3.30 A; E/F=621-697. DR PDB; 6VI3; EM; 3.30 A; E/F=621-697. DR PDB; 6XLI; X-ray; 2.00 A; E/F/P=527-539. DR PDB; 7EYC; X-ray; 2.49 A; P/Q=594-601. DR PDB; 7KQK; X-ray; 2.60 A; C/P=541-550. DR PDB; 7MKF; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7MKG; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7MKH; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRQ; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRS; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRT; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRV; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRX; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P65; EM; 2.70 A; A/B/C/D/E=1-758. DR PDB; 7P66; EM; 3.00 A; A/B/C/D/E=1-758. DR PDB; 7P67; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P68; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P6A; EM; 1.90 A; A/B/C/D/E=1-758. DR PDB; 7P6B; EM; 2.20 A; A/B/C/D/E=1-758. DR PDB; 7P6C; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P6D; EM; 3.30 A; A/B/C/D/E=1-758. DR PDB; 7P6E; EM; 3.40 A; A/B/C/D/E/F/I/J/Q/R=1-758. DR PDB; 7PQC; EM; 4.10 A; O=519-712. DR PDB; 7PQP; EM; 4.10 A; O=519-712. DR PDB; 7QJV; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QJW; EM; 2.81 A; A/B/C/D/E/F=1-758. DR PDB; 7QJX; EM; 2.99 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QJY; EM; 3.14 A; A/B/C/D/E/F=1-758. DR PDB; 7QJZ; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 7QK1; EM; 3.03 A; A/B/C/D/E/F=1-758. DR PDB; 7QK2; EM; 2.61 A; A/B/C/D/E/F=1-758. DR PDB; 7QK3; EM; 2.44 A; A/B/C=1-758. DR PDB; 7QK5; EM; 1.92 A; A/B/C/D/E/F/G/H/K=1-758. DR PDB; 7QK6; EM; 2.27 A; A/B/C=1-758. DR PDB; 7QKF; EM; 2.83 A; A/B/C/D/E/F=1-758. DR PDB; 7QKG; EM; 3.36 A; A/B/C=1-758. DR PDB; 7QKH; EM; 3.17 A; A/B/C/D/E/G=1-758. DR PDB; 7QKI; EM; 3.13 A; A/B/C/D/E/F=1-758. DR PDB; 7QKJ; EM; 3.26 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QKK; EM; 2.80 A; A/B/C=1-758. DR PDB; 7QKL; EM; 2.07 A; A/B/C/D/E/F=1-758. DR PDB; 7QKM; EM; 2.66 A; A/B/C/D/E/F=1-758. DR PDB; 7QKU; EM; 2.57 A; A/B/C/D/E/F=1-758. DR PDB; 7QKV; EM; 3.23 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 7QKW; EM; 2.32 A; A/B/C/D/E/F=1-758. DR PDB; 7QKX; EM; 3.16 A; A/B/C/D/E/G=1-758. DR PDB; 7QKY; EM; 1.86 A; A/B/C/D/E/F=1-758. DR PDB; 7QKZ; EM; 2.65 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 7QL0; EM; 3.13 A; A/B/C/D/E/c=1-758. DR PDB; 7QL1; EM; 3.34 A; A/C/D=1-758. DR PDB; 7QL2; EM; 2.95 A; A/B/C=1-758. DR PDB; 7QL3; EM; 3.32 A; A/B/C/D/E/F=1-758. DR PDB; 7QL4; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 7R4T; EM; 2.75 A; A/B/C/D/E/F=1-758. DR PDB; 7R5H; EM; 2.59 A; A/B/C/D/E/F=1-758. DR PDB; 7SP1; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-758. DR PDB; 7U0Z; EM; 4.20 A; A/B/C=589-698. DR PDB; 7UPE; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7UPF; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7UPG; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7YMN; EM; 3.46 A; A/B/C/D/E/F=614-708. DR PDB; 7YPG; EM; 2.50 A; A/B/C/D/E/F=614-708. DR PDB; 8AZU; EM; 3.10 A; C=1-758. DR PDB; 8BGS; EM; 3.16 A; A/B/C/D/E/F/r=1-758. DR PDB; 8BGV; EM; 3.27 A; A/B/C/D/E/F/n=1-758. DR PDB; 8BYN; EM; 2.60 A; A/B/C/D/E/F=1-758. DR PDB; 8CAQ; EM; 2.30 A; A/B/C/D/E=1-758. DR PDB; 8CAX; EM; 3.70 A; A/B/C/D/E/F=1-758. DR PDB; 8FNZ; EM; 3.88 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f=580-597. DR PDB; 8FUG; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W=623-695. DR PDB; 8FYU; X-ray; 1.85 A; C/E=729-738. DR PDB; 8G54; NMR; -; A/B/C/D/E=515-716. DR PDB; 8G55; NMR; -; A/B/C/D/E/F/G/H/I/J=515-716. DR PDB; 8G58; NMR; -; A/B/C/D/E/F/G/H/I/J=614-708. DR PDB; 8GCK; X-ray; 1.37 A; C/E=733-738. DR PDB; 8KDX; X-ray; 1.01 A; B=524-538. DR PDB; 8OH2; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d=666-680. DR PDB; 8OHI; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=667-679. DR PDB; 8OHP; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679. DR PDB; 8OI0; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679. DR PDB; 8OP0; X-ray; 1.54 A; B=618-629. DR PDB; 8OPI; X-ray; 1.83 A; B=618-629. DR PDB; 8ORE; EM; 2.50 A; A/B/C=404-758. DR PDB; 8ORF; EM; 2.50 A; A/B/C=404-758. DR PDB; 8ORG; EM; 2.30 A; A/B/C=404-758. DR PDB; 8OT6; EM; 2.00 A; A/B/C/D/E=1-758. DR PDB; 8OT9; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 8OTC; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 8OTG; EM; 2.10 A; A/B/C/D/E=1-758. DR PDB; 8OTH; EM; 3.40 A; A/B/C/D/E=1-758. DR PDB; 8OTI; EM; 2.70 A; A/B/C/D/E/F=1-758. DR PDB; 8OTJ; EM; 3.30 A; A/B/C/D/E/F/G=1-758. DR PDB; 8P34; EM; 2.61 A; A=602-695. DR PDB; 8PII; X-ray; 2.35 A; B=618-631. DR PDB; 8PPO; EM; 2.00 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=1-758. DR PDB; 8Q27; EM; 2.02 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2J; EM; 2.23 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2K; EM; 2.88 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2L; EM; 2.20 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7F; EM; 3.72 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7L; EM; 2.82 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7M; EM; 3.26 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q7P; EM; 3.28 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7T; EM; 3.00 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q88; EM; 2.95 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8C; EM; 1.92 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8D; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8E; EM; 3.81 A; A/B/C/D/E/F/G/H/I/J/K/L=427-758. DR PDB; 8Q8F; EM; 2.93 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8L; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8M; EM; 2.95 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8R; EM; 2.10 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8S; EM; 2.68 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q8U; EM; 3.30 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8V; EM; 3.80 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8W; EM; 2.85 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8X; EM; 2.54 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8Y; EM; 2.88 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8Z; EM; 3.16 A; A/B/C/D/E/F=427-758. DR PDB; 8Q92; EM; 3.05 A; A/B/C=588-681. DR PDB; 8Q97; EM; 2.99 A; A/B/C/D/E/F=427-758. DR PDB; 8Q98; EM; 1.75 A; A/B/C/D/E/F=427-758. DR PDB; 8Q99; EM; 2.70 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9A; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9B; EM; 3.10 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9C; EM; 3.40 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9D; EM; 3.16 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9E; EM; 2.97 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9F; EM; 1.91 A; A/B/C/D/E/c=427-758. DR PDB; 8Q9G; EM; 2.65 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9H; EM; 2.18 A; A/B/C/D/E/G=427-758. DR PDB; 8Q9I; EM; 2.56 A; A/C/E=427-758. DR PDB; 8Q9J; EM; 2.96 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9K; EM; 3.20 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9L; EM; 2.76 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q9M; EM; 2.65 A; A/B/C/D/E/G=427-758. DR PDB; 8Q9O; EM; 3.10 A; A/B/C/D/E/G=427-758. DR PDB; 8QCP; EM; 3.21 A; A/B/C/D/E/F=427-758. DR PDB; 8QCR; EM; 2.75 A; A/C/E=427-758. DR PDB; 8QDV; X-ray; 2.50 A; C/F=527-539, C/F=635-648. DR PDB; 8QJJ; EM; 3.35 A; A/B/C/D/E/F=427-758. DR PDB; 8R3T; EM; 3.10 A; A/B/C/D/E/F=1-758. DR PDB; 8SEH; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 8SEI; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 8TTL; EM; 2.60 A; A/B/C/D/E/F=427-758. DR PDB; 8TTN; EM; 2.40 A; A/B/C/D/E=427-758. DR PDB; 8UQ7; EM; 2.31 A; A/B/C/D/E/F=622-696. DR PDB; 8V1N; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J/K/L=612-630. DR PDB; 8WCP; EM; 3.28 A; A/B/C=427-758. DR PDB; 8ZWL; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 8ZWM; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 8ZX6; EM; 3.50 A; A/B/C/D/E/F=1-758. DR PDB; 9B3A; EM; 3.20 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630. DR PDB; 9B3C; EM; 2.95 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630. DR PDB; 9B4L; EM; 3.10 A; 0/1/A/B/C/D/M/N/O/P/Y/Z=1-758. DR PDB; 9B4M; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9B4N; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9B4O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9BBL; EM; 2.50 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 9BBM; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 9BXI; EM; 2.70 A; A/B/C/D/E/F=621-697. DR PDB; 9BXO; EM; 3.00 A; A/B/C/D/E/F=621-697. DR PDB; 9BXQ; EM; 3.10 A; C/D/E/F/G/H=621-697. DR PDB; 9BXR; EM; 3.20 A; C/D/E/F/G/H=621-697. DR PDB; 9CGX; EM; 2.97 A; A/B/C/D/E/F=427-758. DR PDB; 9CGZ; EM; 2.69 A; A/B/C/D/E/F=427-758. DR PDB; 9CZI; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 9CZL; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=622-695. DR PDB; 9DME; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=612-630. DR PDB; 9EO7; EM; 2.80 A; A=1-758. DR PDB; 9EO9; EM; 3.30 A; A/B=1-758. DR PDB; 9EOE; EM; 2.30 A; A=1-758. DR PDB; 9EOG; EM; 3.00 A; A/B/C/D/E/F=1-758. DR PDB; 9EOH; EM; 2.80 A; A/B/C/D/E/F=1-758. DR PDB; 9ERM; EM; 2.30 A; A/B/C/D/E=1-758. DR PDB; 9ERN; EM; 2.50 A; A/B/C/D/E/F=1-758. DR PDB; 9ERO; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9G13; X-ray; 1.80 A; B/D/F/H=686-698. DR PDB; 9GG0; EM; 2.81 A; A/B/C=588-694. DR PDB; 9GG1; EM; 2.26 A; A/B/C/D=590-696. DR PDB; 9GG6; EM; 3.36 A; A/B/C=586-681. DR PDB; 9H5G; EM; 2.48 A; A/B/C/D/E/F=427-758. DR PDB; 9H5J; EM; 2.72 A; A/B/C/D/E/F=427-758. DR PDB; 9HBB; EM; 3.00 A; A/B/C/D/E/F=608-708. DR PDB; 9MR8; EM; 2.90 A; C=590-679. DR PDBsum; 1I8H; -. DR PDBsum; 2MZ7; -. DR PDBsum; 2ON9; -. DR PDBsum; 3OVL; -. DR PDBsum; 4E0M; -. DR PDBsum; 4E0N; -. DR PDBsum; 4E0O; -. DR PDBsum; 4FL5; -. DR PDBsum; 4GLR; -. DR PDBsum; 4NP8; -. DR PDBsum; 4TQE; -. DR PDBsum; 4Y32; -. DR PDBsum; 4Y5I; -. DR PDBsum; 5DMG; -. DR PDBsum; 5E2V; -. DR PDBsum; 5E2W; -. DR PDBsum; 5HF3; -. DR PDBsum; 5K7N; -. DR PDBsum; 5MO3; -. DR PDBsum; 5MP1; -. DR PDBsum; 5MP3; -. DR PDBsum; 5MP5; -. DR PDBsum; 5N5A; -. DR PDBsum; 5N5B; -. DR PDBsum; 5NVB; -. DR PDBsum; 5O3L; -. DR PDBsum; 5O3O; -. DR PDBsum; 5O3T; -. DR PDBsum; 5V5B; -. DR PDBsum; 5V5C; -. DR PDBsum; 5ZIA; -. DR PDBsum; 5ZV3; -. DR PDBsum; 6BB4; -. DR PDBsum; 6CVJ; -. DR PDBsum; 6CVN; -. DR PDBsum; 6DC8; -. DR PDBsum; 6DC9; -. DR PDBsum; 6DCA; -. DR PDBsum; 6FBW; -. DR PDBsum; 6FI5; -. DR PDBsum; 6GK7; -. DR PDBsum; 6GK8; -. DR PDBsum; 6GX5; -. DR PDBsum; 6H06; -. DR PDBsum; 6HRE; -. DR PDBsum; 6HRF; -. DR PDBsum; 6LRA; -. DR PDBsum; 6N4P; -. DR PDBsum; 6NK4; -. DR PDBsum; 6NWP; -. DR PDBsum; 6NWQ; -. DR PDBsum; 6ODG; -. DR PDBsum; 6PXR; -. DR PDBsum; 6QJH; -. DR PDBsum; 6QJM; -. DR PDBsum; 6QJP; -. DR PDBsum; 6QJQ; -. DR PDBsum; 6TJO; -. DR PDBsum; 6TJX; -. DR PDBsum; 6VH7; -. DR PDBsum; 6VHA; -. DR PDBsum; 6VHL; -. DR PDBsum; 6VI3; -. DR PDBsum; 6XLI; -. DR PDBsum; 7EYC; -. DR PDBsum; 7KQK; -. DR PDBsum; 7MKF; -. DR PDBsum; 7MKG; -. DR PDBsum; 7MKH; -. DR PDBsum; 7NRQ; -. DR PDBsum; 7NRS; -. DR PDBsum; 7NRT; -. DR PDBsum; 7NRV; -. DR PDBsum; 7NRX; -. DR PDBsum; 7P65; -. DR PDBsum; 7P66; -. DR PDBsum; 7P67; -. DR PDBsum; 7P68; -. DR PDBsum; 7P6A; -. DR PDBsum; 7P6B; -. DR PDBsum; 7P6C; -. DR PDBsum; 7P6D; -. DR PDBsum; 7P6E; -. DR PDBsum; 7PQC; -. DR PDBsum; 7PQP; -. DR PDBsum; 7QJV; -. DR PDBsum; 7QJW; -. DR PDBsum; 7QJX; -. DR PDBsum; 7QJY; -. DR PDBsum; 7QJZ; -. DR PDBsum; 7QK1; -. DR PDBsum; 7QK2; -. DR PDBsum; 7QK3; -. DR PDBsum; 7QK5; -. DR PDBsum; 7QK6; -. DR PDBsum; 7QKF; -. DR PDBsum; 7QKG; -. DR PDBsum; 7QKH; -. DR PDBsum; 7QKI; -. DR PDBsum; 7QKJ; -. DR PDBsum; 7QKK; -. DR PDBsum; 7QKL; -. DR PDBsum; 7QKM; -. DR PDBsum; 7QKU; -. DR PDBsum; 7QKV; -. DR PDBsum; 7QKW; -. DR PDBsum; 7QKX; -. DR PDBsum; 7QKY; -. DR PDBsum; 7QKZ; -. DR PDBsum; 7QL0; -. DR PDBsum; 7QL1; -. DR PDBsum; 7QL2; -. DR PDBsum; 7QL3; -. DR PDBsum; 7QL4; -. DR PDBsum; 7R4T; -. DR PDBsum; 7R5H; -. DR PDBsum; 7SP1; -. DR PDBsum; 7U0Z; -. DR PDBsum; 7UPE; -. DR PDBsum; 7UPF; -. DR PDBsum; 7UPG; -. DR PDBsum; 7YMN; -. DR PDBsum; 7YPG; -. DR PDBsum; 8AZU; -. DR PDBsum; 8BGS; -. DR PDBsum; 8BGV; -. DR PDBsum; 8BYN; -. DR PDBsum; 8CAQ; -. DR PDBsum; 8CAX; -. DR PDBsum; 8FNZ; -. DR PDBsum; 8FUG; -. DR PDBsum; 8FYU; -. DR PDBsum; 8G54; -. DR PDBsum; 8G55; -. DR PDBsum; 8G58; -. DR PDBsum; 8GCK; -. DR PDBsum; 8KDX; -. DR PDBsum; 8OH2; -. DR PDBsum; 8OHI; -. DR PDBsum; 8OHP; -. DR PDBsum; 8OI0; -. DR PDBsum; 8OP0; -. DR PDBsum; 8OPI; -. DR PDBsum; 8ORE; -. DR PDBsum; 8ORF; -. DR PDBsum; 8ORG; -. DR PDBsum; 8OT6; -. DR PDBsum; 8OT9; -. DR PDBsum; 8OTC; -. DR PDBsum; 8OTG; -. DR PDBsum; 8OTH; -. DR PDBsum; 8OTI; -. DR PDBsum; 8OTJ; -. DR PDBsum; 8P34; -. DR PDBsum; 8PII; -. DR PDBsum; 8PPO; -. DR PDBsum; 8Q27; -. DR PDBsum; 8Q2J; -. DR PDBsum; 8Q2K; -. DR PDBsum; 8Q2L; -. DR PDBsum; 8Q7F; -. DR PDBsum; 8Q7L; -. DR PDBsum; 8Q7M; -. DR PDBsum; 8Q7P; -. DR PDBsum; 8Q7T; -. DR PDBsum; 8Q88; -. DR PDBsum; 8Q8C; -. DR PDBsum; 8Q8D; -. DR PDBsum; 8Q8E; -. DR PDBsum; 8Q8F; -. DR PDBsum; 8Q8L; -. DR PDBsum; 8Q8M; -. DR PDBsum; 8Q8R; -. DR PDBsum; 8Q8S; -. DR PDBsum; 8Q8U; -. DR PDBsum; 8Q8V; -. DR PDBsum; 8Q8W; -. DR PDBsum; 8Q8X; -. DR PDBsum; 8Q8Y; -. DR PDBsum; 8Q8Z; -. DR PDBsum; 8Q92; -. DR PDBsum; 8Q97; -. DR PDBsum; 8Q98; -. DR PDBsum; 8Q99; -. DR PDBsum; 8Q9A; -. DR PDBsum; 8Q9B; -. DR PDBsum; 8Q9C; -. DR PDBsum; 8Q9D; -. DR PDBsum; 8Q9E; -. DR PDBsum; 8Q9F; -. DR PDBsum; 8Q9G; -. DR PDBsum; 8Q9H; -. DR PDBsum; 8Q9I; -. DR PDBsum; 8Q9J; -. DR PDBsum; 8Q9K; -. DR PDBsum; 8Q9L; -. DR PDBsum; 8Q9M; -. DR PDBsum; 8Q9O; -. DR PDBsum; 8QCP; -. DR PDBsum; 8QCR; -. DR PDBsum; 8QDV; -. DR PDBsum; 8QJJ; -. DR PDBsum; 8R3T; -. DR PDBsum; 8SEH; -. DR PDBsum; 8SEI; -. DR PDBsum; 8TTL; -. DR PDBsum; 8TTN; -. DR PDBsum; 8UQ7; -. DR PDBsum; 8V1N; -. DR PDBsum; 8WCP; -. DR PDBsum; 8ZWL; -. DR PDBsum; 8ZWM; -. DR PDBsum; 8ZX6; -. DR PDBsum; 9B3A; -. DR PDBsum; 9B3C; -. DR PDBsum; 9B4L; -. DR PDBsum; 9B4M; -. DR PDBsum; 9B4N; -. DR PDBsum; 9B4O; -. DR PDBsum; 9BBL; -. DR PDBsum; 9BBM; -. DR PDBsum; 9BXI; -. DR PDBsum; 9BXO; -. DR PDBsum; 9BXQ; -. DR PDBsum; 9BXR; -. DR PDBsum; 9CGX; -. DR PDBsum; 9CGZ; -. DR PDBsum; 9CZI; -. DR PDBsum; 9CZL; -. DR PDBsum; 9DME; -. DR PDBsum; 9EO7; -. DR PDBsum; 9EO9; -. DR PDBsum; 9EOE; -. DR PDBsum; 9EOG; -. DR PDBsum; 9EOH; -. DR PDBsum; 9ERM; -. DR PDBsum; 9ERN; -. DR PDBsum; 9ERO; -. DR PDBsum; 9G13; -. DR PDBsum; 9GG0; -. DR PDBsum; 9GG1; -. DR PDBsum; 9GG6; -. DR PDBsum; 9H5G; -. DR PDBsum; 9H5J; -. DR PDBsum; 9HBB; -. DR PDBsum; 9MR8; -. DR AlphaFoldDB; P10636; -. DR BMRB; P10636; -. DR EMDB; EMD-0077; -. DR EMDB; EMD-0259; -. DR EMDB; EMD-0260; -. DR EMDB; EMD-0527; -. DR EMDB; EMD-0528; -. DR EMDB; EMD-10512; -. DR EMDB; EMD-10514; -. DR EMDB; EMD-12549; -. DR EMDB; EMD-12550; -. DR EMDB; EMD-12551; -. DR EMDB; EMD-12552; -. DR EMDB; EMD-12553; -. DR EMDB; EMD-13218; -. DR EMDB; EMD-13219; -. DR EMDB; EMD-13220; -. DR EMDB; EMD-13221; -. DR EMDB; EMD-13223; -. DR EMDB; EMD-13224; -. DR EMDB; EMD-13225; -. DR EMDB; EMD-13226; -. DR EMDB; EMD-13227; -. DR EMDB; EMD-14023; -. DR EMDB; EMD-14024; -. DR EMDB; EMD-14025; -. DR EMDB; EMD-14026; -. DR EMDB; EMD-14027; -. DR EMDB; EMD-14028; -. DR EMDB; EMD-14029; -. DR EMDB; EMD-14030; -. DR EMDB; EMD-14038; -. DR EMDB; EMD-14039; -. DR EMDB; EMD-14040; -. DR EMDB; EMD-14041; -. DR EMDB; EMD-14042; -. DR EMDB; EMD-14043; -. DR EMDB; EMD-14044; -. DR EMDB; EMD-14045; -. DR EMDB; EMD-14046; -. DR EMDB; EMD-14047; -. DR EMDB; EMD-14053; -. DR EMDB; EMD-14054; -. DR EMDB; EMD-14055; -. DR EMDB; EMD-14056; -. DR EMDB; EMD-14057; -. DR EMDB; EMD-14058; -. DR EMDB; EMD-14059; -. DR EMDB; EMD-14060; -. DR EMDB; EMD-14061; -. DR EMDB; EMD-14062; -. DR EMDB; EMD-14063; -. DR EMDB; EMD-14316; -. DR EMDB; EMD-14320; -. DR EMDB; EMD-15772; -. DR EMDB; EMD-16035; -. DR EMDB; EMD-16039; -. DR EMDB; EMD-16329; -. DR EMDB; EMD-16532; -. DR EMDB; EMD-16535; -. DR EMDB; EMD-16876; -. DR EMDB; EMD-16881; -. DR EMDB; EMD-16883; -. DR EMDB; EMD-16886; -. DR EMDB; EMD-17121; -. DR EMDB; EMD-17122; -. DR EMDB; EMD-17123; -. DR EMDB; EMD-17171; -. DR EMDB; EMD-17173; -. DR EMDB; EMD-17174; -. DR EMDB; EMD-17178; -. DR EMDB; EMD-17179; -. DR EMDB; EMD-17180; -. DR EMDB; EMD-17181; -. DR EMDB; EMD-17383; -. DR EMDB; EMD-17806; -. DR EMDB; EMD-18070; -. DR EMDB; EMD-18109; -. DR EMDB; EMD-18111; -. DR EMDB; EMD-18112; -. DR EMDB; EMD-18215; -. DR EMDB; EMD-18219; -. DR EMDB; EMD-18224; -. DR EMDB; EMD-18228; -. DR EMDB; EMD-18233; -. DR EMDB; EMD-18249; -. DR EMDB; EMD-18250; -. DR EMDB; EMD-18251; -. DR EMDB; EMD-18252; -. DR EMDB; EMD-18253; -. DR EMDB; EMD-18254; -. DR EMDB; EMD-18255; -. DR EMDB; EMD-18258; -. DR EMDB; EMD-18259; -. DR EMDB; EMD-18261; -. DR EMDB; EMD-18262; -. DR EMDB; EMD-18263; -. DR EMDB; EMD-18264; -. DR EMDB; EMD-18265; -. DR EMDB; EMD-18266; -. DR EMDB; EMD-18268; -. DR EMDB; EMD-18270; -. DR EMDB; EMD-18271; -. DR EMDB; EMD-18272; -. DR EMDB; EMD-18273; -. DR EMDB; EMD-18275; -. DR EMDB; EMD-18276; -. DR EMDB; EMD-18277; -. DR EMDB; EMD-18278; -. DR EMDB; EMD-18279; -. DR EMDB; EMD-18280; -. DR EMDB; EMD-18281; -. DR EMDB; EMD-18282; -. DR EMDB; EMD-18283; -. DR EMDB; EMD-18284; -. DR EMDB; EMD-18285; -. DR EMDB; EMD-18286; -. DR EMDB; EMD-18287; -. DR EMDB; EMD-18331; -. DR EMDB; EMD-18333; -. DR EMDB; EMD-18448; -. DR EMDB; EMD-18874; -. DR EMDB; EMD-18990; -. DR EMDB; EMD-19846; -. DR EMDB; EMD-19849; -. DR EMDB; EMD-19852; -. DR EMDB; EMD-19854; -. DR EMDB; EMD-19855; -. DR EMDB; EMD-19926; -. DR EMDB; EMD-19927; -. DR EMDB; EMD-19928; -. DR EMDB; EMD-21200; -. DR EMDB; EMD-21201; -. DR EMDB; EMD-21207; -. DR EMDB; EMD-26268; -. DR EMDB; EMD-29458; -. DR EMDB; EMD-33934; -. DR EMDB; EMD-33999; -. DR EMDB; EMD-35403; -. DR EMDB; EMD-35404; -. DR EMDB; EMD-35405; -. DR EMDB; EMD-35406; -. DR EMDB; EMD-35407; -. DR EMDB; EMD-35408; -. DR EMDB; EMD-35409; -. DR EMDB; EMD-3741; -. DR EMDB; EMD-3742; -. DR EMDB; EMD-3743; -. DR EMDB; EMD-3744; -. DR EMDB; EMD-40411; -. DR EMDB; EMD-40413; -. DR EMDB; EMD-41610; -. DR EMDB; EMD-41611; -. DR EMDB; EMD-42463; -. DR EMDB; EMD-42886; -. DR EMDB; EMD-44133; -. DR EMDB; EMD-44134; -. DR EMDB; EMD-44184; -. DR EMDB; EMD-44185; -. DR EMDB; EMD-44186; -. DR EMDB; EMD-44187; -. DR EMDB; EMD-44421; -. DR EMDB; EMD-44422; -. DR EMDB; EMD-45005; -. DR EMDB; EMD-45007; -. DR EMDB; EMD-45008; -. DR EMDB; EMD-45009; -. DR EMDB; EMD-45588; -. DR EMDB; EMD-45589; -. DR EMDB; EMD-4563; -. DR EMDB; EMD-4565; -. DR EMDB; EMD-4566; -. DR EMDB; EMD-46417; -. DR EMDB; EMD-46420; -. DR EMDB; EMD-46689; -. DR EMDB; EMD-47002; -. DR EMDB; EMD-48555; -. DR EMDB; EMD-50148; -. DR EMDB; EMD-50152; -. DR EMDB; EMD-50153; -. DR EMDB; EMD-50155; -. DR EMDB; EMD-50156; -. DR EMDB; EMD-50157; -. DR EMDB; EMD-50159; -. DR EMDB; EMD-50160; -. DR EMDB; EMD-50161; -. DR EMDB; EMD-50162; -. DR EMDB; EMD-50441; -. DR EMDB; EMD-51319; -. DR EMDB; EMD-51320; -. DR EMDB; EMD-51325; -. DR EMDB; EMD-51884; -. DR EMDB; EMD-51886; -. DR EMDB; EMD-52014; -. DR EMDB; EMD-53527; -. DR EMDB; EMD-53530; -. DR EMDB; EMD-54485; -. DR EMDB; EMD-60531; -. DR EMDB; EMD-60532; -. DR EMDB; EMD-60533; -. DR EMDB; EMD-60539; -. DR EMDB; EMD-71636; -. DR EMDB; EMD-7520; -. DR EMDB; EMD-7522; -. DR EMDB; EMD-7523; -. DR EMDB; EMD-7769; -. DR EMDB; EMD-7771; -. DR EMDB; EMD-8634; -. DR EMDB; EMD-8635; -. DR SASBDB; P10636; -. DR SMR; P10636; -. DR BioGRID; 110308; 1104. DR CORUM; P10636; -. DR DIP; DIP-29753N; -. DR ELM; P10636; -. DR FunCoup; P10636; 523. DR IntAct; P10636; 2082. DR MINT; P10636; -. DR STRING; 9606.ENSP00000340820; -. DR BindingDB; P10636; -. DR ChEMBL; CHEMBL1293224; -. DR DrugBank; DB00637; Astemizole. DR DrugBank; DB15033; Flortaucipir. DR DrugBank; DB14914; Flortaucipir F-18. DR DrugBank; DB00448; Lansoprazole. DR DrugBank; DB05565; PBT-1033. DR DrugCentral; P10636; -. DR GlyConnect; 2885; 1 O-GlcNAc glycan (6 sites). DR GlyCosmos; P10636; 34 sites, 1 glycan. DR GlyGen; P10636; 12 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (6 sites). DR iPTMnet; P10636; -. DR MetOSite; P10636; -. DR PhosphoSitePlus; P10636; -. DR SwissPalm; P10636; -. DR BioMuta; MAPT; -. DR DMDM; 334302961; -. DR jPOST; P10636; -. DR MassIVE; P10636; -. DR PaxDb; 9606-ENSP00000340820; -. DR PeptideAtlas; P10636; -. DR ProteomicsDB; 52624; -. [P10636-1] DR ProteomicsDB; 52625; -. [P10636-2] DR ProteomicsDB; 52626; -. [P10636-3] DR ProteomicsDB; 52627; -. [P10636-4] DR ProteomicsDB; 52628; -. [P10636-5] DR ProteomicsDB; 52629; -. [P10636-6] DR ProteomicsDB; 52630; -. [P10636-7] DR ProteomicsDB; 52631; -. [P10636-8] DR ProteomicsDB; 52632; -. [P10636-9] DR Pumba; P10636; -. DR TopDownProteomics; P10636-3; -. [P10636-3] DR ABCD; P10636; 86 sequenced antibodies. DR Antibodypedia; 3124; 5679 antibodies from 54 providers. DR DNASU; 4137; -. DR Ensembl; ENST00000334239.12; ENSP00000334886.8; ENSG00000186868.19. [P10636-2] DR Ensembl; ENST00000351559.10; ENSP00000303214.7; ENSG00000186868.19. [P10636-8] DR Ensembl; ENST00000415613.6; ENSP00000410838.2; ENSG00000186868.19. [P10636-9] DR Ensembl; ENST00000420682.7; ENSP00000413056.2; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000431008.7; ENSP00000389250.3; ENSG00000186868.19. [P10636-5] DR Ensembl; ENST00000446361.7; ENSP00000408975.3; ENSG00000186868.19. [P10636-6] DR Ensembl; ENST00000535772.6; ENSP00000443028.2; ENSG00000186868.19. [P10636-4] DR Ensembl; ENST00000571987.5; ENSP00000458742.1; ENSG00000186868.19. [P10636-1] DR Ensembl; ENST00000574436.5; ENSP00000460965.1; ENSG00000186868.19. [P10636-8] DR Ensembl; ENST00000612872.4; ENSP00000478602.1; ENSG00000277956.4. [P10636-7] DR Ensembl; ENST00000613360.4; ENSP00000483784.1; ENSG00000276155.4. [P10636-7] DR Ensembl; ENST00000620070.4; ENSP00000484491.1; ENSG00000277956.4. [P10636-8] DR Ensembl; ENST00000620818.4; ENSP00000484321.1; ENSG00000277956.4. [P10636-5] DR Ensembl; ENST00000620981.4; ENSP00000481769.1; ENSG00000276155.4. [P10636-5] DR Ensembl; ENST00000621329.4; ENSP00000477703.1; ENSG00000276155.4. [P10636-8] DR Ensembl; ENST00000622106.2; ENSP00000482244.1; ENSG00000277956.4. [P10636-6] DR Ensembl; ENST00000622728.1; ENSP00000479142.1; ENSG00000276155.4. [P10636-6] DR Ensembl; ENST00000626571.2; ENSP00000486039.1; ENSG00000276155.4. [P10636-6] DR Ensembl; ENST00000628393.2; ENSP00000487570.1; ENSG00000276155.4. [P10636-2] DR Ensembl; ENST00000631447.1; ENSP00000488373.1; ENSG00000277956.4. [P10636-5] DR Ensembl; ENST00000632500.1; ENSP00000487837.1; ENSG00000277956.4. [P10636-7] DR Ensembl; ENST00000633047.1; ENSP00000488245.1; ENSG00000277956.4. [P10636-2] DR Ensembl; ENST00000634049.1; ENSP00000487819.1; ENSG00000277956.4. [P10636-8] DR Ensembl; ENST00000680542.1; ENSP00000505258.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703922.1; ENSP00000515557.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703923.1; ENSP00000515558.1; ENSG00000186868.19. [P10636-6] DR Ensembl; ENST00000703924.1; ENSP00000515559.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703978.1; ENSP00000515600.1; ENSG00000186868.19. [P10636-8] DR GeneID; 4137; -. DR KEGG; hsa:4137; -. DR UCSC; uc002ijr.5; human. [P10636-1] DR AGR; HGNC:6893; -. DR ClinPGx; PA238; -. DR CTD; 4137; -. DR DisGeNET; 4137; -. DR GeneCards; MAPT; -. DR GeneReviews; MAPT; -. DR HGNC; HGNC:6893; MAPT. DR HPA; ENSG00000186868; Tissue enhanced (brain, skeletal muscle). DR MalaCards; MAPT; -. DR MIM; 157140; gene+phenotype. DR MIM; 172700; phenotype. DR MIM; 260540; phenotype. DR MIM; 600274; phenotype. DR MIM; 601104; phenotype. DR OpenTargets; ENSG00000186868; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 240071; Classic progressive supranuclear palsy syndrome. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 240103; Progressive supranuclear palsy-corticobasal syndrome. DR Orphanet; 240085; Progressive supranuclear palsy-predominant parkinsonism syndrome. DR Orphanet; 240112; Progressive supranuclear palsy-progressive non-fluent aphasia syndrome. DR Orphanet; 240094; Progressive supranuclear palsy-pure akinesia with gait freezing syndrome. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000186868; -. DR eggNOG; KOG2418; Eukaryota. DR GeneTree; ENSGT00940000155494; -. DR HOGENOM; CLU_021741_2_0_1; -. DR InParanoid; P10636; -. DR OrthoDB; 9378527at2759; -. DR PAN-GO; P10636; 4 GO annotations based on evolutionary models. DR PathwayCommons; P10636; -. DR Reactome; R-HSA-264870; Caspase-mediated cleavage of cytoskeletal proteins. DR Reactome; R-HSA-9619483; Activation of AMPK downstream of NMDARs. [P10636-8] DR Reactome; R-HSA-9833482; PKR-mediated signaling. [P10636-8] DR SABIO-RK; P10636; -. DR SignaLink; P10636; -. DR SIGNOR; P10636; -. DR Agora; ENSG00000186868; -. DR BioGRID-ORCS; 4137; 23 hits in 1151 CRISPR screens. DR CD-CODE; 03D56D03; Tau inclusion. DR CD-CODE; 24B12ACB; Synthetic Condensate 000346. DR CD-CODE; 804901D1; Nuclear speckle. DR CD-CODE; 8188F968; Tau-Prion Multiphasic condensate. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; MAPT; human. DR EvolutionaryTrace; P10636; -. DR GeneWiki; Tau_protein; -. DR GenomeRNAi; 4137; -. DR Pharos; P10636; Tclin. DR PRO; PR:P10636; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P10636; protein. DR Bgee; ENSG00000186868; Expressed in cortical plate and 104 other cell types or tissues. DR ExpressionAtlas; P10636; baseline and differential. DR GO; GO:0030673; C:axolemma; IDA:CAFA. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:CAFA. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0043197; C:dendritic spine; TAS:ARUK-UCL. DR GO; GO:0005576; C:extracellular region; NAS:ARUK-UCL. DR GO; GO:0097386; C:glial cell projection; ISS:ARUK-UCL. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0044304; C:main axon; ISS:ARUK-UCL. DR GO; GO:0045121; C:membrane raft; ISS:ARUK-UCL. DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW. DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:CAFA. DR GO; GO:0005739; C:mitochondrion; TAS:ARUK-UCL. DR GO; GO:0097418; C:neurofibrillary tangle; IDA:CAFA. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0043025; C:neuronal cell body; IMP:ParkinsonsUK-UCL. DR GO; GO:0034399; C:nuclear periphery; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:ParkinsonsUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0036477; C:somatodendritic compartment; IMP:ParkinsonsUK-UCL. DR GO; GO:0045298; C:tubulin complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; TAS:ARUK-UCL. DR GO; GO:0034185; F:apolipoprotein binding; IPI:BHF-UCL. DR GO; GO:0003677; F:DNA binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0003690; F:double-stranded DNA binding; TAS:ARUK-UCL. DR GO; GO:0034452; F:dynactin binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:ARUK-UCL. DR GO; GO:0099077; F:histone-dependent DNA binding; TAS:ARUK-UCL. DR GO; GO:0051879; F:Hsp90 protein binding; IPI:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IDA:CAFA. DR GO; GO:0071813; F:lipoprotein particle binding; IPI:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0099609; F:microtubule lateral binding; IMP:CAFA. DR GO; GO:0003680; F:minor groove of adenine-thymine-rich DNA binding; TAS:ARUK-UCL. DR GO; GO:0035091; F:phosphatidylinositol binding; TAS:ARUK-UCL. DR GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; TAS:ARUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL. DR GO; GO:0051721; F:protein phosphatase 2A binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:ARUK-UCL. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; TAS:ARUK-UCL. DR GO; GO:0003723; F:RNA binding; TAS:ARUK-UCL. DR GO; GO:0043565; F:sequence-specific DNA binding; TAS:ARUK-UCL. DR GO; GO:0017124; F:SH3 domain binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; TAS:ARUK-UCL. DR GO; GO:1990000; P:amyloid fibril formation; IDA:DisProt. DR GO; GO:0048143; P:astrocyte activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0061564; P:axon development; TAS:ARUK-UCL. DR GO; GO:0098930; P:axonal transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0019896; P:axonal transport of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0007267; P:cell-cell signaling; NAS:ARUK-UCL. DR GO; GO:1990416; P:cellular response to brain-derived neurotrophic factor stimulus; TAS:ARUK-UCL. DR GO; GO:0034605; P:cellular response to heat; TAS:ParkinsonsUK-UCL. DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; TAS:ARUK-UCL. DR GO; GO:0034614; P:cellular response to reactive oxygen species; TAS:ARUK-UCL. DR GO; GO:0021954; P:central nervous system neuron development; TAS:ARUK-UCL. DR GO; GO:0031122; P:cytoplasmic microtubule organization; TAS:ParkinsonsUK-UCL. DR GO; GO:0006974; P:DNA damage response; IMP:ParkinsonsUK-UCL. DR GO; GO:0048699; P:generation of neurons; NAS:UniProtKB. DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:ParkinsonsUK-UCL. DR GO; GO:0007611; P:learning or memory; IMP:ARUK-UCL. DR GO; GO:0007613; P:memory; IMP:ParkinsonsUK-UCL. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0000226; P:microtubule cytoskeleton organization; IDA:UniProtKB. DR GO; GO:0046785; P:microtubule polymerization; IDA:ARUK-UCL. DR GO; GO:1903748; P:negative regulation of establishment of protein localization to mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ARUK-UCL. DR GO; GO:0010917; P:negative regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:1902988; P:neurofibrillary tangle assembly; NAS:ParkinsonsUK-UCL. DR GO; GO:0031175; P:neuron projection development; IBA:GO_Central. DR GO; GO:0072386; P:plus-end-directed organelle transport along microtubule; TAS:ParkinsonsUK-UCL. DR GO; GO:0045773; P:positive regulation of axon extension; IDA:UniProtKB. DR GO; GO:0031116; P:positive regulation of microtubule polymerization; IDA:UniProtKB. DR GO; GO:1903829; P:positive regulation of protein localization; IMP:CAFA. DR GO; GO:1902474; P:positive regulation of protein localization to synapse; IMP:ParkinsonsUK-UCL. DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IMP:ARUK-UCL. DR GO; GO:0051260; P:protein homooligomerization; IPI:ARUK-UCL. DR GO; GO:0051258; P:protein polymerization; IMP:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IGI:MGI. DR GO; GO:0050848; P:regulation of calcium-mediated signaling; IDA:ARUK-UCL. DR GO; GO:1900034; P:regulation of cellular response to heat; IMP:ParkinsonsUK-UCL. DR GO; GO:0033044; P:regulation of chromosome organization; TAS:ARUK-UCL. DR GO; GO:1900452; P:regulation of long-term synaptic depression; TAS:ARUK-UCL. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IMP:CAFA. DR GO; GO:0031113; P:regulation of microtubule polymerization; TAS:ARUK-UCL. DR GO; GO:0031110; P:regulation of microtubule polymerization or depolymerization; IMP:CAFA. DR GO; GO:0060632; P:regulation of microtubule-based movement; IGI:ARUK-UCL. DR GO; GO:0090140; P:regulation of mitochondrial fission; IC:ParkinsonsUK-UCL. DR GO; GO:0048167; P:regulation of synaptic plasticity; TAS:ARUK-UCL. DR GO; GO:0010288; P:response to lead ion; ISS:ARUK-UCL. DR GO; GO:0016072; P:rRNA metabolic process; TAS:ARUK-UCL. DR GO; GO:0034063; P:stress granule assembly; TAS:ARUK-UCL. DR GO; GO:0097435; P:supramolecular fiber organization; IDA:CAFA. DR GO; GO:0007416; P:synapse assembly; IMP:ARUK-UCL. DR GO; GO:0050808; P:synapse organization; IMP:ParkinsonsUK-UCL. DR DisProt; DP01100; -. [P10636-8] DR DisProt; DP03552; -. [P10636-2] DR InterPro; IPR027324; MAP2/MAP4/Tau. DR InterPro; IPR001084; MAP_tubulin-bd_rpt. DR InterPro; IPR002955; Tau. DR PANTHER; PTHR11501; MICROTUBULE-ASSOCIATED PROTEIN; 1. DR PANTHER; PTHR11501:SF14; MICROTUBULE-ASSOCIATED PROTEIN TAU; 1. DR Pfam; PF00418; Tubulin-binding; 4. DR PRINTS; PR01261; TAUPROTEIN. DR PROSITE; PS00229; TAU_MAP_1; 4. DR PROSITE; PS51491; TAU_MAP_2; 4. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Cell membrane; Cell projection; Cytoplasm; Cytoskeleton; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycation; KW Glycoprotein; Isopeptide bond; Membrane; Methylation; Microtubule; KW Neurodegeneration; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:1512244" FT CHAIN 2..758 FT /note="Microtubule-associated protein tau" FT /id="PRO_0000072739" FT REPEAT 561..591 FT /note="Tau/MAP 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 592..622 FT /note="Tau/MAP 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 623..653 FT /note="Tau/MAP 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 654..685 FT /note="Tau/MAP 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REGION 1..573 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 561..685 FT /note="Microtubule-binding domain" FT /evidence="ECO:0000269|PubMed:7706316" FT REGION 715..734 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..26 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 61..71 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 179..189 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 207..216 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 217..228 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 314..323 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 324..340 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 344..356 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 381..393 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 442..453 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 455..466 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 491..503 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 504..531 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 718..733 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 24 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 44 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 67 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 381 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 391 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 392 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 394 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 465 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 497 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 507 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 541 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 557 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 571 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 574 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 584 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 591 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 607 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 611 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 615 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 628 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 634 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 638 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 648 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 657 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 660 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 687 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 692 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 700 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 702 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 712 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 755 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 18 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:14999081" FT MOD_RES 29 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 46 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 61 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 69 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 71 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 111 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 214 FT /note="Phosphoserine; by SGK1" FT /evidence="ECO:0000269|PubMed:16982696" FT MOD_RES 470 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:9614189" FT MOD_RES 472 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 480 FT /note="N6,N6-dimethyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 480 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 484 FT /note="Deamidated asparagine; in tau and PHF-tau; partial" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 486 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 492 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 498 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:15546861" FT MOD_RES 502 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 512 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 514 FT /note="Phosphotyrosine; by TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 515 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 516 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 519 FT /note="Phosphoserine; by CK1, PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16923168, FT ECO:0000269|PubMed:19451179, ECO:0000269|PubMed:21327254, FT ECO:0000269|PubMed:9614189, ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 522 FT /note="Phosphothreonine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179" FT MOD_RES 529 FT /note="Phosphothreonine; by BRSK1, BRSK2, DYRK2 and PDPK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:9614189" FT MOD_RES 531 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 534 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:19451179" FT MOD_RES 542 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 548 FT /note="Phosphothreonine; by GSK3-beta and PDPK1" FT /evidence="ECO:0000269|PubMed:14690523, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, FT ECO:0007744|PubMed:23186163" FT MOD_RES 552 FT /note="Phosphoserine; by PDPK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:8999860" FT MOD_RES 576 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 576 FT /note="N6-methyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 579 FT /note="Phosphoserine; by MARK1, MARK2, MARK3, MARK4, BRSK1, FT BRSK2 and PHK" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:23666762, FT ECO:0000269|PubMed:7706316, ECO:0000269|PubMed:8999860, FT ECO:0000269|PubMed:9614189" FT MOD_RES 596 FT /note="Deamidated asparagine; in tau and PHF-tau; partial" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 598 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 602 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:8999860" FT MOD_RES 607 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 610 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 615 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 622 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:7706316, FT ECO:0000269|PubMed:8999860" FT MOD_RES 628 FT /note="N6,N6-dimethyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 628 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 634 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 638 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 641 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 648 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 660 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 664 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 666 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 669 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:8999860" FT MOD_RES 673 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 686 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 702 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 711 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 713 FT /note="Phosphoserine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:1899488, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 717 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 720 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 721 FT /note="Phosphoserine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 726 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0007744|PubMed:19690332" FT MOD_RES 733 FT /note="Phosphoserine; by CaMK2 and TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 739 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 744 FT /note="Phosphothreonine; by TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT CARBOHYD 87 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 383 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 467 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 480 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 491 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 525 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000269|PubMed:21327254" FT CARBOHYD 542 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 551 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 555 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000269|PubMed:21327254" FT CARBOHYD 576 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 597 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 598 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 664 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 670 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 686 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 717 FT /note="O-linked (GlcNAc) serine; alternate" FT /evidence="ECO:0000269|PubMed:21327254" FT DISULFID 608..639 FT /evidence="ECO:0000250" FT CROSSLNK 44 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 571 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 576 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 584 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 598 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 615 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 628 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 634 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 638 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 648 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 660 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 664 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 670 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 686 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 692 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 702 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT VAR_SEQ 1..44 FT /note="MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLK -> MLRA FT LQQRKR (in isoform Tau-A)" FT /evidence="ECO:0000303|PubMed:2516729" FT /id="VSP_003175" FT VAR_SEQ 45..73 FT /note="Missing (in isoform Tau-A, isoform Tau-D and isoform FT Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2498079, ECO:0000303|PubMed:2516729, FT ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7" FT /id="VSP_003176" FT VAR_SEQ 74..102 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-D, isoform Tau-E and isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003177" FT VAR_SEQ 103..104 FT /note="Missing (in isoform Tau-A)" FT /evidence="ECO:0000303|PubMed:2516729" FT /id="VSP_003178" FT VAR_SEQ 125..375 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and FT isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003179" FT VAR_SEQ 395..460 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and FT isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003180" FT VAR_SEQ 502 FT /note="S -> SATKQVQRRPPPAGPRSER (in isoform Tau-G)" FT /evidence="ECO:0000305" FT /id="VSP_026780" FT VAR_SEQ 592..622 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C and isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2516729, FT ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7" FT /id="VSP_003181" FT VARIANT 5 FT /note="R -> H (in FTD1; reduces the ability of tau to FT promote microtubule assembly and promotes fibril formation FT in vitro; dbSNP:rs63750959)" FT /evidence="ECO:0000269|PubMed:11921059" FT /id="VAR_019660" FT VARIANT 5 FT /note="R -> L (in PSNP1; delays assembly initiation and FT lowers the mass of microtubules formed; but the assembly FT rate is increased compared to normal tau; FT dbSNP:rs63750959)" FT /evidence="ECO:0000269|PubMed:12325083" FT /id="VAR_019661" FT VARIANT 17 FT /note="T -> M (in dbSNP:rs144611688)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064622" FT VARIANT 30 FT /note="T -> A (in dbSNP:rs748728879)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064623" FT VARIANT 285 FT /note="D -> N (risk factor for PSNP1; dbSNP:rs62063786)" FT /evidence="ECO:0000269|PubMed:10534245, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010340" FT VARIANT 289 FT /note="V -> A (risk factor for PSNP1; dbSNP:rs62063787)" FT /evidence="ECO:0000269|PubMed:10534245, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010341" FT VARIANT 370 FT /note="R -> W (in dbSNP:rs17651549)" FT /id="VAR_056121" FT VARIANT 441 FT /note="Y -> H (in dbSNP:rs2258689)" FT /evidence="ECO:0000269|PubMed:1420178, FT ECO:0000269|PubMed:15365985, ECO:0000269|PubMed:9629852" FT /id="VAR_010342" FT VARIANT 447 FT /note="S -> P (in dbSNP:rs10445337)" FT /evidence="ECO:0000269|PubMed:9629852" FT /id="VAR_010343" FT VARIANT 574 FT /note="K -> T (in PIDB; reduces the ability to promote FT microtubule assembly by 70%; dbSNP:rs63750129)" FT /evidence="ECO:0000269|PubMed:11089577, FT ECO:0000269|PubMed:11117542" FT /id="VAR_010344" FT VARIANT 583 FT /note="L -> V (in FTD1; less able to promote microtubule FT assembly than wild-type tau; dbSNP:rs63750349)" FT /evidence="ECO:0000269|PubMed:12509859" FT /id="VAR_019662" FT VARIANT 589 FT /note="G -> V (in FTD1; dbSNP:rs63750376)" FT /evidence="ECO:0000269|PubMed:9641683, FT ECO:0000269|PubMed:9973279" FT /id="VAR_010345" FT VARIANT 590 FT /note="G -> R (in FTD1; increased aggregation propensity FT and altered binding affinity towards microtubules and F- FT actin; dbSNP:rs1247408229)" FT /evidence="ECO:0000269|PubMed:32961270" FT /id="VAR_084361" FT VARIANT 596 FT /note="N -> K (in FTD1; with parkinsonism; FT dbSNP:rs63750756)" FT /evidence="ECO:0000269|PubMed:10412802, FT ECO:0000269|PubMed:10489057, ECO:0000269|PubMed:10802785, FT ECO:0000269|PubMed:12473774, ECO:0000269|PubMed:9789048" FT /id="VAR_010346" FT VARIANT 597 FT /note="Missing (in FTD1; dbSNP:rs63750688)" FT /evidence="ECO:0000269|PubMed:9973279" FT /id="VAR_010347" FT VARIANT 613 FT /note="N -> H (in FTD1; reduced the ability of tau to FT promote microtubule assembly without having a significant FT effect on tau filament formation; effects at both the RNA FT and the protein level; dbSNP:rs63750416)" FT /evidence="ECO:0000269|PubMed:11585254, FT ECO:0000269|PubMed:11906000" FT /id="VAR_019663" FT VARIANT 613 FT /note="Missing (in PSNP1/atypical PSNP1; heterozygosity may FT be a risk factor for both a PSNP1-like syndrome and FT Parkinson disease; reduced the ability of tau to promote FT microtubule assembly without having a significant effect on FT tau filament formation; effects at both the RNA and the FT protein level)" FT /evidence="ECO:0000269|PubMed:11220749, FT ECO:0000269|PubMed:11906000, ECO:0000269|PubMed:14991828, FT ECO:0000269|PubMed:14991829" FT /id="VAR_019664" FT VARIANT 617 FT /note="V -> I (in dbSNP:rs116733906)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064624" FT VARIANT 618 FT /note="P -> L (in FTD1; most common mutation; reduction in FT the ability to promote microtubule assembly; accelerates FT aggregation of tau into filaments; dbSNP:rs63751273)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9736786, FT ECO:0000269|PubMed:9789048, ECO:0000269|PubMed:9973279" FT /id="VAR_010348" FT VARIANT 618 FT /note="P -> S (in FTD1 and CBD; reduction in the ability to FT promote microtubule assembly; dbSNP:rs63751438)" FT /evidence="ECO:0000269|PubMed:10374757, FT ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:11071507, FT ECO:0000269|PubMed:16240366" FT /id="VAR_010349" FT VARIANT 620 FT /note="G -> V (in PSNP1; dbSNP:rs63751391)" FT /evidence="ECO:0000269|PubMed:16157753" FT /id="VAR_037439" FT VARIANT 622 FT /note="S -> N (in FTD1; minimal parkinsonism; very early FT age of onset; dbSNP:rs63751165)" FT /evidence="ECO:0000269|PubMed:10208578" FT /id="VAR_010350" FT VARIANT 634 FT /note="K -> M (in FTD1; dbSNP:rs63750092)" FT /evidence="ECO:0000269|PubMed:15883319" FT /id="VAR_037440" FT VARIANT 637 FT /note="S -> F (in PIDB; markedly reduced ability of tau to FT promote microtubule assembly; dbSNP:rs63750635)" FT /evidence="ECO:0000269|PubMed:11891833" FT /id="VAR_019665" FT VARIANT 654 FT /note="V -> M (in FTD1; ultrastructural and biochemical FT characteristics indistinguishable from Alzheimer disease; FT accelerates aggregation of tau into filaments; FT dbSNP:rs63750570)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010351" FT VARIANT 659 FT /note="E -> V (in FTD1; dbSNP:rs63750711)" FT /evidence="ECO:0000269|PubMed:11117541" FT /id="VAR_019666" FT VARIANT 669 FT /note="S -> L (in fatal respiratory hypoventilation; FT unusual apparent autosomal recessive inheritance; reduced FT binding to microtubules as well as increased fibrillization FT and aggregation; dbSNP:rs63750425)" FT /evidence="ECO:0000269|PubMed:14595660" FT /id="VAR_019667" FT VARIANT 686 FT /note="K -> I (in PIDB; 90% reduction in the rate of FT microtubule assembly; dbSNP:rs63751264)" FT /evidence="ECO:0000269|PubMed:11601501" FT /id="VAR_019668" FT VARIANT 706 FT /note="G -> R (in PIDB; in vitro the mutation reduces the FT ability of tau to promote microtubule assembly by 25 to FT 30%; dbSNP:rs63750512)" FT /evidence="ECO:0000269|PubMed:10604746, FT ECO:0000269|PubMed:11117542" FT /id="VAR_010352" FT VARIANT 723 FT /note="R -> W (in FTD1/Alzheimer disease; accelerates FT aggregation of tau into filaments; reduces tau FT phosphorylation in cells compared to both the wild-type and FT other mutant forms; dbSNP:rs63750424)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11889249, FT ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902, FT ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9973279" FT /id="VAR_010353" FT MUTAGEN 515 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 516 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 519 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 531 FT /note="S->A: No decrease in microtubule-binding and FT nucleation activity after in vitro phosphorylation of FT mutant protein." FT MUTAGEN 548 FT /note="T->A: 50% Decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 548 FT /note="T->E: No association with plasma membrane." FT MUTAGEN 552 FT /note="S->A: 70% decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 552 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 579 FT /note="S->A: 8% decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 713 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 721 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 726 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 730 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 739 FT /note="S->E: No association with plasma membrane." FT CONFLICT 48 FT /note="L -> P (in Ref. 6; AAU45390)" FT /evidence="ECO:0000305" FT CONFLICT 414 FT /note="H -> L (in Ref. 5; AAC04277)" FT /evidence="ECO:0000305" FT CONFLICT 557 FT /note="K -> M (in Ref. 12; AAS17881)" FT /evidence="ECO:0000305" FT CONFLICT 591 FT /note="K -> S (in Ref. 12; AAS17881)" FT /evidence="ECO:0000305" FT CONFLICT 617 FT /note="V -> Q (in Ref. 17; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 622 FT /note="S -> K (in Ref. 17; AA sequence)" FT /evidence="ECO:0000305" FT STRAND 7..9 FT /evidence="ECO:0007829|PDB:6N4P" FT HELIX 60..62 FT /evidence="ECO:0007829|PDB:5ZV3" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:5ZV3" FT TURN 579..582 FT /evidence="ECO:0007829|PDB:6CVJ" FT STRAND 587..590 FT /evidence="ECO:0007829|PDB:5N5A" FT STRAND 592..610 FT /evidence="ECO:0007829|PDB:7P6A" FT STRAND 613..615 FT /evidence="ECO:0007829|PDB:7QK6" FT STRAND 618..620 FT /evidence="ECO:0007829|PDB:5MP5" FT STRAND 624..626 FT /evidence="ECO:0007829|PDB:8OP0" FT STRAND 629..631 FT /evidence="ECO:0007829|PDB:7QKZ" FT STRAND 634..643 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 645..648 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 654..660 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 662..665 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 667..671 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 673..679 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 682..684 FT /evidence="ECO:0007829|PDB:7P6A" FT STRAND 685..695 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 698..703 FT /evidence="ECO:0007829|PDB:7R5H" FT STRAND 709..712 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 716..720 FT /evidence="ECO:0007829|PDB:7SP1" FT STRAND 723..732 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 734..736 FT /evidence="ECO:0007829|PDB:8FYU" FT STRAND 741..751 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 753..755 FT /evidence="ECO:0007829|PDB:7QKY" SQ SEQUENCE 758 AA; 78928 MW; D46C66CDBCD196E8 CRC64; MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAG HVTQEPESGK VVQEGFLREP GPPGLSHQLM SGMPGAPLLP EGPREATRQP SGTGPEDTEG GRHAPELLKH QLLGDLHQEG PPLKGAGGKE RPGSKEEVDE DRDVDESSPQ DSPPSKASPA QDGRPPQTAA REATSIPGFP AEGAIPLPVD FLSKVSTEIP ASEPDGPSVG RAKGQDAPLE FTFHVEITPN VQKEQAHSEE HLGRAAFPGA PGEGPEARGP SLGEDTKEAD LPEPSEKQPA AAPRGKPVSR VPQLKARMVS KSKDGTGSDD KKAKTSTRSS AKTLKNRPCL SPKHPTPGSS DPLIQPSSPA VCPEPPSSPK YVSSVTSRTG SSGAKEMKLK GADGKTKIAT PRGAAPPGQK GQANATRIPA KTPPAPKTPP SSGEPPKSGD RSGYSSPGSP GTPGSRSRTP SLPTPPTREP KKVAVVRTPP KSPSSAKSRL QTAPVPMPDL KNVKSKIGST ENLKHQPGGG KVQIINKKLD LSNVQSKCGS KDNIKHVPGG GSVQIVYKPV DLSKVTSKCG SLGNIHHKPG GGQVEVKSEK LDFKDRVQSK IGSLDNITHV PGGGNKKIET HKLTFRENAK AKTDHGAEIV YKSPVVSGDT SPRHLSNVSS TGSIDMVDSP QLATLADEVS ASLAKQGL // ID TERA_HUMAN Reviewed; 806 AA. AC P55072; B2R5T8; Q0V924; Q2TAI5; Q969G7; Q9UCD5; V9HW80; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 248. DE RecName: Full=Transitional endoplasmic reticulum ATPase; DE Short=TER ATPase; DE EC=3.6.4.6 {ECO:0000269|PubMed:26471729}; DE AltName: Full=15S Mg(2+)-ATPase p97 subunit; DE AltName: Full=Valosin-containing protein; DE Short=VCP; GN Name=VCP; GN Synonyms=HEL-220 {ECO:0000312|EMBL:ACI46036.1}, GN HEL-S-70 {ECO:0000312|EMBL:ACI46044.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W., RA Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S., Phan H., RA Velasco N., Garnes J., Danganan L., Poundstone P., Christensen M., RA Georgescu A., Avila J., Liu S., Attix C., Andreise T., Trankheim M., RA Amico-Keller G., Coefield J., Duarte S., Lucas S., Bruce R., Thomas P., RA Quan G., Kronmiller B., Arellano A., Montgomery M., Ow D., Nolan M., RA Trong S., Kobayashi A., Olsen A.O., Carrano A.V.; RT "Sequence analysis of a human P1 clone containing the XRCC9 DNA repair RT gene."; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Li J., Wang H., Liu J., Liu F.; RL Submitted (SEP-2008) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pituitary; RX PubMed=10931946; DOI=10.1073/pnas.160270997; RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J., RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., RA Chen M.-D., Chen J.-L.; RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis RT and full-length cDNA cloning."; RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 2-25. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [9] RP PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487; RP 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION RP AT ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Platelet; RA Bienvenut W.V., Claeys D.; RL Submitted (NOV-2005) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 27-41 AND 233-238, AND INTERACTION WITH CLATHRIN. RC TISSUE=Glial tumor; RX PubMed=8413590; DOI=10.1038/365459a0; RA Pleasure I.T., Black M.M., Keen J.H.; RT "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding RT protein."; RL Nature 365:459-462(1993). RN [11] RP PROTEIN SEQUENCE OF 46-53; 66-81; 96-109; 148-155; 240-251; 323-336; RP 454-502; 530-560; 600-614; 639-651; 678-693; 714-732 AND 754-766, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [12] RP PROTEIN SEQUENCE OF 314-322, IDENTIFICATION BY MASS SPECTROMETRY, RP METHYLATION AT LYS-315, MUTAGENESIS OF LYS-315, CHARACTERIZATION OF RP VARIANTS IBMPFD1 HIS-155 AND GLN-191, AND CHARACTERIZATION OF VARIANT RP FTDALS6 GLY-159. RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210; RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.; RT "A newly uncovered group of distantly related lysine methyltransferases RT preferentially interact with molecular chaperones to regulate their RT activity."; RL PLoS Genet. 9:E1003210-E1003210(2013). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 388-483. RC TISSUE=Fetal brain; RA Dmitrenko V.V., Garifulin O.M., Kavsan V.M.; RT "Characterization of different mRNA types expressed in human brain."; RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases. RN [14] RP INTERACTION WITH NGLY1. RX PubMed=15362974; DOI=10.1042/bj20041498; RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.; RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is RT a substrate for SAPKs."; RL Biochem. J. 384:391-400(2004). RN [15] RP FUNCTION, INTERACTION WITH RNF19A, IDENTIFICATION BY MASS SPECTROMETRY, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-524. RX PubMed=15456787; DOI=10.1074/jbc.m406683200; RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S., RA Kakizuka A., Tanaka K., Sobue G.; RT "Physical and functional interaction between dorfin and valosin-containing RT protein that are colocalized in ubiquitylated inclusions in RT neurodegenerative disorders."; RL J. Biol. Chem. 279:51376-51385(2004). RN [16] RP INTERACTION WITH SELENOS, AND SUBCELLULAR LOCATION. RX PubMed=15215856; DOI=10.1038/nature02656; RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.; RT "A membrane protein complex mediates retro-translocation from the ER lumen RT into the cytosol."; RL Nature 429:841-847(2004). RN [17] RP ISGYLATION. RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132; RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J., RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.; RT "Proteomic identification of proteins conjugated to ISG15 in mouse and RT human cells."; RL Biochem. Biophys. Res. Commun. 336:496-506(2005). RN [18] RP INTERACTION WITH SYVN1 AND DERL1. RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020; RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S., Wiertz E., RA Koning F., Kloetzel P.-M., Seeger M.; RT "The ubiquitin-domain protein HERP forms a complex with components of the RT endoplasmic reticulum associated degradation pathway."; RL J. Mol. Biol. 354:1021-1027(2005). RN [19] RP INTERACTION WITH AMFR, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP LYS-251 AND LYS-524. RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009; RA Song B.L., Sever N., DeBose-Boyd R.A.; RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and RT couples sterol-regulated ubiquitination to degradation of HMG CoA RT reductase."; RL Mol. Cell 19:829-840(2005). RN [20] RP FUNCTION, AND INTERACTION WITH DERL1; AMFR; SYVN1 AND SELENOS. RX PubMed=16186510; DOI=10.1073/pnas.0505006102; RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E., Rapoport T.A.; RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of RT retrotranslocation at the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005). RN [21] RP INTERACTION WITH DERL1 AND DERL2. RX PubMed=16186509; DOI=10.1073/pnas.0505014102; RA Lilley B.N., Ploegh H.L.; RT "Multiprotein complexes that link dislocation, ubiquitination, and RT extraction of misfolded proteins from the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005). RN [22] RP INTERACTION WITH CASR AND RNF19A. RX PubMed=16513638; DOI=10.1074/jbc.m513552200; RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.; RT "Calcium-sensing receptor ubiquitination and degradation mediated by the E3 RT ubiquitin ligase dorfin."; RL J. Biol. Chem. 281:11610-11617(2006). RN [23] RP INTERACTION WITH DERL1; DERL2 AND DERL3. RX PubMed=16449189; DOI=10.1083/jcb.200507057; RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.; RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein RT response and are required for ER-associated degradation."; RL J. Cell Biol. 172:383-393(2006). RN [24] RP INTERACTION WITH UBXN4. RX PubMed=16968747; DOI=10.1242/jcs.03163; RA Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A., RA Monteiro M.J.; RT "Characterization of erasin (UBXD2): a new ER protein that promotes ER- RT associated protein degradation."; RL J. Cell Sci. 119:4011-4024(2006). RN [25] RP INTERACTION WITH SVIP AND DERL1. RX PubMed=17872946; DOI=10.1074/jbc.m704446200; RA Ballar P., Zhong Y., Nagahama M., Tagaya M., Shen Y., Fang S.; RT "Identification of SVIP as an endogenous inhibitor of endoplasmic RT reticulum-associated degradation."; RL J. Biol. Chem. 282:33908-33914(2007). RN [26] RP INTERACTION WITH TRIM13. RX PubMed=17314412; DOI=10.1091/mbc.e06-03-0248; RA Lerner M., Corcoran M., Cepeda D., Nielsen M.L., Zubarev R., Ponten F., RA Uhlen M., Hober S., Grander D., Sangfelt O.; RT "The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin RT ligase involved in ERAD."; RL Mol. Biol. Cell 18:1670-1682(2007). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [28] RP INTERACTION WITH RNF103. RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126; RA Maruyama Y., Yamada M., Takahashi K., Yamada M.; RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-associated RT degradation pathway."; RL Biochem. Biophys. Res. Commun. 374:737-741(2008). RN [29] RP INTERACTION WITH UBXN6. RX PubMed=18656546; DOI=10.1016/j.biocel.2008.06.008; RA Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M., RA Hartmann-Petersen R.; RT "Ubxd1 is a novel co-factor of the human p97 ATPase."; RL Int. J. Biochem. Cell Biol. 40:2927-2942(2008). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-436 AND SER-787, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [31] RP INTERACTION WITH TRIM21. RX PubMed=18022694; DOI=10.1016/j.molimm.2007.10.023; RA Takahata M., Bohgaki M., Tsukiyama T., Kondo T., Asaka M., Hatakeyama S.; RT "Ro52 functionally interacts with IgG1 and regulates its quality control RT via the ERAD system."; RL Mol. Immunol. 45:2045-2054(2008). RN [32] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [33] RP INTERACTION WITH UBXN6. RX PubMed=19174149; DOI=10.1016/j.bbrc.2009.01.076; RA Kern M., Fernandez-Saiz V., Schaefer Z., Buchberger A.; RT "UBXD1 binds p97 through two independent binding sites."; RL Biochem. Biophys. Res. Commun. 380:303-307(2009). RN [34] RP INTERACTION WITH UBXN6. RX PubMed=19275885; DOI=10.1016/j.bbrc.2009.03.012; RA Nagahama M., Ohnishi M., Kawate Y., Matsui T., Miyake H., Yuasa K., RA Tani K., Tagaya M., Tsuji A.; RT "UBXD1 is a VCP-interacting protein that is involved in ER-associated RT degradation."; RL Biochem. Biophys. Res. Commun. 382:303-308(2009). RN [35] RP INTERACTION WITH UBXN4, AND IDENTIFICATION IN A COMPLEX WITH UBQLN1 AND RP UBXN4. RX PubMed=19822669; DOI=10.1083/jcb.200903024; RA Lim P.J., Danner R., Liang J., Doong H., Harman C., Srinivasan D., RA Rothenberg C., Wang H., Ye Y., Fang S., Monteiro M.J.; RT "Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD."; RL J. Cell Biol. 187:201-217(2009). RN [36] RP INTERACTION WITH YOD1. RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016; RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.; RT "The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to RT facilitate protein dislocation from the ER."; RL Mol. Cell 36:28-38(2009). RN [37] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3 AND SER-37, CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-775, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [39] RP INTERACTION WITH WASHC5. RX PubMed=20833645; DOI=10.1093/brain/awq222; RA Clemen C.S., Tangavelou K., Strucksberg K.H., Just S., Gaertner L., RA Regus-Leidig H., Stumpf M., Reimann J., Coras R., Morgan R.O., RA Fernandez M.P., Hofmann A., Muller S., Schoser B., Hanisch F.G., RA Rottbauer W., Blumcke I., von Horsten S., Eichinger L., Schroder R.; RT "Strumpellin is a novel valosin-containing protein binding partner linking RT hereditary spastic paraplegia to protein aggregation diseases."; RL Brain 133:2920-2941(2010). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [41] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [42] RP FUNCTION IN OMM PROTEIN TURNOVER. RX PubMed=21118995; DOI=10.1091/mbc.e10-09-0748; RA Xu S., Peng G., Wang Y., Fang S., Karbowski M.; RT "The AAA-ATPase p97 is essential for outer mitochondrial membrane protein RT turnover."; RL Mol. Biol. Cell 22:291-300(2011). RN [43] RP INTERACTION WITH BAG6. RX PubMed=21636303; DOI=10.1016/j.molcel.2011.05.010; RA Wang Q., Liu Y., Soetandyo N., Baek K., Hegde R., Ye Y.; RT "A ubiquitin ligase-associated chaperone holdase maintains polypeptides in RT soluble states for proteasome degradation."; RL Mol. Cell 42:758-770(2011). RN [44] RP FUNCTION, INTERACTION WITH CAV1 AND UBXN6, CHARACTERIZATION OF VARIANTS RP IBMPFD1 GLY-95; HIS-155 AND GLU-232, AND MUTAGENESIS OF GLU-578. RX PubMed=21822278; DOI=10.1038/ncb2301; RA Ritz D., Vuk M., Kirchner P., Bug M., Schuetz S., Hayer A., Bremer S., RA Lusk C., Baloh R.H., Lee H., Glatter T., Gstaiger M., Aebersold R., RA Weihl C.C., Meyer H.; RT "Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and RT UBXD1 and impaired by VCP disease mutations."; RL Nat. Cell Biol. 13:1116-1123(2011). RN [45] RP FUNCTION. RX PubMed=22020440; DOI=10.1038/ncb2367; RA Meerang M., Ritz D., Paliwal S., Garajova Z., Bosshard M., Mailand N., RA Janscak P., Hubscher U., Meyer H., Ramadan K.; RT "The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA RT double-strand breaks."; RL Nat. Cell Biol. 13:1376-1382(2011). RN [46] RP FUNCTION, INTERACTION WITH L3MBTL1, AND SUBCELLULAR LOCATION. RX PubMed=22120668; DOI=10.1038/nsmb.2188; RA Acs K., Luijsterburg M.S., Ackermann L., Salomons F.A., Hoppe T., RA Dantuma N.P.; RT "The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from RT DNA double-strand breaks."; RL Nat. Struct. Mol. Biol. 18:1345-1350(2011). RN [47] RP INTERACTION WITH UBXN8. RX PubMed=21949850; DOI=10.1371/journal.pone.0025061; RA Madsen L., Kriegenburg F., Vala A., Best D., Prag S., Hofmann K., RA Seeger M., Adams I.R., Hartmann-Petersen R.; RT "The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum RT membrane for degradation of misfolded proteins."; RL PLoS ONE 6:E25061-E25061(2011). RN [48] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3, CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE RP ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [49] RP INTERACTION WITH UBXN7. RX PubMed=22537386; DOI=10.1186/1741-7007-10-36; RA Bandau S., Knebel A., Gage Z.O., Wood N.T., Alexandru G.; RT "UBXN7 docks on neddylated cullin complexes using its UIM motif and causes RT HIF1alpha accumulation."; RL BMC Biol. 10:36-36(2012). RN [50] RP INTERACTION WITH RHBDD1, MUTAGENESIS OF LYS-251; LYS-524 AND GLU-578, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22795130; DOI=10.1016/j.molcel.2012.06.008; RA Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L., Lemberg M.K.; RT "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of RT membrane proteins."; RL Mol. Cell 47:558-569(2012). RN [51] RP INTERACTION WITH SPRTN. RX PubMed=22902628; DOI=10.1074/jbc.m112.400135; RA Ghosal G., Leung J.W., Nair B.C., Fong K.W., Chen J.; RT "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a RT regulator of translesion synthesis."; RL J. Biol. Chem. 287:34225-34233(2012). RN [52] RP FUNCTION IN ERAD PATHWAY. RX PubMed=22607976; DOI=10.1016/j.molcel.2012.04.015; RA Sato T., Sako Y., Sho M., Momohara M., Suico M.A., Shuto T., Nishitoh H., RA Okiyoneda T., Kokame K., Kaneko M., Taura M., Miyata M., Chosa K., Koga T., RA Morino-Koga S., Wada I., Kai H.; RT "STT3B-dependent posttranslational N-glycosylation as a surveillance system RT for secretory protein."; RL Mol. Cell 47:99-110(2012). RN [53] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [54] RP METHYLATION AT LYS-315, AND MUTAGENESIS OF LYS-312; ARG-313; GLU-314; RP LYS-315; THR-316; HIS-317 AND GLY-318. RX PubMed=22948820; DOI=10.1038/ncomms2041; RA Kernstock S., Davydova E., Jakobsson M., Moen A., Pettersen S., RA Maelandsmo G.M., Egge-Jacobsen W., Falnes P.O.; RT "Lysine methylation of VCP by a member of a novel human protein RT methyltransferase family."; RL Nat. Commun. 3:1038-1038(2012). RN [55] RP FUNCTION, AND INTERACTION WITH SPRTN. RX PubMed=23042607; DOI=10.1038/nsmb.2394; RA Davis E.J., Lachaud C., Appleton P., Macartney T.J., Nathke I., Rouse J.; RT "DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA RT damage."; RL Nat. Struct. Mol. Biol. 19:1093-1100(2012). RN [56] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SPRTN. RX PubMed=23042605; DOI=10.1038/nsmb.2395; RA Mosbech A., Gibbs-Seymour I., Kagias K., Thorslund T., Beli P., Povlsen L., RA Nielsen S.V., Smedegaard S., Sedgwick G., Lukas C., Hartmann-Petersen R., RA Lukas J., Choudhary C., Pocock R., Bekker-Jensen S., Mailand N.; RT "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes RT ubiquitin-dependent responses to replication blocks."; RL Nat. Struct. Mol. Biol. 19:1084-1092(2012). RN [57] RP FUNCTION. RX PubMed=23335559; DOI=10.1074/jbc.m112.429076; RA Kirchner P., Bug M., Meyer H.; RT "Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal RT sorting by the VCP/p97 AAA-ATPase."; RL J. Biol. Chem. 288:7363-7372(2013). RN [58] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-7; SER-13; SER-462 AND RP SER-702, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [59] RP INTERACTION WITH ZFAND2B. RX PubMed=24160817; DOI=10.1042/bj20130710; RA Glinka T., Alter J., Braunstein I., Tzach L., Wei Sheng C., Geifman S., RA Edelmann M.J., Kessler B.M., Stanhill A.; RT "Signal-peptide-mediated translocation is regulated by a p97-AIRAPL RT complex."; RL Biochem. J. 457:253-261(2014). RN [60] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [61] RP INTERACTION WITH RNF31. RX PubMed=24726327; DOI=10.1016/j.molcel.2014.03.016; RA Schaeffer V., Akutsu M., Olma M.H., Gomes L.C., Kawasaki M., Dikic I.; RT "Binding of OTULIN to the PUB domain of HOIP controls NF-kappaB RT signaling."; RL Mol. Cell 54:349-361(2014). RN [62] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH STUB1; UBXN2A AND CHRNA3, AND RP INTERACTION WITH UBXN2A. RX PubMed=26265139; DOI=10.1016/j.bcp.2015.08.084; RA Teng Y., Rezvani K., De Biasi M.; RT "UBXN2A regulates nicotinic receptor degradation by modulating the E3 RT ligase activity of CHIP."; RL Biochem. Pharmacol. 97:518-530(2015). RN [63] RP FUNCTION. RX PubMed=26565908; DOI=10.1016/j.celrep.2015.09.047; RA Kadowaki H., Nagai A., Maruyama T., Takami Y., Satrimafitrah P., Kato H., RA Honda A., Hatta T., Natsume T., Sato T., Kai H., Ichijo H., Nishitoh H.; RT "Pre-emptive quality control protects the ER from protein overload via the RT proximity of ERAD components and SRP."; RL Cell Rep. 13:944-956(2015). RN [64] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH RIGI AND RNF125, AND RP MUTAGENESIS OF 52-PHE--ASP-55; TYR-110; GLU-305 AND GLU-578. RX PubMed=26471729; DOI=10.15252/embj.201591888; RA Hao Q., Jiao S., Shi Z., Li C., Meng X., Zhang Z., Wang Y., Song X., RA Wang W., Zhang R., Zhao Y., Wong C.C., Zhou Z.; RT "A non-canonical role of the p97 complex in RIG-I antiviral signaling."; RL EMBO J. 34:2903-2920(2015). RN [65] RP INTERACTION WITH ZFAND2B. RX PubMed=26337389; DOI=10.1091/mbc.e15-02-0085; RA Braunstein I., Zach L., Allan S., Kalies K.U., Stanhill A.; RT "Proteasomal degradation of preemptive quality control (pQC) substrates is RT mediated by an AIRAPL-p97 complex."; RL Mol. Biol. Cell 26:3719-3727(2015). RN [66] RP INTERACTION WITH UBXN10. RX PubMed=26389662; DOI=10.1038/ncb3238; RA Raman M., Sergeev M., Garnaas M., Lydeard J.R., Huttlin E.L., Goessling W., RA Shah J.V., Harper J.W.; RT "Systematic proteomics of the VCP-UBXD adaptor network identifies a role RT for UBXN10 in regulating ciliogenesis."; RL Nat. Cell Biol. 17:1356-1369(2015). RN [67] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [68] RP INTERACTION WITH FAF1, AND SUBCELLULAR LOCATION. RX PubMed=26842564; DOI=10.1038/ncomms10612; RA Franz A., Pirson P.A., Pilger D., Halder S., Achuthankutty D., Kashkar H., RA Ramadan K., Hoppe T.; RT "Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard RT DNA replication fork progression."; RL Nat. Commun. 7:10612-10612(2016). RN [69] RP FUNCTION. RX PubMed=26692333; DOI=10.1038/nm.4013; RA Osorio F.G., Soria-Valles C., Santiago-Fernandez O., Bernal T., RA Mittelbrunn M., Colado E., Rodriguez F., Bonzon-Kulichenko E., Vazquez J., RA Porta-de-la-Riva M., Ceron J., Fueyo A., Li J., Green A.R., Freije J.M., RA Lopez-Otin C.; RT "Loss of the proteostasis factor AIRAPL causes myeloid transformation by RT deregulating IGF-1 signaling."; RL Nat. Med. 22:91-96(2016). RN [70] RP INTERACTION WITH ANKZF1. RX PubMed=28302725; DOI=10.1074/jbc.m116.772038; RA van Haaften-Visser D.Y., Harakalova M., Mocholi E., van Montfrans J.M., RA Elkadri A., Rieter E., Fiedler K., van Hasselt P.M., Triffaux E.M.M., RA van Haelst M.M., Nijman I.J., Kloosterman W.P., Nieuwenhuis E.E.S., RA Muise A.M., Cuppen E., Houwen R.H.J., Coffer P.J.; RT "Ankyrin repeat and zinc-finger domain-containing 1 mutations are RT associated with infantile-onset inflammatory bowel disease."; RL J. Biol. Chem. 292:7904-7920(2017). RN [71] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-8 AND LYS-18, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [72] RP INTERACTION WITH ATXN3. RX PubMed=30455355; DOI=10.1074/jbc.ra118.005801; RA Weishaeupl D., Schneider J., Peixoto Pinheiro B., Ruess C., Dold S.M., RA von Zweydorf F., Gloeckner C.J., Schmidt J., Riess O., Schmidt T.; RT "Physiological and pathophysiological characteristics of ataxin-3 RT isoforms."; RL J. Biol. Chem. 294:644-661(2019). RN [73] RP INTERACTION WITH LMBR1L. RX PubMed=31073040; DOI=10.1126/science.aau0812; RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J., RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M., RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y., RA Beutler B.; RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling."; RL Science 364:0-0(2019). RN [74] RP FUNCTION, AND INTERACTION WITH TEX264. RX PubMed=32152270; DOI=10.1038/s41467-020-15000-w; RA Fielden J., Wiseman K., Torrecilla I., Li S., Hume S., Chiang S.C., RA Ruggiano A., Narayan Singh A., Freire R., Hassanieh S., Domingo E., RA Vendrell I., Fischer R., Kessler B.M., Maughan T.S., El-Khamisy S.F., RA Ramadan K.; RT "TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1- RT DNA adducts."; RL Nat. Commun. 11:1274-1274(2020). RN [75] RP FUNCTION. RX PubMed=34739333; DOI=10.1126/science.abf6548; RA Gwon Y., Maxwell B.A., Kolaitis R.M., Zhang P., Kim H.J., Taylor J.P.; RT "Ubiquitination of G3BP1 mediates stress granule disassembly in a context- RT specific manner."; RL Science 372:eabf6548-eabf6548(2021). RN [76] RP FUNCTION. RX PubMed=35013556; DOI=10.1038/s41556-021-00807-6; RA Krastev D.B., Li S., Sun Y., Wicks A.J., Hoslett G., Weekes D., RA Badder L.M., Knight E.G., Marlow R., Pardo M.C., Yu L., Talele T.T., RA Bartek J., Choudhary J.S., Pommier Y., Pettitt S.J., Tutt A.N.J., RA Ramadan K., Lord C.J.; RT "The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from RT chromatin."; RL Nat. Cell Biol. 24:62-73(2022). RN [77] RP FUNCTION, UFMYLATION AT LYS-109, INTERACTION WITH NPLOC4, AND MUTAGENESIS RP OF LYS-109 AND TYR-110. RX PubMed=38762759; DOI=10.1080/15548627.2024.2356488; RA Wang Z., Xiong S., Wu Z., Wang X., Gong Y., Zhu W.G., Xu X.; RT "VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of RT autophagy."; RL Autophagy 20:2041-2054(2024). RN [78] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP ANALOG, RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155, MUTAGENESIS OF RP ARG-53 AND ARG-86, AND SUBUNIT. RX PubMed=20512113; DOI=10.1038/emboj.2010.104; RA Tang W.K., Li D., Li C.C., Esser L., Dai R., Guo L., Xia D.; RT "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by RT crystal structures of disease-related mutants."; RL EMBO J. 29:2217-2229(2010). RN [79] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 797-806 IN COMPLEX WITH PLAA. RX PubMed=19887378; DOI=10.1074/jbc.m109.044685; RA Qiu L., Pashkova N., Walker J.R., Winistorfer S., Allali-Hassani A., RA Akutsu M., Piper R., Dhe-Paganon S.; RT "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex."; RL J. Biol. Chem. 285:365-372(2010). RN [80] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-187 IN COMPLEX WITH AMFR. RX PubMed=21914798; DOI=10.1074/jbc.m111.274506; RA Hanzelmann P., Schindelin H.; RT "The structural and functional basis of the p97/valosin-containing protein RT (VCP)-interacting motif (VIM): mutually exclusive binding of cofactors to RT the N-terminal domain of p97."; RL J. Biol. Chem. 286:38679-38690(2011). RN [81] {ECO:0007744|PDB:5GLF} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 21-199 IN COMPLEX WITH DERL1, RP INTERACTION WITH DERL1, AND MUTAGENESIS OF 113-ARG--HIS-115; PHE-131; RP LEU-140; ASP-179 AND HIS-183. RX PubMed=27714797; DOI=10.1002/1873-3468.12447; RA Lim J.J., Lee Y., Yoon S.Y., Ly T.T., Kang J.Y., Youn H.S., An J.Y., RA Lee J.G., Park K.R., Kim T.G., Yang J.K., Jun Y., Eom S.H.; RT "Structural insights into the interaction of human p97 N-terminal domain RT and SHP motif in Derlin-1 rhomboid pseudoprotease."; RL FEBS Lett. 590:4402-4413(2016). RN [82] RP VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND GLU-232. RX PubMed=15034582; DOI=10.1038/ng1332; RA Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D., RA Pestronk A., Whyte M.P., Kimonis V.E.; RT "Inclusion body myopathy associated with Paget disease of bone and RT frontotemporal dementia is caused by mutant valosin-containing protein."; RL Nat. Genet. 36:377-381(2004). RN [83] RP VARIANT IBMPFD1 CYS-155. RX PubMed=15732117; DOI=10.1002/ana.20407; RA Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P., RA Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R.; RT "Mutant valosin-containing protein causes a novel type of frontotemporal RT dementia."; RL Ann. Neurol. 57:457-461(2005). RN [84] RP VARIANT IBMPFD1 HIS-159. RX PubMed=16247064; DOI=10.1212/01.wnl.0000180407.15369.92; RA Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F., Mannhalter C., RA Wagner L., Mineva I., Vass K., Auff E., Zimprich A.; RT "Inclusion body myopathy and Paget disease is linked to a novel mutation in RT the VCP gene."; RL Neurology 65:1304-1305(2005). RN [85] RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155. RX PubMed=16321991; DOI=10.1093/hmg/ddi426; RA Weihl C.C., Dalal S., Pestronk A., Hanson P.I.; RT "Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic RT reticulum-associated degradation."; RL Hum. Mol. Genet. 15:189-199(2006). RN [86] RP VARIANTS IBMPFD1 TRP-198 AND HIS-387. RX PubMed=17935506; DOI=10.1111/j.1399-0004.2007.00887.x; RA Watts G.D., Thomasova D., Ramdeen S.K., Fulchiero E.C., Mehta S.G., RA Drachman D.A., Weihl C.C., Jamrozik Z., Kwiecinski H., Kaminska A., RA Kimonis V.E.; RT "Novel VCP mutations in inclusion body myopathy associated with Paget RT disease of bone and frontotemporal dementia."; RL Clin. Genet. 72:420-426(2007). RN [87] RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; SER-155 AND GLU-232, RP MUTAGENESIS OF GLU-305 AND GLU-578, AND FUNCTION. RX PubMed=20104022; DOI=10.4161/auto.6.2.11014; RA Tresse E., Salomons F.A., Vesa J., Bott L.C., Kimonis V., Yao T.P., RA Dantuma N.P., Taylor J.P.; RT "VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes RT and this function is impaired by mutations that cause IBMPFD."; RL Autophagy 6:217-227(2010). RN [88] RP FUNCTION, INTERACTION WITH ZFAND1, MUTAGENESIS OF GLU-578, AND RP CHARACTERIZATION OF VARIANT IBMPFD1 HIS-155. RX PubMed=29804830; DOI=10.1016/j.molcel.2018.04.021; RA Turakhiya A., Meyer S.R., Marincola G., Boehm S., Vanselow J.T., RA Schlosser A., Hofmann K., Buchberger A.; RT "ZFAND1 recruits p97 and the 26S proteasome to promote the clearance of RT arsenite-induced stress granules."; RL Mol. Cell 70:906-919(2018). RN [89] RP INTERACTION WITH FBXL4. RX PubMed=36896912; DOI=10.15252/embj.2022113033; RA Cao Y., Zheng J., Wan H., Sun Y., Fu S., Liu S., He B., Cai G., Cao Y., RA Huang H., Li Q., Ma Y., Chen S., Wang F., Jiang H.; RT "A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and RT NIX to restrain mitophagy and prevent mitochondrial disease."; RL EMBO J. 42:e113033-e113033(2023). RN [90] RP VARIANTS IBMPFD1 LEU-155 AND TRP-198. RX PubMed=20335036; DOI=10.1016/j.nmd.2010.03.002; RA Kumar K.R., Needham M., Mina K., Davis M., Brewer J., Staples C., Ng K., RA Sue C.M., Mastaglia F.L.; RT "Two Australian families with inclusion-body myopathy, Paget's disease of RT bone and frontotemporal dementia: novel clinical and genetic findings."; RL Neuromuscul. Disord. 20:330-334(2010). RN [91] RP VARIANTS FTDALS6 HIS-155; GLY-159; GLN-191 AND ASN-592. RX PubMed=21145000; DOI=10.1016/j.neuron.2010.11.036; RA Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M., RA Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J., Ding J., RA McCluskey L., Martinez-Lage M., Falcone D., Hernandez D.G., Arepalli S., RA Chong S., Schymick J.C., Rothstein J., Landi F., Wang Y.D., Calvo A., RA Mora G., Sabatelli M., Monsurro M.R., Battistini S., Salvi F., Spataro R., RA Sola P., Borghero G., Galassi G., Scholz S.W., Taylor J.P., Restagno G., RA Chio A., Traynor B.J.; RT "Exome sequencing reveals VCP mutations as a cause of familial ALS."; RL Neuron 68:857-864(2010). RN [92] RP VARIANT CMT2Y LYS-185, CHARACTERIZATION OF VARIANT CMT2Y LYS-185, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155 AND GLU-232. RX PubMed=25125609; DOI=10.1093/brain/awu224; RA Gonzalez M.A., Feely S.M., Speziani F., Strickland A.V., Danzi M., RA Bacon C., Lee Y., Chou T.F., Blanton S.H., Weihl C.C., Zuchner S., RA Shy M.E.; RT "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."; RL Brain 137:2897-2902(2014). RN [93] RP VARIANT CMT2Y GLU-97, CHARACTERIZATION OF VARIANT CMT2Y GLU-97, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232. RX PubMed=25878907; DOI=10.1155/2015/239167; RA Jerath N.U., Crockett C.D., Moore S.A., Shy M.E., Weihl C.C., Chou T.F., RA Grider T., Gonzalez M.A., Zuchner S., Swenson A.; RT "Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation."; RL Case Rep. Genet. 2015:239167-239167(2015). RN [94] RP VARIANT IBMPFD1 PHE-126. RX PubMed=27209344; DOI=10.1016/j.nmd.2016.05.001; RA Matsubara S., Shimizu T., Komori T., Mori-Yoshimura M., Minami N., RA Hayashi Y.K.; RT "Nuclear inclusions mimicking poly(A)-binding protein nuclear 1 inclusions RT in a case of inclusion body myopathy associated with Paget disease of bone RT and frontotemporal dementia with a novel mutation in the valosin-containing RT protein gene."; RL Neuromuscul. Disord. 26:436-440(2016). RN [95] RP FUNCTION, INTERACTION WITH PLAA; UBXN6 AND YOD1, SUBCELLULAR LOCATION, RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232, AND RP MUTAGENESIS OF GLU-578. RX PubMed=27753622; DOI=10.15252/embj.201695148; RA Papadopoulos C., Kirchner P., Bug M., Grum D., Koerver L., Schulze N., RA Poehler R., Dressler A., Fengler S., Arhzaouy K., Lux V., Ehrmann M., RA Weihl C.C., Meyer H.; RT "VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of RT ruptured lysosomes by autophagy."; RL EMBO J. 36:135-150(2017). RN [96] RP VARIANTS IBMPFD1 THR-160; PHE-254 AND THR-369. RX PubMed=36980948; DOI=10.3390/genes14030676; RA Columbres R.C.A., Chin Y., Pratti S., Quinn C., Gonzalez-Cuyar L.F., RA Weiss M., Quintero-Rivera F., Kimonis V.; RT "Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1."; RL Genes (Basel) 14:0-0(2023). CC -!- FUNCTION: Necessary for the fragmentation of Golgi stacks during CC mitosis and for their reassembly after mitosis. Involved in the CC formation of the transitional endoplasmic reticulum (tER). The transfer CC of membranes from the endoplasmic reticulum to the Golgi apparatus CC occurs via 50-70 nm transition vesicles which derive from part-rough, CC part-smooth transitional elements of the endoplasmic reticulum (tER). CC Vesicle budding from the tER is an ATP-dependent process. The ternary CC complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins CC and is necessary for the export of misfolded proteins from the ER to CC the cytoplasm, where they are degraded by the proteasome. The NPLOC4- CC UFD1-VCP complex regulates spindle disassembly at the end of mitosis CC and is necessary for the formation of a closed nuclear envelope. CC Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of CC the VCP/p97-AMFR/gp78 complex that participates in the final step of CC the sterol-mediated ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum- CC associated degradation of CHRNA3 in cortical neurons as part of the CC STUB1-VCP-UBXN2A complex (PubMed:26265139). Involved in endoplasmic CC reticulum stress-induced pre-emptive quality control, a mechanism that CC selectively attenuates the translocation of newly synthesized proteins CC into the endoplasmic reticulum and reroutes them to the cytosol for CC proteasomal degradation (PubMed:26565908). Involved in clearance CC process by mediating G3BP1 extraction from stress granules CC (PubMed:29804830, PubMed:34739333). Also involved in DNA damage CC response: recruited to double-strand breaks (DSBs) sites in a RNF8- and CC RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA CC damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled CC replication forks by SPRTN: may act by mediating extraction of DNA CC polymerase eta (POLH) to prevent excessive translesion DNA synthesis CC and limit the incidence of mutations induced by DNA damage CC (PubMed:23042605, PubMed:23042607). Together with SPRTN CC metalloprotease, involved in the repair of covalent DNA-protein cross- CC links (DPCs) during DNA synthesis (PubMed:32152270). Involved in CC interstrand cross-link repair in response to replication stress by CC mediating unloading of the ubiquitinated CMG helicase complex (By CC similarity). Mediates extraction of PARP1 trapped to chromatin: CC recognizes and binds ubiquitinated PARP1 and promotes its removal CC (PubMed:35013556). Required for cytoplasmic retrotranslocation of CC stressed/damaged mitochondrial outer-membrane proteins and their CC subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). CC Essential for the maturation of ubiquitin-containing autophagosomes and CC the clearance of ubiquitinated protein by autophagy (PubMed:20104022, CC PubMed:27753622, PubMed:38762759). Acts as a negative regulator of type CC I interferon production by interacting with RIGI: interaction takes CC place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CC CARD domains, leading to recruit RNF125 and promote ubiquitination and CC degradation of RIGI (PubMed:26471729). May play a role in the CC ubiquitin-dependent sorting of membrane proteins to lysosomes where CC they undergo degradation (PubMed:21822278). May more particularly play CC a role in caveolins sorting in cells (PubMed:21822278, CC PubMed:23335559). By controlling the steady-state expression of the CC IGF1R receptor, indirectly regulates the insulin-like growth factor CC receptor signaling pathway (PubMed:26692333). CC {ECO:0000250|UniProtKB:P23787, ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21118995, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22020440, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:23335559, ECO:0000269|PubMed:26265139, CC ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:26565908, CC ECO:0000269|PubMed:26692333, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:32152270, CC ECO:0000269|PubMed:34739333, ECO:0000269|PubMed:35013556, CC ECO:0000269|PubMed:38762759}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.6; CC Evidence={ECO:0000269|PubMed:26471729}; CC -!- SUBUNIT: Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, CC that displays 6-fold radial symmetry. Part of a ternary complex CC containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds CC to one end of a VCP homohexamer. The complex binds to membranes CC enriched in phosphatidylethanolamine-containing lipids and promotes CC Golgi membrane fusion. Binds to a heterodimer of NPLOC4 and UFD1, CC binding to this heterodimer inhibits Golgi-membrane fusion CC (PubMed:26471729, PubMed:38762759). Interaction with VCIP135 leads to CC dissociation of the complex via ATP hydrolysis by VCP. Part of a CC ternary complex containing NPLOC4, UFD1 and VCP. Interacts with NSFL1C- CC like protein p37; the complex has membrane fusion activity and is CC required for Golgi and endoplasmic reticulum biogenesis. Interacts with CC SELENOS and SYVN1, as well as with DERL1 (via SHP-box motif), DERL2 and CC DERL3; which probably transfer misfolded proteins from the ER to VCP CC (PubMed:15215856, PubMed:16186509, PubMed:16186510, PubMed:16289116, CC PubMed:16449189, PubMed:27714797). Interacts with SVIP and forms a CC complex with SVIP and DERL1 (PubMed:17872946). Component of a complex CC required to couple retrotranslocation, ubiquitination and CC deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Part of CC a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that CC modulates the ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of CHRNA3 (PubMed:26265139). Within the complex CC UBXN2A acts as a scaffold protein required for the interaction of CC CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 CC ubiquitination by STUB1/CHIP and subsequently ERAD (PubMed:26265139). CC Interacts with UBXN2A (via UBX domain); the interaction is required for CC the interaction of CHRNA3 in the STUB1-VCP-UBXN2A complex CC (PubMed:26265139). Directly interacts with UBXN4 and RNF19A. Interacts CC with CASR. Interacts with UBE4B and YOD1. Interacts with clathrin. CC Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component of a CC VCP/p97-AMFR/gp78 complex that participates in the final step of the CC endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Interacts CC directly with AMFR/gp78 (via its VIM). Interacts with RHBDD1 (via C- CC terminal domain). Interacts with SPRTN; leading to recruitment to CC stalled replication forks (PubMed:23042605, PubMed:23042607). Interacts CC with WASHC5. Interacts with UBOX5. Interacts (via N-terminus) with CC UBXN7, UBXN8, and probably several other UBX domain-containing proteins CC (via UBX domains); the interactions are mutually exclusive with VIM- CC dependent interactions such as those with AMFR and SELENOS. Forms a CC complex with UBQLN1 and UBXN4. Interacts (via the PIM motif) with RNF31 CC (via the PUB domain) (PubMed:24726327). Interacts with RIGI and RNF125; CC interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked CC ubiquitin on its CARD domains, leading to recruit RNF125 and promote CC ubiquitination and degradation of RIGI (PubMed:26471729). Interacts CC with BAG6 (PubMed:21636303). Interacts with UBXN10 (PubMed:26389662). CC Interacts with UBXN6; the interaction with UBXN6 is direct and CC competitive with UFD1 (PubMed:19174149, PubMed:19275885). Forms a CC ternary complex with CAV1 and UBXN6 (PubMed:18656546, PubMed:19174149, CC PubMed:21822278). Interacts with PLAA, UBXN6 and YOD1; may form a CC complex involved in macroautophagy (PubMed:27753622). Interacts with CC ANKZF1 (PubMed:28302725). Interacts with ubiquitin-binding protein FAF1 CC (PubMed:26842564). Interacts with ZFAND2B (via VIM motif); the CC interaction is direct (PubMed:24160817, PubMed:26337389). Interacts CC with ZFAND1 (via its ubiquitin-like region); this interaction occurs in CC an arsenite-dependent manner (PubMed:29804830). Interacts with CCDC47 CC (By similarity). Interacts with UBAC2 (By similarity). Interacts with CC LMBR1L (PubMed:31073040). Interacts with ATXN3 (PubMed:30455355). CC Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links CC (DPCs) (PubMed:32152270). Interacts with FBXL4 (PubMed:36896912). CC {ECO:0000250|UniProtKB:P46462, ECO:0000250|UniProtKB:Q01853, CC ECO:0000269|PubMed:15215856, ECO:0000269|PubMed:15362974, CC ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, CC ECO:0000269|PubMed:16186509, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:16289116, ECO:0000269|PubMed:16449189, CC ECO:0000269|PubMed:16513638, ECO:0000269|PubMed:16968747, CC ECO:0000269|PubMed:17314412, ECO:0000269|PubMed:17872946, CC ECO:0000269|PubMed:18022694, ECO:0000269|PubMed:18656546, CC ECO:0000269|PubMed:18675248, ECO:0000269|PubMed:19174149, CC ECO:0000269|PubMed:19275885, ECO:0000269|PubMed:19818707, CC ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:19887378, CC ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:20833645, CC ECO:0000269|PubMed:21636303, ECO:0000269|PubMed:21822278, CC ECO:0000269|PubMed:21914798, ECO:0000269|PubMed:21949850, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22537386, CC ECO:0000269|PubMed:22795130, ECO:0000269|PubMed:22902628, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:24160817, ECO:0000269|PubMed:24726327, CC ECO:0000269|PubMed:26265139, ECO:0000269|PubMed:26337389, CC ECO:0000269|PubMed:26389662, ECO:0000269|PubMed:26471729, CC ECO:0000269|PubMed:26842564, ECO:0000269|PubMed:27714797, CC ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:28302725, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:30455355, CC ECO:0000269|PubMed:32152270, ECO:0000269|PubMed:36896912, CC ECO:0000269|PubMed:38762759, ECO:0000269|PubMed:8413590, CC ECO:0000305|PubMed:31073040}. CC -!- INTERACTION: CC P55072; Q9UKV5: AMFR; NbExp=12; IntAct=EBI-355164, EBI-1046367; CC P55072; Q9BZE9: ASPSCR1; NbExp=36; IntAct=EBI-355164, EBI-1993677; CC P55072; A9UGY9: ATG5; NbExp=3; IntAct=EBI-355164, EBI-10175276; CC P55072; P54253: ATXN1; NbExp=3; IntAct=EBI-355164, EBI-930964; CC P55072; P54252: ATXN3; NbExp=4; IntAct=EBI-355164, EBI-946046; CC P55072; P54252-1: ATXN3; NbExp=18; IntAct=EBI-355164, EBI-946068; CC P55072; Q96LK0: CEP19; NbExp=6; IntAct=EBI-355164, EBI-741885; CC P55072; O96017: CHEK2; NbExp=2; IntAct=EBI-355164, EBI-1180783; CC P55072; O75175: CNOT3; NbExp=3; IntAct=EBI-355164, EBI-743073; CC P55072; Q13619: CUL4A; NbExp=2; IntAct=EBI-355164, EBI-456106; CC P55072; O60941: DTNB; NbExp=4; IntAct=EBI-355164, EBI-740402; CC P55072; O60941-5: DTNB; NbExp=3; IntAct=EBI-355164, EBI-11984733; CC P55072; P26378-2: ELAVL4; NbExp=3; IntAct=EBI-355164, EBI-21603100; CC P55072; Q96J88-3: EPSTI1; NbExp=3; IntAct=EBI-355164, EBI-25885343; CC P55072; Q9UNN5: FAF1; NbExp=3; IntAct=EBI-355164, EBI-718246; CC P55072; Q9UNN5-1: FAF1; NbExp=4; IntAct=EBI-355164, EBI-15930546; CC P55072; Q96CS3: FAF2; NbExp=16; IntAct=EBI-355164, EBI-1055805; CC P55072; O94868: FCHSD2; NbExp=2; IntAct=EBI-355164, EBI-1215612; CC P55072; P09471: GNAO1; NbExp=5; IntAct=EBI-355164, EBI-715087; CC P55072; P62993: GRB2; NbExp=5; IntAct=EBI-355164, EBI-401755; CC P55072; P04792: HSPB1; NbExp=3; IntAct=EBI-355164, EBI-352682; CC P55072; P42858: HTT; NbExp=10; IntAct=EBI-355164, EBI-466029; CC P55072; Q8TBB1: LNX1; NbExp=7; IntAct=EBI-355164, EBI-739832; CC P55072; Q8WZA0: LZIC; NbExp=3; IntAct=EBI-355164, EBI-5774346; CC P55072; Q9H7H0-2: METTL17; NbExp=3; IntAct=EBI-355164, EBI-11098807; CC P55072; Q9HC29: NOD2; NbExp=5; IntAct=EBI-355164, EBI-7445625; CC P55072; Q8TAT6: NPLOC4; NbExp=17; IntAct=EBI-355164, EBI-1994109; CC P55072; Q9UNZ2: NSFL1C; NbExp=28; IntAct=EBI-355164, EBI-721577; CC P55072; Q96HA8: NTAQ1; NbExp=6; IntAct=EBI-355164, EBI-741158; CC P55072; Q9Y263: PLAA; NbExp=9; IntAct=EBI-355164, EBI-1994037; CC P55072; Q07869: PPARA; NbExp=3; IntAct=EBI-355164, EBI-78615; CC P55072; P62136: PPP1CA; NbExp=3; IntAct=EBI-355164, EBI-357253; CC P55072; P07602-1: PSAP; NbExp=3; IntAct=EBI-355164, EBI-10635648; CC P55072; P25786: PSMA1; NbExp=8; IntAct=EBI-355164, EBI-359352; CC P55072; P62191: PSMC1; NbExp=5; IntAct=EBI-355164, EBI-357598; CC P55072; P26045: PTPN3; NbExp=2; IntAct=EBI-355164, EBI-1047946; CC P55072; Q9Y4L5: RNF115; NbExp=3; IntAct=EBI-355164, EBI-2129242; CC P55072; Q96EQ8: RNF125; NbExp=3; IntAct=EBI-355164, EBI-2339208; CC P55072; O76064: RNF8; NbExp=3; IntAct=EBI-355164, EBI-373337; CC P55072; P32969: RPL9P9; NbExp=7; IntAct=EBI-355164, EBI-358122; CC P55072; Q9H0K1: SIK2; NbExp=4; IntAct=EBI-355164, EBI-1181664; CC P55072; Q8NBI5: SLC43A3; NbExp=3; IntAct=EBI-355164, EBI-2855542; CC P55072; Q16560-2: SNRNP35; NbExp=3; IntAct=EBI-355164, EBI-12938570; CC P55072; P46977: STT3A; NbExp=3; IntAct=EBI-355164, EBI-719212; CC P55072; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-355164, EBI-359276; CC P55072; P51668: UBE2D1; NbExp=3; IntAct=EBI-355164, EBI-743540; CC P55072; B1AQ61: UBE4B; NbExp=4; IntAct=EBI-355164, EBI-7931266; CC P55072; O94941: UBOX5; NbExp=6; IntAct=EBI-355164, EBI-751901; CC P55072; Q04323: UBXN1; NbExp=9; IntAct=EBI-355164, EBI-1058647; CC P55072; Q96LJ8: UBXN10; NbExp=7; IntAct=EBI-355164, EBI-1993941; CC P55072; Q5T124-6: UBXN11; NbExp=7; IntAct=EBI-355164, EBI-11524408; CC P55072; P68543: UBXN2A; NbExp=20; IntAct=EBI-355164, EBI-1993668; CC P55072; Q14CS0: UBXN2B; NbExp=16; IntAct=EBI-355164, EBI-1993619; CC P55072; Q92575: UBXN4; NbExp=12; IntAct=EBI-355164, EBI-723441; CC P55072; Q9BZV1: UBXN6; NbExp=26; IntAct=EBI-355164, EBI-1993899; CC P55072; Q9BZV1-2: UBXN6; NbExp=3; IntAct=EBI-355164, EBI-21851820; CC P55072; O94888: UBXN7; NbExp=19; IntAct=EBI-355164, EBI-1993627; CC P55072; O00124: UBXN8; NbExp=9; IntAct=EBI-355164, EBI-1993850; CC P55072; Q92890: UFD1; NbExp=10; IntAct=EBI-355164, EBI-1994090; CC P55072; P63027: VAMP2; NbExp=5; IntAct=EBI-355164, EBI-520113; CC P55072; Q969W3: VCF1; NbExp=10; IntAct=EBI-355164, EBI-10281506; CC P55072; P55072: VCP; NbExp=8; IntAct=EBI-355164, EBI-355164; CC P55072; Q6GPH4: XAF1; NbExp=3; IntAct=EBI-355164, EBI-2815120; CC P55072; Q5VVQ6: YOD1; NbExp=3; IntAct=EBI-355164, EBI-2510804; CC P55072; P63104: YWHAZ; NbExp=4; IntAct=EBI-355164, EBI-347088; CC P55072; P24278: ZBTB25; NbExp=3; IntAct=EBI-355164, EBI-739899; CC P55072; Q9WTX6: Cul1; Xeno; NbExp=2; IntAct=EBI-355164, EBI-1551052; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15456787}. CC Endoplasmic reticulum {ECO:0000269|PubMed:15215856}. Nucleus CC {ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:26842564}. Cytoplasm, CC Stress granule {ECO:0000269|PubMed:29804830}. Note=Present in the CC neuronal hyaline inclusion bodies specifically found in motor neurons CC from amyotrophic lateral sclerosis patients (PubMed:15456787). Present CC in the Lewy bodies specifically found in neurons from Parkinson disease CC patients (PubMed:15456787). Recruited to the cytoplasmic surface of the CC endoplasmic reticulum via interaction with AMFR/gp78 (PubMed:16168377). CC Following DNA double-strand breaks, recruited to the sites of damage CC (PubMed:22120668). Recruited to stalled replication forks via CC interaction with SPRTN (PubMed:23042605). Recruited to damaged CC lysosomes decorated with K48-linked ubiquitin chains (PubMed:27753622). CC Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules CC (SGs) in response to arsenite-induced stress treatment CC (PubMed:29804830). {ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22120668, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830}. CC -!- DOMAIN: The PIM (PUB-interaction motif) motif mediates interaction with CC the PUB domain of RNF31. {ECO:0000269|PubMed:24726327}. CC -!- PTM: Phosphorylated by tyrosine kinases in response to T-cell antigen CC receptor activation. Phosphorylated in mitotic cells. CC {ECO:0000250|UniProtKB:P46462}. CC -!- PTM: ISGylated. {ECO:0000269|PubMed:16139798}. CC -!- PTM: Methylation at Lys-315 catalyzed by VCPKMT is increased in the CC presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity. CC {ECO:0000269|PubMed:22948820, ECO:0000269|PubMed:23349634}. CC -!- PTM: UFMylated al Lys-109; UFMylation enhances the interactions between CC BECN1 and other components of the PtdIns3K complex and thereby promotes CC cellular autophagy initiation. {ECO:0000269|PubMed:38762759}. CC -!- DISEASE: Inclusion body myopathy with early-onset Paget disease with or CC without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal CC dominant disease characterized by disabling muscle weakness clinically CC resembling to limb girdle muscular dystrophy, osteolytic bone lesions CC consistent with Paget disease, and premature frontotemporal dementia. CC Clinical features show incomplete penetrance. CC {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, CC ECO:0000269|PubMed:16247064, ECO:0000269|PubMed:16321991, CC ECO:0000269|PubMed:17935506, ECO:0000269|PubMed:20104022, CC ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:20512113, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, CC ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, CC ECO:0000269|PubMed:27209344, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:36980948}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 CC (FTDALS6) [MIM:613954]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia (FTD) is characterized by frontal and temporal CC lobe atrophy associated with neuronal loss, gliosis, and dementia. CC Patients exhibit progressive changes in social, behavioral, and/or CC language function. Amyotrophic lateral sclerosis (ALS) is characterized CC by the death of motor neurons in the brain, brainstem, and spinal cord, CC resulting in fatal paralysis. FTDALS6 is an autosomal dominant form CC characterized by onset of ALS or FTD in adulthood. Some patients with CC the disorder may have features of both diseases. CC {ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Charcot-Marie-Tooth disease, axonal, type 2Y (CMT2Y) CC [MIM:616687]: An autosomal dominant, axonal form of Charcot-Marie-Tooth CC disease, a disorder of the peripheral nervous system, characterized by CC progressive weakness and atrophy, initially of the peroneal muscles and CC later of the distal muscles of the arms. Charcot-Marie-Tooth disease is CC classified in two main groups on the basis of electrophysiologic CC properties and histopathology: primary peripheral demyelinating CC neuropathies (designated CMT1 when they are dominantly inherited) and CC primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 CC group are characterized by signs of axonal degeneration in the absence CC of obvious myelin alterations, normal or slightly reduced nerve CC conduction velocities, and progressive distal muscle weakness and CC atrophy. {ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the AAA ATPase family. {ECO:0000305}. CC -!- CAUTION: It is unclear how it participates in the recruitment of CC TP53BP1 at DNA damage sites. According to a first report, participates CC in the recruitment of TP53BP1 by promoting ubiquitination and removal CC of L3MBTL1 from DNA damage sites (PubMed:22120668). According to a CC second report, it acts by removing 'Lys-48'-linked ubiquitination from CC sites of DNA damage (PubMed:22020440). {ECO:0000305|PubMed:22020440, CC ECO:0000305|PubMed:22120668}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AC004472; AAC07984.1; -; Genomic_DNA. DR EMBL; FJ224344; ACI46036.1; -; mRNA. DR EMBL; FJ224352; ACI46044.1; -; mRNA. DR EMBL; AF100752; AAD43016.1; -; mRNA. DR EMBL; AK312310; BAG35235.1; -; mRNA. DR EMBL; AL353795; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471071; EAW58404.1; -; Genomic_DNA. DR EMBL; BC110913; AAI10914.1; -; mRNA. DR EMBL; BC121794; AAI21795.1; -; mRNA. DR EMBL; Z70768; CAA94809.1; -; mRNA. DR CCDS; CCDS6573.1; -. DR PIR; T02243; T02243. DR RefSeq; NP_009057.1; NM_007126.5. DR PDB; 3EBB; X-ray; 1.90 A; E/F/G/H=797-806. DR PDB; 3HU1; X-ray; 2.81 A; A/B/C/D/E/F=1-481. DR PDB; 3HU2; X-ray; 2.85 A; A/B/C/D/E/F=1-481. DR PDB; 3HU3; X-ray; 2.20 A; A/B=1-481. DR PDB; 3QC8; X-ray; 2.20 A; A=21-196. DR PDB; 3QQ7; X-ray; 2.65 A; A=2-187. DR PDB; 3QQ8; X-ray; 2.00 A; A=2-187. DR PDB; 3QWZ; X-ray; 2.00 A; A=1-208. DR PDB; 3TIW; X-ray; 1.80 A; A/B=1-187. DR PDB; 4KDI; X-ray; 1.86 A; A/B=21-196. DR PDB; 4KDL; X-ray; 1.81 A; A=21-196. DR PDB; 4KLN; X-ray; 2.62 A; A/B/C/D/E/F=1-481. DR PDB; 4KO8; X-ray; 1.98 A; A/B=1-481. DR PDB; 4KOD; X-ray; 2.96 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 4P0A; X-ray; 2.30 A; B/D=797-806. DR PDB; 5B6C; X-ray; 1.55 A; A=21-191. DR PDB; 5C18; X-ray; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 5C19; X-ray; 4.20 A; A/B/C/D/E/F=2-806. DR PDB; 5C1A; X-ray; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 5C1B; X-ray; 3.08 A; A/B/C/D/E/F=2-806. DR PDB; 5DYG; X-ray; 2.20 A; A=1-460. DR PDB; 5DYI; X-ray; 3.71 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 5EPP; X-ray; 1.88 A; A=21-199. DR PDB; 5FTJ; EM; 2.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTK; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 5FTL; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTM; EM; 3.20 A; A/B/C/D/E/F=1-806. DR PDB; 5FTN; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5GLF; X-ray; 2.25 A; A/C/E/G=21-199. DR PDB; 5IFS; X-ray; 2.46 A; B/D=1-481. DR PDB; 5IFW; X-ray; 3.40 A; B=2-806. DR PDB; 5KIW; X-ray; 3.41 A; A/B=1-460. DR PDB; 5KIY; X-ray; 2.79 A; A=1-460. DR PDB; 5X4L; X-ray; 2.40 A; A/B=23-196. DR PDB; 6G2V; X-ray; 1.90 A; A=462-764. DR PDB; 6G2W; X-ray; 2.68 A; A=462-764. DR PDB; 6G2X; X-ray; 2.08 A; A=462-764. DR PDB; 6G2Y; X-ray; 2.15 A; A=462-764. DR PDB; 6G2Z; X-ray; 1.92 A; A=462-764. DR PDB; 6G30; X-ray; 2.42 A; A=462-764. DR PDB; 6HD0; X-ray; 3.73 A; A/B/C/T/U/V=1-481. DR PDB; 6MCK; X-ray; 3.77 A; A/B/C/D/E/F/G/H/I/J/K/L=210-806. DR PDB; 7BP8; EM; 3.90 A; A/B/C/D/E/F=1-806. DR PDB; 7BP9; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 7BPA; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 7BPB; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7JY5; EM; 2.89 A; A/B/C/D/E/F=1-806. DR PDB; 7K56; EM; 3.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K57; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K59; EM; 4.20 A; A/B/C/D/E/F=1-806. DR PDB; 7L5W; EM; 3.34 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7L5X; EM; 6.10 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7LMY; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LMZ; EM; 3.06 A; A/B/C/D/E/F=1-806. DR PDB; 7LN0; EM; 2.98 A; A/B/C/D/E/F=1-806. DR PDB; 7LN1; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LN2; EM; 3.63 A; A/B/C/D/E/F=1-806. DR PDB; 7LN3; EM; 3.45 A; A/B/C/D/E/F=1-806. DR PDB; 7LN4; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7LN5; EM; 3.09 A; A/B/C/D/E/F=1-806. DR PDB; 7LN6; EM; 3.58 A; A/B/C/D/E/F=1-806. DR PDB; 7MDM; EM; 4.86 A; A/B/C/D/E/F=1-806. DR PDB; 7MDO; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 7MHS; EM; 3.60 A; A/B/C/D/E=1-806. DR PDB; 7OAT; X-ray; 3.00 A; B=2-480. DR PDB; 7PUX; X-ray; 1.73 A; A=1-460. DR PDB; 7R7S; EM; 4.23 A; A/B/C/D/E/F=1-806. DR PDB; 7R7T; EM; 4.50 A; A/B/C/D/E/F=1-806. DR PDB; 7R7U; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7RL6; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RL7; EM; 3.00 A; A/B/C/D/E/F=2-806. DR PDB; 7RL9; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLA; EM; 3.10 A; A/B/C/D/E/F=2-806. DR PDB; 7RLB; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLC; EM; 3.20 A; A/B/C/D/E/F=2-806. DR PDB; 7RLD; EM; 3.40 A; A/B/C/D/E/F=2-806. DR PDB; 7RLF; EM; 3.10 A; A/B/C/D/E/F=1-806. DR PDB; 7RLG; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RLH; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7RLI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 7RLJ; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=21-775. DR PDB; 7VCS; EM; 3.32 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCT; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCU; EM; 3.15 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCV; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCX; EM; 3.24 A; A/B/C/D/E/F=1-806. DR PDB; 7Y4W; EM; 3.67 A; A/B/C/D/E/F=21-806. DR PDB; 7Y53; EM; 3.61 A; A/B/C/D/E/F=21-806. DR PDB; 7Y59; EM; 4.51 A; A/B/C/D/E/F=21-806. DR PDB; 8B5R; EM; 6.10 A; A/B/C/D/E/F=2-806. DR PDB; 8FCL; EM; 3.51 A; A/B/C/D/E/F=1-806. DR PDB; 8FCM; EM; 3.27 A; A/B/C/D/E/F=1-806. DR PDB; 8FCN; EM; 2.95 A; A/B/C/D/E/F=1-806. DR PDB; 8FCO; EM; 3.31 A; A/B/C/D/E/F=1-806. DR PDB; 8FCP; EM; 3.52 A; A/B/C/D/E/F=1-806. DR PDB; 8FCQ; EM; 3.93 A; A/B/C/D/E/F=1-806. DR PDB; 8FCR; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 8FCT; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8HL7; X-ray; 2.80 A; B=23-458. DR PDB; 8HRZ; X-ray; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8KG2; X-ray; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8OOI; EM; 2.61 A; A/B/C/D/E/F=1-806. DR PDB; 8PQX; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 8R0E; EM; 2.70 A; A/B/C/D/E/F=1-806. DR PDB; 8RS9; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSB; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSC; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UV2; EM; 3.23 A; A/B/C/D/E/F=1-806. DR PDB; 8UVO; EM; 3.22 A; A/B/C/D/E/F=1-806. DR PDB; 8UVP; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UVQ; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8VKU; EM; 3.50 A; A/B/C/D/E/F=1-806. DR PDB; 8VLS; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 8VOV; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8YKA; EM; 3.45 A; A/B/C/D/E/F=12-775. DR PDB; 9BOQ; EM; 3.33 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 9DIL; EM; 3.30 A; A/B=1-806. DR PDB; 9MQ6; EM; 3.30 A; A/B=1-806. DR PDBsum; 3EBB; -. DR PDBsum; 3HU1; -. DR PDBsum; 3HU2; -. DR PDBsum; 3HU3; -. DR PDBsum; 3QC8; -. DR PDBsum; 3QQ7; -. DR PDBsum; 3QQ8; -. DR PDBsum; 3QWZ; -. DR PDBsum; 3TIW; -. DR PDBsum; 4KDI; -. DR PDBsum; 4KDL; -. DR PDBsum; 4KLN; -. DR PDBsum; 4KO8; -. DR PDBsum; 4KOD; -. DR PDBsum; 4P0A; -. DR PDBsum; 5B6C; -. DR PDBsum; 5C18; -. DR PDBsum; 5C19; -. DR PDBsum; 5C1A; -. DR PDBsum; 5C1B; -. DR PDBsum; 5DYG; -. DR PDBsum; 5DYI; -. DR PDBsum; 5EPP; -. DR PDBsum; 5FTJ; -. DR PDBsum; 5FTK; -. DR PDBsum; 5FTL; -. DR PDBsum; 5FTM; -. DR PDBsum; 5FTN; -. DR PDBsum; 5GLF; -. DR PDBsum; 5IFS; -. DR PDBsum; 5IFW; -. DR PDBsum; 5KIW; -. DR PDBsum; 5KIY; -. DR PDBsum; 5X4L; -. DR PDBsum; 6G2V; -. DR PDBsum; 6G2W; -. DR PDBsum; 6G2X; -. DR PDBsum; 6G2Y; -. DR PDBsum; 6G2Z; -. DR PDBsum; 6G30; -. DR PDBsum; 6HD0; -. DR PDBsum; 6MCK; -. DR PDBsum; 7BP8; -. DR PDBsum; 7BP9; -. DR PDBsum; 7BPA; -. DR PDBsum; 7BPB; -. DR PDBsum; 7JY5; -. DR PDBsum; 7K56; -. DR PDBsum; 7K57; -. DR PDBsum; 7K59; -. DR PDBsum; 7L5W; -. DR PDBsum; 7L5X; -. DR PDBsum; 7LMY; -. DR PDBsum; 7LMZ; -. DR PDBsum; 7LN0; -. DR PDBsum; 7LN1; -. DR PDBsum; 7LN2; -. DR PDBsum; 7LN3; -. DR PDBsum; 7LN4; -. DR PDBsum; 7LN5; -. DR PDBsum; 7LN6; -. DR PDBsum; 7MDM; -. DR PDBsum; 7MDO; -. DR PDBsum; 7MHS; -. DR PDBsum; 7OAT; -. DR PDBsum; 7PUX; -. DR PDBsum; 7R7S; -. DR PDBsum; 7R7T; -. DR PDBsum; 7R7U; -. DR PDBsum; 7RL6; -. DR PDBsum; 7RL7; -. DR PDBsum; 7RL9; -. DR PDBsum; 7RLA; -. DR PDBsum; 7RLB; -. DR PDBsum; 7RLC; -. DR PDBsum; 7RLD; -. DR PDBsum; 7RLF; -. DR PDBsum; 7RLG; -. DR PDBsum; 7RLH; -. DR PDBsum; 7RLI; -. DR PDBsum; 7RLJ; -. DR PDBsum; 7VCS; -. DR PDBsum; 7VCT; -. DR PDBsum; 7VCU; -. DR PDBsum; 7VCV; -. DR PDBsum; 7VCX; -. DR PDBsum; 7Y4W; -. DR PDBsum; 7Y53; -. DR PDBsum; 7Y59; -. DR PDBsum; 8B5R; -. DR PDBsum; 8FCL; -. DR PDBsum; 8FCM; -. DR PDBsum; 8FCN; -. DR PDBsum; 8FCO; -. DR PDBsum; 8FCP; -. DR PDBsum; 8FCQ; -. DR PDBsum; 8FCR; -. DR PDBsum; 8FCT; -. DR PDBsum; 8HL7; -. DR PDBsum; 8HRZ; -. DR PDBsum; 8KG2; -. DR PDBsum; 8OOI; -. DR PDBsum; 8PQX; -. DR PDBsum; 8R0E; -. DR PDBsum; 8RS9; -. DR PDBsum; 8RSB; -. DR PDBsum; 8RSC; -. DR PDBsum; 8UV2; -. DR PDBsum; 8UVO; -. DR PDBsum; 8UVP; -. DR PDBsum; 8UVQ; -. DR PDBsum; 8VKU; -. DR PDBsum; 8VLS; -. DR PDBsum; 8VOV; -. DR PDBsum; 8YKA; -. DR PDBsum; 9BOQ; -. DR PDBsum; 9DIL; -. DR PDBsum; 9MQ6; -. DR AlphaFoldDB; P55072; -. DR EMDB; EMD-15774; -. DR EMDB; EMD-15861; -. DR EMDB; EMD-16781; -. DR EMDB; EMD-17016; -. DR EMDB; EMD-17024; -. DR EMDB; EMD-17128; -. DR EMDB; EMD-17827; -. DR EMDB; EMD-17837; -. DR EMDB; EMD-18517; -. DR EMDB; EMD-18790; -. DR EMDB; EMD-19473; -. DR EMDB; EMD-19475; -. DR EMDB; EMD-19476; -. DR EMDB; EMD-22521; -. DR EMDB; EMD-22675; -. DR EMDB; EMD-22676; -. DR EMDB; EMD-22678; -. DR EMDB; EMD-23191; -. DR EMDB; EMD-23192; -. DR EMDB; EMD-23442; -. DR EMDB; EMD-23443; -. DR EMDB; EMD-23444; -. DR EMDB; EMD-23445; -. DR EMDB; EMD-23446; -. DR EMDB; EMD-23447; -. DR EMDB; EMD-23448; -. DR EMDB; EMD-23449; -. DR EMDB; EMD-23450; -. DR EMDB; EMD-23451; -. DR EMDB; EMD-23452; -. DR EMDB; EMD-23453; -. DR EMDB; EMD-23454; -. DR EMDB; EMD-23455; -. DR EMDB; EMD-23456; -. DR EMDB; EMD-23457; -. DR EMDB; EMD-23458; -. DR EMDB; EMD-23775; -. DR EMDB; EMD-23776; -. DR EMDB; EMD-23835; -. DR EMDB; EMD-24302; -. DR EMDB; EMD-24304; -. DR EMDB; EMD-24305; -. DR EMDB; EMD-24306; -. DR EMDB; EMD-24518; -. DR EMDB; EMD-24519; -. DR EMDB; EMD-24522; -. DR EMDB; EMD-24523; -. DR EMDB; EMD-24524; -. DR EMDB; EMD-24525; -. DR EMDB; EMD-24526; -. DR EMDB; EMD-24528; -. DR EMDB; EMD-24529; -. DR EMDB; EMD-24530; -. DR EMDB; EMD-24531; -. DR EMDB; EMD-24532; -. DR EMDB; EMD-28982; -. DR EMDB; EMD-28983; -. DR EMDB; EMD-28984; -. DR EMDB; EMD-28985; -. DR EMDB; EMD-28986; -. DR EMDB; EMD-28987; -. DR EMDB; EMD-28988; -. DR EMDB; EMD-28989; -. DR EMDB; EMD-28990; -. DR EMDB; EMD-28991; -. DR EMDB; EMD-28992; -. DR EMDB; EMD-30147; -. DR EMDB; EMD-30148; -. DR EMDB; EMD-30149; -. DR EMDB; EMD-30150; -. DR EMDB; EMD-31894; -. DR EMDB; EMD-31895; -. DR EMDB; EMD-31896; -. DR EMDB; EMD-31897; -. DR EMDB; EMD-31899; -. DR EMDB; EMD-32827; -. DR EMDB; EMD-3295; -. DR EMDB; EMD-3296; -. DR EMDB; EMD-3297; -. DR EMDB; EMD-3298; -. DR EMDB; EMD-3299; -. DR EMDB; EMD-3323; -. DR EMDB; EMD-3324; -. DR EMDB; EMD-3325; -. DR EMDB; EMD-3326; -. DR EMDB; EMD-3327; -. DR EMDB; EMD-3328; -. DR EMDB; EMD-33608; -. DR EMDB; EMD-33611; -. DR EMDB; EMD-33613; -. DR EMDB; EMD-38770; -. DR EMDB; EMD-38771; -. DR EMDB; EMD-38772; -. DR EMDB; EMD-39360; -. DR EMDB; EMD-42603; -. DR EMDB; EMD-42625; -. DR EMDB; EMD-42626; -. DR EMDB; EMD-42627; -. DR EMDB; EMD-43329; -. DR EMDB; EMD-43343; -. DR EMDB; EMD-43392; -. DR EMDB; EMD-44748; -. DR EMDB; EMD-46912; -. DR EMDB; EMD-48514; -. DR SMR; P55072; -. DR BioGRID; 113258; 1454. DR ComplexPortal; CPX-137; VCP-NPL4-UFD1 AAA ATPase complex. DR ComplexPortal; CPX-262; VCP-NSFL1C AAA ATPase complex. DR ComplexPortal; CPX-8095; VCP-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8096; VCP-NPL4-UFD1-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8101; VCP-NPL4-UFD1-UBXN7 AAA ATPase complex. DR ComplexPortal; CPX-8104; VCP-NPL4-UFD1-FAF2 AAA ATPase complex. DR ComplexPortal; CPX-8105; VCP-NPL4-UFD1-UBXN1 AAA ATPase complex. DR ComplexPortal; CPX-8121; VCP-UBXN2B AAA ATPase complex. DR ComplexPortal; CPX-8124; VCP-UBXN2A AAA ATPase complex. DR ComplexPortal; CPX-8128; VCP-YOD1 AAA ATPase complex. DR ComplexPortal; CPX-8129; VCP-PLAA AAA ATPase complex. DR ComplexPortal; CPX-8132; VCP-VCPIP1 AAA ATPase complex. DR ComplexPortal; CPX-8133; VCP-UBXN6 AAA ATPase complex. DR ComplexPortal; CPX-8134; VCP-AMFR AAA ATPase complex. DR ComplexPortal; CPX-8570; VCP-DERL1 AAA ATPase complex. DR ComplexPortal; CPX-8782; VCP-DERL2 AAA ATPase complex. DR ComplexPortal; CPX-8783; VCP-DERL3 AAA ATPase complex. DR CORUM; P55072; -. DR DIP; DIP-33543N; -. DR FunCoup; P55072; 2295. DR IntAct; P55072; 915. DR MINT; P55072; -. DR STRING; 9606.ENSP00000351777; -. DR BindingDB; P55072; -. DR ChEMBL; CHEMBL1075145; -. DR DrugBank; DB16874; CB-5083. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR DrugCentral; P55072; -. DR MoonDB; P55072; Predicted. DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family. DR CarbonylDB; P55072; -. DR GlyGen; P55072; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P55072; -. DR MetOSite; P55072; -. DR PhosphoSitePlus; P55072; -. DR SwissPalm; P55072; -. DR BioMuta; VCP; -. DR DMDM; 6094447; -. DR OGP; P55072; -. DR REPRODUCTION-2DPAGE; IPI00022774; -. DR REPRODUCTION-2DPAGE; P55072; -. DR CPTAC; CPTAC-295; -. DR CPTAC; CPTAC-296; -. DR jPOST; P55072; -. DR MassIVE; P55072; -. DR PaxDb; 9606-ENSP00000351777; -. DR PeptideAtlas; P55072; -. DR PRIDE; P55072; -. DR ProteomicsDB; 56776; -. DR Pumba; P55072; -. DR TopDownProteomics; P55072; -. DR ABCD; P55072; 1 sequenced antibody. DR Antibodypedia; 2215; 680 antibodies from 44 providers. DR DNASU; 7415; -. DR Ensembl; ENST00000358901.11; ENSP00000351777.6; ENSG00000165280.19. DR GeneID; 7415; -. DR KEGG; hsa:7415; -. DR MANE-Select; ENST00000358901.11; ENSP00000351777.6; NM_007126.5; NP_009057.1. DR AGR; HGNC:12666; -. DR ClinPGx; PA37289; -. DR CTD; 7415; -. DR DisGeNET; 7415; -. DR GeneCards; VCP; -. DR GeneReviews; VCP; -. DR HGNC; HGNC:12666; VCP. DR HPA; ENSG00000165280; Low tissue specificity. DR MalaCards; VCP; -. DR MIM; 167320; phenotype. DR MIM; 601023; gene. DR MIM; 613954; phenotype. DR MIM; 616687; phenotype. DR OpenTargets; ENSG00000165280; -. DR Orphanet; 329478; Adult-onset distal myopathy due to VCP mutation. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 435387; Autosomal dominant Charcot-Marie-Tooth disease type 2Y. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR Orphanet; 52430; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 329475; Spastic paraplegia-Paget disease of bone syndrome. DR VEuPathDB; HostDB:ENSG00000165280; -. DR eggNOG; KOG0730; Eukaryota. DR GeneTree; ENSGT00900000141071; -. DR HOGENOM; CLU_000688_12_3_1; -. DR InParanoid; P55072; -. DR OMA; VWPAYPE; -. DR OrthoDB; 27435at2759; -. DR PAN-GO; P55072; 10 GO annotations based on evolutionary models. DR PhylomeDB; P55072; -. DR BRENDA; 3.6.4.6; 2681. DR PathwayCommons; P55072; -. DR Reactome; R-HSA-110320; Translesion Synthesis by POLH. DR Reactome; R-HSA-3371511; HSF1 activation. DR Reactome; R-HSA-382556; ABC-family proteins mediated transport. DR Reactome; R-HSA-532668; N-glycan trimming in the ER and Calnexin/Calreticulin cycle. DR Reactome; R-HSA-5358346; Hedgehog ligand biogenesis. DR Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD. DR Reactome; R-HSA-5678895; Defective CFTR causes cystic fibrosis. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-8866654; E3 ubiquitin ligases ubiquitinate target proteins. DR Reactome; R-HSA-8876725; Protein methylation. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9013407; RHOH GTPase cycle. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-9678110; Attachment and Entry. DR Reactome; R-HSA-9694614; Attachment and Entry. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR SignaLink; P55072; -. DR SIGNOR; P55072; -. DR Agora; ENSG00000165280; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7415; 852 hits in 1138 CRISPR screens. DR CD-CODE; 550E224B; Proteasome condensate. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; VCP; human. DR EvolutionaryTrace; P55072; -. DR GeneWiki; Valosin-containing_protein; -. DR GenomeRNAi; 7415; -. DR Pharos; P55072; Tchem. DR PRO; PR:P55072; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; P55072; protein. DR Bgee; ENSG00000165280; Expressed in stromal cell of endometrium and 210 other cell types or tissues. DR ExpressionAtlas; P55072; baseline and differential. DR GO; GO:1904949; C:ATPase complex; IEA:Ensembl. DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0097542; C:ciliary tip; IDA:HPA. DR GO; GO:0035869; C:ciliary transition zone; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0000153; C:cytoplasmic ubiquitin ligase complex; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0036513; C:Derlin-1 retrotranslocation complex; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB. DR GO; GO:0005811; C:lipid droplet; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0000502; C:proteasome complex; IDA:BHF-UCL. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0034098; C:VCP-NPL4-UFD1 AAA ATPase complex; IPI:ComplexPortal. DR GO; GO:1990730; C:VCP-NSFL1C complex; IPI:ComplexPortal. DR GO; GO:0043531; F:ADP binding; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:UniProt. DR GO; GO:1904288; F:BAT3 complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0035800; F:deubiquitinase activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0036435; F:K48-linked polyubiquitin modification-dependent protein binding; IDA:UniProt. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0042288; F:MHC class I protein binding; IEA:Ensembl. DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IEA:Ensembl. DR GO; GO:0046034; P:ATP metabolic process; IEA:Ensembl. DR GO; GO:0097352; P:autophagosome maturation; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1903843; P:cellular response to arsenite ion; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IMP:UniProtKB. DR GO; GO:0071218; P:cellular response to misfolded protein; IMP:ParkinsonsUK-UCL. DR GO; GO:0140455; P:cytoplasm protein quality control; IDA:UniProt. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; NAS:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0061857; P:endoplasmic reticulum stress-induced pre-emptive quality control; IMP:UniProtKB. DR GO; GO:0006888; P:endoplasmic reticulum to Golgi vesicle-mediated transport; IEA:Ensembl. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:UniProtKB. DR GO; GO:0032510; P:endosome to lysosome transport via multivesicular body sorting pathway; IMP:UniProtKB. DR GO; GO:0036503; P:ERAD pathway; IDA:UniProtKB. DR GO; GO:0045184; P:establishment of protein localization; TAS:UniProtKB. DR GO; GO:0072389; P:flavin adenine dinucleotide catabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036297; P:interstrand cross-link repair; ISS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IMP:UniProtKB. DR GO; GO:0051228; P:mitotic spindle disassembly; IBA:GO_Central. DR GO; GO:0019674; P:NAD+ metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0035331; P:negative regulation of hippo signaling; IGI:FlyBase. DR GO; GO:0120186; P:negative regulation of protein localization to chromatin; IDA:UniProt. DR GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:FlyBase. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:FlyBase. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:1903862; P:positive regulation of oxidative phosphorylation; IMP:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL. DR GO; GO:1903006; P:positive regulation of protein K63-linked deubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProt. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0106300; P:protein-DNA covalent cross-linking repair; IDA:UniProtKB. DR GO; GO:1903715; P:regulation of aerobic respiration; IMP:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:1905634; P:regulation of protein localization to chromatin; IDA:UniProtKB. DR GO; GO:0050807; P:regulation of synapse organization; IEA:Ensembl. DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB. DR GO; GO:0035617; P:stress granule disassembly; IDA:UniProtKB. DR GO; GO:0019985; P:translesion synthesis; IMP:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:ComplexPortal. DR GO; GO:0019079; P:viral genome replication; IMP:CACAO. DR CDD; cd19519; RecA-like_CDC48_r1-like; 1. DR CDD; cd19528; RecA-like_CDC48_r2-like; 1. DR DisProt; DP03238; -. DR FunFam; 1.10.8.60:FF:000004; Cell division control 48; 1. DR FunFam; 3.10.330.10:FF:000001; Cell division control 48; 1. DR FunFam; 2.40.40.20:FF:000003; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000012; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000048; Transitional endoplasmic reticulum ATPase; 1. DR Gene3D; 1.10.8.60; -; 1. DR Gene3D; 2.40.40.20; -; 1. DR Gene3D; 3.10.330.10; -; 1. DR Gene3D; 6.10.20.150; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR IDEAL; IID00201; -. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR005938; AAA_ATPase_CDC48. DR InterPro; IPR050168; AAA_ATPase_domain. DR InterPro; IPR041569; AAA_lid_3. DR InterPro; IPR009010; Asp_de-COase-like_dom_sf. DR InterPro; IPR003959; ATPase_AAA_core. DR InterPro; IPR003960; ATPase_AAA_CS. DR InterPro; IPR004201; Cdc48_dom2. DR InterPro; IPR029067; CDC48_domain_2-like_sf. DR InterPro; IPR003338; CDC4_N-term_subdom. DR InterPro; IPR027417; P-loop_NTPase. DR NCBIfam; TIGR01243; CDC48; 1. DR PANTHER; PTHR23077; AAA-FAMILY ATPASE; 1. DR PANTHER; PTHR23077:SF69; TRANSITIONAL ENDOPLASMIC RETICULUM ATPASE; 1. DR Pfam; PF00004; AAA; 2. DR Pfam; PF17862; AAA_lid_3; 2. DR Pfam; PF02933; CDC48_2; 1. DR Pfam; PF02359; CDC48_N; 1. DR SMART; SM00382; AAA; 2. DR SMART; SM01072; CDC48_2; 1. DR SMART; SM01073; CDC48_N; 1. DR SUPFAM; SSF50692; ADC-like; 1. DR SUPFAM; SSF54585; Cdc48 domain 2-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR PROSITE; PS00674; AAA; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; ATP-binding; KW Autophagy; Charcot-Marie-Tooth disease; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; KW Endoplasmic reticulum; Hydrolase; Isopeptide bond; Lipid-binding; KW Methylation; Neurodegeneration; Neuropathy; Nucleotide-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Transport; KW Ubl conjugation; Ubl conjugation pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.9, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:22223895, FT ECO:0007744|PubMed:25944712" FT CHAIN 2..806 FT /note="Transitional endoplasmic reticulum ATPase" FT /id="PRO_0000084572" FT REGION 708..727 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 768..806 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 797..806 FT /note="Interaction with UBXN6" FT /evidence="ECO:0000269|PubMed:18656546" FT MOTIF 802..806 FT /note="PIM motif" FT /evidence="ECO:0000269|PubMed:24726327" FT COMPBIAS 777..793 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 247..253 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 348 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 384 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 521..526 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.9, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:25944712" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 13 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 37 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 315 FT /note="N6,N6,N6-trimethyllysine; by VCPKMT" FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MOD_RES 436 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 462 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 502 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 505 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 702 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 770 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 775 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 787 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 805 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT CROSSLNK 8 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 18 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 109 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in UFM1)" FT /evidence="ECO:0000269|PubMed:38762759" FT VARIANT 95 FT /note="R -> G (in IBMPFD1; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; abolishes FT enhancement of K-315 methylation by ASPSCR1; decreased FT interaction with CAV1 and UBXN6; dbSNP:rs121909332)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20512113, FT ECO:0000269|PubMed:21822278" FT /id="VAR_033016" FT VARIANT 97 FT /note="G -> E (in CMT2Y; increased ATPase activity; FT dbSNP:rs864309502)" FT /evidence="ECO:0000269|PubMed:25878907" FT /id="VAR_076464" FT VARIANT 126 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:27209344" FT /id="VAR_076465" FT VARIANT 155 FT /note="R -> C (in IBMPFD1; also in one patient without FT evidence of Paget disease of the bone; dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:15732117" FT /id="VAR_033017" FT VARIANT 155 FT /note="R -> H (in FTDALS6 and IBMPFD1; properly assembles FT into a hexameric structure; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; shows normal ATPase FT activity according to PubMed:16321991 while according to FT PubMed:25878907 and PubMed:25125609 shows increased ATPase FT activity; no defect in ubiquitin-dependent protein FT degradation by the proteasome; impaired autophagic FT function; defective maturation of ubiquitin-containing FT autophagosomes; decreased interaction with CAV1 and UBXN6; FT decreased endosome to lysosome transport via multivesicular FT body sorting pathway of CAV1; decreases the arsenite- FT induced stress granules (SGs) clearance process; FT dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:29804830" FT /id="VAR_033018" FT VARIANT 155 FT /note="R -> L (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:20335036" FT /id="VAR_078910" FT VARIANT 155 FT /note="R -> P (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582" FT /id="VAR_033019" FT VARIANT 155 FT /note="R -> S (in IBMPFD1; impaired autophagic function; FT dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:20104022" FT /id="VAR_076466" FT VARIANT 159 FT /note="R -> G (in FTDALS6; dbSNP:rs387906789)" FT /evidence="ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:23349634" FT /id="VAR_065910" FT VARIANT 159 FT /note="R -> H (in IBMPFD1; without frontotemporal dementia; FT abolishes enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909335)" FT /evidence="ECO:0000269|PubMed:16247064" FT /id="VAR_033020" FT VARIANT 160 FT /note="A -> T (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088265" FT VARIANT 185 FT /note="E -> K (in CMT2Y; normal ATPase activity; impaired FT autophagic function; dbSNP:rs864309501)" FT /evidence="ECO:0000269|PubMed:25125609" FT /id="VAR_076467" FT VARIANT 191 FT /note="R -> Q (in FTDALS6 and IBMPFD1; abolishes FT enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909334)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634" FT /id="VAR_033021" FT VARIANT 198 FT /note="L -> W (in IBMPFD1; increased ATPase activity; FT impaired autophagic function; dbSNP:rs748447593)" FT /evidence="ECO:0000269|PubMed:17935506, FT ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_076468" FT VARIANT 232 FT /note="A -> E (in IBMPFD1; increased ATPase activity; no FT defect in ubiquitin-dependent protein degradation by the FT proteasome; impaired autophagic function; defect in FT maturation of ubiquitin-containing autophagosomes; FT decreased interaction with CAV1 and UBXN6; FT dbSNP:rs121909331)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21822278, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_033022" FT VARIANT 254 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088266" FT VARIANT 369 FT /note="I -> T (in IBMPFD1; uncertain significance; FT dbSNP:rs1828723406)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088267" FT VARIANT 387 FT /note="N -> H (in IBMPFD1; uncertain significance; FT dbSNP:rs1554668420)" FT /evidence="ECO:0000269|PubMed:17935506" FT /id="VAR_078911" FT VARIANT 592 FT /note="D -> N (in FTDALS6; dbSNP:rs387906790)" FT /evidence="ECO:0000269|PubMed:21145000" FT /id="VAR_065911" FT MUTAGEN 52..55 FT /note="FRGD->ARGA: Abolishes interaction with NPLOC4; when FT associated with A-110." FT /evidence="ECO:0000269|PubMed:26471729" FT MUTAGEN 53 FT /note="R->A: Minor effect on affinity for ATP and ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 86 FT /note="R->A: Strongly increased affinity for ATP. Strongly FT reduced affinity for ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 109 FT /note="K->R: Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:38762759" FT MUTAGEN 110 FT /note="Y->A: Abolishes interaction with NPLOC4; when FT associated with 52-A--A-55. Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:26471729, FT ECO:0000269|PubMed:38762759" FT MUTAGEN 113..115 FT /note="RIH->TIT: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 131 FT /note="F->R: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 140 FT /note="L->D: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 179 FT /note="D->R: No effect on binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 183 FT /note="H->W: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 251 FT /note="K->Q: Impairs ERAD degradation of HMGCR and does not FT inhibit interaction with RHBDD1; when associated with Q- FT 524." FT /evidence="ECO:0000269|PubMed:16168377, FT ECO:0000269|PubMed:22795130" FT MUTAGEN 305 FT /note="E->Q: Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-578." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:26471729" FT MUTAGEN 312 FT /note="K->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 313 FT /note="R->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="E->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="Missing: Strongly impairs methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 315 FT /note="K->L,Q,R: Abolishes methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MUTAGEN 316 FT /note="T->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 317 FT /note="H->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 318 FT /note="G->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 524 FT /note="K->A: Impairs catalytic activity of RNF19A toward FT SOD1 mutant. Does not inhibit interaction with RHBDD1; when FT associated with A-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 524 FT /note="K->Q: Impairs ERAD degradation of HMGCR; when FT associated with Q-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 578 FT /note="E->Q: Does not inhibit interaction with RHBDD1. FT Increased interaction with CAV1 and UBXN6. Impaired FT autophagic function. Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-305. FT Increases interaction with ZFAND1 in an arsenite-dependent FT manner." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22795130, FT ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:29804830" FT CONFLICT 169 FT /note="D -> H (in Ref. 7; AAI21795)" FT /evidence="ECO:0000305" FT CONFLICT 312 FT /note="K -> I (in Ref. 4; BAG35235)" FT /evidence="ECO:0000305" FT HELIX 15..17 FT /evidence="ECO:0007829|PDB:7LMY" FT TURN 21..23 FT /evidence="ECO:0007829|PDB:7BPA" FT STRAND 25..29 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 38..41 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 43..48 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 56..60 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 62..64 FT /evidence="ECO:0007829|PDB:3QQ8" FT STRAND 66..73 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 86..92 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 94..97 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 99..104 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 112..119 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 120..123 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 126..128 FT /evidence="ECO:0007829|PDB:5IFS" FT HELIX 130..133 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 135..139 FT /evidence="ECO:0007829|PDB:5B6C" FT TURN 140..142 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 144..147 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 151..154 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:4KDI" FT STRAND 161..176 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 191..193 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 203..205 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 210..225 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 229..232 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 240..244 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4KLN" FT HELIX 251..262 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 278..280 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 281..295 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 298..304 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 306..308 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 313..315 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 319..334 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 335..337 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 338..340 FT /evidence="ECO:0007829|PDB:8HRZ" FT STRAND 341..348 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 350..352 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 355..358 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 360..362 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 365..368 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 374..384 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 385..387 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:5DYG" FT HELIX 392..394 FT /evidence="ECO:0007829|PDB:8PQX" FT HELIX 396..402 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 408..427 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 428..430 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 432..436 FT /evidence="ECO:0007829|PDB:3HU1" FT HELIX 439..444 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 449..456 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 458..461 FT /evidence="ECO:0007829|PDB:4KO8" FT TURN 462..468 FT /evidence="ECO:0007829|PDB:4KO8" FT HELIX 476..478 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 483..498 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 500..505 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 513..519 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 520..523 FT /evidence="ECO:0007829|PDB:8UV2" FT HELIX 524..534 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 538..543 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 544..547 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 550..553 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 557..568 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 571..577 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 579..581 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 584..586 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 588..590 FT /evidence="ECO:0007829|PDB:5FTJ" FT STRAND 592..594 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 597..609 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 617..624 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 626..628 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 631..634 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 635..639 FT /evidence="ECO:0007829|PDB:5FTK" FT STRAND 641..644 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 650..661 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 662..664 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 672..677 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 678..681 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 684..711 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 718..721 FT /evidence="ECO:0007829|PDB:7VCU" FT STRAND 722..724 FT /evidence="ECO:0007829|PDB:5IFW" FT STRAND 729..731 FT /evidence="ECO:0007829|PDB:7LMY" FT HELIX 733..739 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 740..742 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 749..761 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 763..765 FT /evidence="ECO:0007829|PDB:7JY5" FT STRAND 767..770 FT /evidence="ECO:0007829|PDB:7RLI" SQ SEQUENCE 806 AA; 89322 MW; 501B721D3A77BA8A CRC64; MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG AGPSQGSGGG TGGSVYTEDN DDDLYG // ID TM175_HUMAN Reviewed; 504 AA. AC Q9BSA9; D3DVN4; Q8ND13; DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 148. DE RecName: Full=Endosomal/lysosomal proton channel TMEM175 {ECO:0000305}; DE AltName: Full=Potassium channel TMEM175 {ECO:0000305}; DE AltName: Full=Transmembrane protein 175 {ECO:0000303|PubMed:26317472}; DE Short=hTMEM175 {ECO:0000303|PubMed:26317472, ECO:0000303|PubMed:28723891, ECO:0000303|PubMed:32228865}; GN Name=TMEM175 {ECO:0000303|PubMed:26317472, ECO:0000312|HGNC:HGNC:28709}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-6, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [5] RP FUNCTION, TRANSPORTER ACTIVITY, DOMAIN, SUBCELLULAR LOCATION, TOPOLOGY, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF ARG-35; PHE-39; SER-40 AND ASP-41. RX PubMed=26317472; DOI=10.1016/j.cell.2015.08.002; RA Cang C., Aranda K., Seo Y.J., Gasnier B., Ren D.; RT "TMEM175 is an organelle K(+) channel regulating lysosomal function."; RL Cell 162:1101-1112(2015). RN [6] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ILE-46; RP VAL-50; LEU-53; ILE-271; LEU-275 AND LEU-278. RX PubMed=28723891; DOI=10.1038/nature23269; RA Lee C., Guo J., Zeng W., Kim S., She J., Cang C., Ren D., Jiang Y.; RT "The lysosomal potassium channel TMEM175 adopts a novel tetrameric RT architecture."; RL Nature 547:472-475(2017). RN [7] RP POSSIBLE INVOLVEMENT IN PARK. RX PubMed=28193887; DOI=10.1073/pnas.1616332114; RA Jinn S., Drolet R.E., Cramer P.E., Wong A.H., Toolan D.M., Gretzula C.A., RA Voleti B., Vassileva G., Disa J., Tadin-Strapps M., Stone D.J.; RT "TMEM175 deficiency impairs lysosomal and mitochondrial function and RT increases alpha-synuclein aggregation."; RL Proc. Natl. Acad. Sci. U.S.A. 114:2389-2394(2017). RN [8] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANTS PRO-65 AND THR-393, AND RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393. RX PubMed=31658403; DOI=10.1002/ana.25629; RA Krohn L., Oeztuerk T.N., Vanderperre B., Ouled Amar Bencheikh B., RA Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., RA Hu M.T.M., Dauvilliers Y., Hoegl B., Stefani A., Monaca C.C., Plazzi G., RA Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., RA Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., RA Liong C., Gagnon J.F., Desautels A., Hassin-Baer S., Montplaisir J.Y., RA Dupre N., Rouleau G.A., Fon E.A., Trempe J.F., Lamoureux G., Alcalay R.N., RA Gan-Or Z.; RT "Genetic, structural, and functional evidence link TMEM175 to RT synucleinopathies."; RL Ann. Neurol. 87:139-153(2020). RN [9] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANT THR-393, AND RP CHARACTERIZATION OF VARIANT THR-393. RX PubMed=31261387; DOI=10.1093/hmg/ddz136; RA Jinn S., Blauwendraat C., Toolan D., Gretzula C.A., Drolet R.E., Smith S., RA Nalls M.A., Marcus J., Singleton A.B., Stone D.J.; RT "Functionalization of the TMEM175 p.M393T variant as a risk factor for RT Parkinson disease."; RL Hum. Mol. Genet. 28:3244-3254(2019). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF 45-SER--THR-49; THR-49 RP AND THR-274. RX PubMed=32267231; DOI=10.7554/elife.53683; RA Brunner J.D., Jakob R.P., Schulze T., Neldner Y., Moroni A., Thiel G., RA Maier T., Schenck S.; RT "Structural basis for ion selectivity in TMEM175 K+ channels."; RL Elife 9:0-0(2020). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH AKT1, RP IDENTIFICATION IN THE LYSOK(GF) COMPLEX, INVOLVEMENT IN PARK, RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393, AND MUTAGENESIS OF RP SER-241; THR-338 AND MET-393. RX PubMed=33505021; DOI=10.1038/s41586-021-03185-z; RA Wie J., Liu Z., Song H., Tropea T.F., Yang L., Wang H., Liang Y., Cang C., RA Aranda K., Lohmann J., Yang J., Lu B., Chen-Plotkin A.S., Luk K.C., Ren D.; RT "A growth-factor-activated lysosomal K+ channel regulates Parkinson's RT pathology."; RL Nature 591:431-437(2021). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF RP ASP-41 AND SER-45. RX PubMed=35750034; DOI=10.1016/j.cell.2022.05.021; RA Hu M., Li P., Wang C., Feng X., Geng Q., Chen W., Marthi M., Zhang W., RA Gao C., Reid W., Swanson J., Du W., Hume R.I., Xu H.; RT "Parkinson's disease-risk protein TMEM175 is a proton-activated proton RT channel in lysosomes."; RL Cell 185:2292-2308(2022). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF SER-38; SER-45; ILE-46; RP THR-49; ILE-271; THR-274; ASP-279; ASP-283; ARG-309; HIS-327; HIS-328; RP ASN-345; GLN-360 AND HIS-449. RX PubMed=35333573; DOI=10.1126/sciadv.abm1568; RA Zheng W., Shen C., Wang L., Rawson S., Xie W.J., Nist-Lund C., Wu J., RA Shen Z., Xia S., Holt J.R., Wu H., Fu T.M.; RT "pH regulates potassium conductance and drives a constitutive proton RT current in human TMEM175."; RL Sci. Adv. 8:eabm1568-eabm1568(2022). RN [14] {ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS), FUNCTION, TRANSPORTER RP ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF SER-45 RP AND THR-274. RX PubMed=32228865; DOI=10.7554/elife.53430; RA Oh S., Paknejad N., Hite R.K.; RT "Gating and selectivity mechanisms for the lysosomal K+ channel TMEM175."; RL Elife 9:0-0(2020). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.45 ANGSTROMS), FUNCTION, SUBUNIT, AND RP MUTAGENESIS OF ILE-46 AND ILE-271. RX PubMed=35608336; DOI=10.7554/elife.75122; RA Oh S., Marinelli F., Zhou W., Lee J., Choi H.J., Kim M., RA Faraldo-Gomez J.D., Hite R.K.; RT "Differential ion dehydration energetics explains selectivity in the non- RT canonical lysosomal K+ channel TMEM175."; RL Elife 11:0-0(2022). RN [16] {ECO:0007744|PDB:8FY5} RP STRUCTURE BY ELECTRON MICROSCOPY (3.4 ANGSTROMS) IN COMPLEX WITH LAMP1, RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH LAMP1 RP AND LAMP2, AND MUTAGENESIS OF THR-395. RX PubMed=37390818; DOI=10.1016/j.molcel.2023.06.004; RA Zhang J., Zeng W., Han Y., Lee W.R., Liou J., Jiang Y.; RT "Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the RT TMEM175 channel."; RL Mol. Cell 83:2524-2539(2023). CC -!- FUNCTION: Proton-activated proton channel that catalyzes proton efflux CC from endosomes and lysosomes to maintain a steady-state pH CC (PubMed:35333573, PubMed:35750034, PubMed:37390818). Activated at low CC pH (under pH 4.6) by luminal side protons: selectively mediates CC lysosomal proton release from lysosomes, eliciting a proton leak that CC balances V-ATPase activity to maintain pH homeostasis CC (PubMed:35750034). Regulation of lumenal pH stability is required for CC autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). Also CC acts as a potassium channel at higher pH, regulating potassium CC conductance in endosomes and lysosomes (PubMed:26317472, CC PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). CC Constitutes the pore-forming subunit of the lysoK(GF) complex, a CC complex activated by extracellular growth factors (PubMed:33505021). CC The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or CC AKT3), a major target of growth factor receptors: in the complex, CC TMEM175 channel is opened by conformational changes by AKT, leading to CC its activation (PubMed:33505021). The lysoK(GF) complex is required to CC protect neurons against stress-induced damage (PubMed:33505021). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35333573, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}; CC -!- CATALYTIC ACTIVITY: CC Reaction=K(+)(in) = K(+)(out); Xref=Rhea:RHEA:29463, ChEBI:CHEBI:29103; CC Evidence={ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021}; CC -!- ACTIVITY REGULATION: Active at low pH (under pH 4.6): proton channel CC activity is activated by luminal side protons (PubMed:35750034). CC Polyunsaturated fatty acids, such as arachidonic acid, also activate CC the channel activity (PubMed:35750034). Proton channel activity is CC directly inhibited by LAMP1 or LAMP2, facilitating lysosomal CC acidification (PubMed:37390818). Channel activity is activated CC following interaction with AKT (AKT1, AKT2 or AKT3): interaction CC promotes activation from closed to an open state (PubMed:33505021). CC Activation by AKT is independent of AKT serine/threonine-protein kinase CC activity (PubMed:33505021). {ECO:0000269|PubMed:33505021, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- SUBUNIT: Homodimer (PubMed:28723891, PubMed:32228865, PubMed:35608336). CC Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the CC lysoK(GF) complex, which activates the channel (PubMed:33505021). CC Interacts with LAMP1; inhibiting the proton channel activity of TMEM175 CC (PubMed:37390818). Interacts with LAMP2; inhibiting the proton channel CC activity of TMEM175 (PubMed:37390818). {ECO:0000269|PubMed:32228865, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35608336, CC ECO:0000269|PubMed:37390818, ECO:0000305|PubMed:28723891}. CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:26317472, CC ECO:0000269|PubMed:32228865}; Multi-pass membrane protein CC {ECO:0000269|PubMed:32228865}. Lysosome membrane CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:31261387, CC ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:32228865}; Multi-pass CC membrane protein {ECO:0000269|PubMed:32228865}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9BSA9-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BSA9-2; Sequence=VSP_024213; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:26317472}. CC -!- DOMAIN: Composed of two modules of six transmembranes, forming a CC homodimer with a tetrameric architecture (PubMed:28723891, CC PubMed:32228865). The six transmembrane regions of each module are CC tightly packed within each subunit without undergoing domain swapping CC (PubMed:32228865). Forms a central ion-conduction pore lined by the CC side chains of the pore-lining helices (PubMed:32228865). Conserved CC isoleucine residues (Ile-46 in the first module and Ile-271 in the CC second module) in the center of the pore serve as the gate in the CC closed conformation (PubMed:32228865). In the widened channel in the CC open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 CC and Ile-271 in the second module), establish a constriction essential CC for potassium selectivity (PubMed:32228865). CC {ECO:0000269|PubMed:28723891, ECO:0000269|PubMed:32228865}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:28193887, CC ECO:0000269|PubMed:31261387, ECO:0000269|PubMed:31658403, CC ECO:0000269|PubMed:33505021}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC TMEM175 defects result in unstable lysosomal pH, leading to decreased CC lysosomal catalytic activity, decreased glucocerebrosidase activity, CC impaired autophagosome clearance by the lysosome and decreased CC mitochondrial respiration (PubMed:28193887). CC {ECO:0000269|PubMed:28193887}. CC -!- SIMILARITY: Belongs to the TMEM175 family. {ECO:0000305}. CC -!- CAUTION: A publication claims that potassium transport was initially CC measured with a luminal side pH above 7.0, which is non-physiological CC for lysosomal channels (PubMed:35750034). This statement is however CC incorrect as potassium transport was tested at lumenal pH of 5.5, which CC is considered physiological (PubMed:26317472). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:35750034}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL834199; CAD38888.1; -; mRNA. DR EMBL; CH471131; EAW82633.1; -; Genomic_DNA. DR EMBL; CH471131; EAW82638.1; -; Genomic_DNA. DR EMBL; BC005158; AAH05158.1; -; mRNA. DR CCDS; CCDS3341.1; -. [Q9BSA9-1] DR CCDS; CCDS75088.1; -. [Q9BSA9-2] DR RefSeq; NP_001284355.1; NM_001297426.2. [Q9BSA9-2] DR RefSeq; NP_001284356.1; NM_001297427.2. [Q9BSA9-2] DR RefSeq; NP_001284357.1; NM_001297428.2. [Q9BSA9-2] DR RefSeq; NP_115702.1; NM_032326.4. [Q9BSA9-1] DR RefSeq; XP_016864190.1; XM_017008701.2. [Q9BSA9-1] DR RefSeq; XP_054207016.1; XM_054351041.1. [Q9BSA9-1] DR PDB; 6W8N; EM; 3.20 A; A/B=1-504. DR PDB; 6W8O; EM; 3.40 A; A/B=1-504. DR PDB; 6W8P; EM; 3.60 A; A/B=1-504. DR PDB; 6WC9; EM; 2.64 A; A/B=1-504. DR PDB; 6WCA; EM; 3.03 A; A/B=1-504. DR PDB; 6WCB; EM; 3.17 A; A/B=1-504. DR PDB; 6WCC; EM; 3.24 A; A/B=1-504. DR PDB; 7LF6; EM; 3.50 A; A/B=1-504. DR PDB; 7UNL; EM; 2.45 A; A/B=1-504. DR PDB; 7UNM; EM; 2.61 A; A/B=1-504. DR PDB; 8DHM; EM; 2.73 A; A/B=1-504. DR PDB; 8FY5; EM; 3.40 A; A/B=1-504. DR PDB; 8FYF; EM; 3.40 A; A/B=1-504. DR PDB; 8VIC; EM; 3.48 A; A/B=1-504. DR PDB; 8VIE; EM; 3.52 A; A/B=1-504. DR PDBsum; 6W8N; -. DR PDBsum; 6W8O; -. DR PDBsum; 6W8P; -. DR PDBsum; 6WC9; -. DR PDBsum; 6WCA; -. DR PDBsum; 6WCB; -. DR PDBsum; 6WCC; -. DR PDBsum; 7LF6; -. DR PDBsum; 7UNL; -. DR PDBsum; 7UNM; -. DR PDBsum; 8DHM; -. DR PDBsum; 8FY5; -. DR PDBsum; 8FYF; -. DR PDBsum; 8VIC; -. DR PDBsum; 8VIE; -. DR AlphaFoldDB; Q9BSA9; -. DR EMDB; EMD-21575; -. DR EMDB; EMD-21576; -. DR EMDB; EMD-21577; -. DR EMDB; EMD-21603; -. DR EMDB; EMD-21604; -. DR EMDB; EMD-21605; -. DR EMDB; EMD-21606; -. DR EMDB; EMD-23300; -. DR EMDB; EMD-26626; -. DR EMDB; EMD-26627; -. DR EMDB; EMD-27436; -. DR EMDB; EMD-29553; -. DR EMDB; EMD-29572; -. DR EMDB; EMD-43257; -. DR EMDB; EMD-43259; -. DR SMR; Q9BSA9; -. DR BioGRID; 124013; 9. DR FunCoup; Q9BSA9; 1264. DR IntAct; Q9BSA9; 9. DR MINT; Q9BSA9; -. DR STRING; 9606.ENSP00000264771; -. DR TCDB; 1.A.78.1.1; the k+-selective channel in endosomes and lysosomes (kel) family. DR iPTMnet; Q9BSA9; -. DR PhosphoSitePlus; Q9BSA9; -. DR SwissPalm; Q9BSA9; -. DR BioMuta; TMEM175; -. DR DMDM; 74732981; -. DR jPOST; Q9BSA9; -. DR MassIVE; Q9BSA9; -. DR PaxDb; 9606-ENSP00000264771; -. DR PeptideAtlas; Q9BSA9; -. DR ProteomicsDB; 78871; -. [Q9BSA9-1] DR ProteomicsDB; 78872; -. [Q9BSA9-2] DR Antibodypedia; 8167; 61 antibodies from 20 providers. DR DNASU; 84286; -. DR Ensembl; ENST00000264771.9; ENSP00000264771.4; ENSG00000127419.18. [Q9BSA9-1] DR Ensembl; ENST00000515740.5; ENSP00000427039.1; ENSG00000127419.18. [Q9BSA9-2] DR Ensembl; ENST00000622959.3; ENSP00000485461.1; ENSG00000127419.18. [Q9BSA9-2] DR GeneID; 84286; -. DR KEGG; hsa:84286; -. DR MANE-Select; ENST00000264771.9; ENSP00000264771.4; NM_032326.4; NP_115702.1. DR UCSC; uc003gbq.4; human. [Q9BSA9-1] DR AGR; HGNC:28709; -. DR ClinPGx; PA162405946; -. DR CTD; 84286; -. DR DisGeNET; 84286; -. DR GeneCards; TMEM175; -. DR HGNC; HGNC:28709; TMEM175. DR HPA; ENSG00000127419; Low tissue specificity. DR MIM; 168600; phenotype. DR MIM; 616660; gene. DR OpenTargets; ENSG00000127419; -. DR VEuPathDB; HostDB:ENSG00000127419; -. DR eggNOG; ENOG502QR5C; Eukaryota. DR GeneTree; ENSGT00390000015667; -. DR InParanoid; Q9BSA9; -. DR OMA; FFFPVSY; -. DR OrthoDB; 203835at2759; -. DR PAN-GO; Q9BSA9; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9BSA9; -. DR PathwayCommons; Q9BSA9; -. DR SignaLink; Q9BSA9; -. DR Agora; ENSG00000127419; -. DR BioGRID-ORCS; 84286; 16 hits in 1152 CRISPR screens. DR ChiTaRS; TMEM175; human. DR GenomeRNAi; 84286; -. DR Pharos; Q9BSA9; Tbio. DR PRO; PR:Q9BSA9; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q9BSA9; protein. DR Bgee; ENSG00000127419; Expressed in right hemisphere of cerebellum and 157 other cell types or tissues. DR ExpressionAtlas; Q9BSA9; baseline and differential. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0050544; F:arachidonate binding; IDA:UniProtKB. DR GO; GO:0005267; F:potassium channel activity; IDA:UniProtKB. DR GO; GO:0022841; F:potassium ion leak channel activity; IDA:UniProtKB. DR GO; GO:0015252; F:proton channel activity; IDA:UniProtKB. DR GO; GO:0035752; P:lysosomal lumen pH elevation; IDA:UniProtKB. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:UniProtKB. DR GO; GO:0090385; P:phagosome-lysosome fusion; IEA:Ensembl. DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:1902600; P:proton transmembrane transport; IDA:UniProtKB. DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IDA:UniProt. DR InterPro; IPR010617; TMEM175-like. DR PANTHER; PTHR31462; ENDOSOMAL/LYSOSOMAL POTASSIUM CHANNEL TMEM175; 1. DR PANTHER; PTHR31462:SF5; ENDOSOMAL_LYSOSOMAL PROTON CHANNEL TMEM175; 1. DR Pfam; PF06736; TMEM175; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Endosome; Hydrogen ion transport; KW Ion channel; Ion transport; Lysosome; Membrane; Neurodegeneration; KW Parkinson disease; Parkinsonism; Phosphoprotein; Potassium; KW Potassium channel; Potassium transport; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..504 FT /note="Endosomal/lysosomal proton channel TMEM175" FT /id="PRO_0000282588" FT TOPO_DOM 1..33 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT TRANSMEM 34..56 FT /note="Helical; Name=TM1-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 57..77 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 78..100 FT /note="Helical; Name=TM2-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 101..106 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 107..128 FT /note="Helical; Name=TM3-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 129..138 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 139..160 FT /note="Helical; Name=TM4-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 161..184 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 185..205 FT /note="Helical; Name=TM5-1" FT /evidence="ECO:0000255" FT TOPO_DOM 206..210 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 211..230 FT /note="Helical; Name=TM6-1" FT /evidence="ECO:0000255" FT TOPO_DOM 231..257 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 258..282 FT /note="Helical; Name=TM1-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 283..309 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 310..332 FT /note="Helical; Name=TM2-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 333..338 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 339..360 FT /note="Helical; Name=TM3-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 361..375 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 376..396 FT /note="Helical; Name=TM4-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 397..416 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 417..440 FT /note="Helical; Name=TM5-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 441..442 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 443..469 FT /note="Helical; Name=TM6-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 470..504 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT REGION 1..27 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 58..63 FT /note="Short helix H1-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 65..71 FT /note="Short helix H2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 288..296 FT /note="Short helix H1-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 298..304 FT /note="Short helix H2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 483..504 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 35..41 FT /note="RxxxFSD motif 1" FT /evidence="ECO:0000269|PubMed:26317472" FT MOTIF 260..266 FT /note="RxxxFSD motif 2" FT /evidence="ECO:0000305|PubMed:26317472" FT COMPBIAS 493..504 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 46 FT /note="Hydrophobic filter residue 1-1" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 50 FT /note="Hydrophobic filter residue 2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 53 FT /note="Hydrophobic filter residue 3-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 271 FT /note="Hydrophobic filter residue 1-2" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 275 FT /note="Hydrophobic filter residue 2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 278 FT /note="Hydrophobic filter residue 3-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT MOD_RES 6 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT VAR_SEQ 1..116 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_024213" FT VARIANT 65 FT /note="Q -> P (associated with decreased risk for Parkinson FT disease; gain-of-function variant; does not affect FT lysosomal localization; dbSNP:rs34884217)" FT /evidence="ECO:0000269|PubMed:31658403, FT ECO:0000269|PubMed:33505021" FT /id="VAR_053873" FT VARIANT 393 FT /note="M -> T (associated with increased risk for Parkinson FT disease; reduced potassium channel activity; does not FT affect lysosomal localization; dbSNP:rs34311866)" FT /evidence="ECO:0000269|PubMed:31261387, FT ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:33505021" FT /id="VAR_053874" FT MUTAGEN 35 FT /note="R->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 38 FT /note="S->A: Does not affect proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 39 FT /note="F->V: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 40 FT /note="S->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 41 FT /note="D->A: Abolished proton permeability without altering FT potassium permeability." FT /evidence="ECO:0000269|PubMed:35750034" FT MUTAGEN 41 FT /note="D->E,N: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 45..49 FT /note="SIIAT->AIIAA: Decreased selectivity for potassium FT ion; when associated with A-274." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 45 FT /note="S->A: Reduced potassium channel activity without FT altering proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573, FT ECO:0000269|PubMed:35750034" FT MUTAGEN 45 FT /note="S->T: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 46 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 46 FT /note="I->M: Abolished proton and potassium channel FT activity; when associated with M-271." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 46 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-271." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 49 FT /note="T->A: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 49 FT /note="T->V: Abolished potassium channel activity and FT decreased proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 50 FT /note="V->A: Does not affect selectivity; when associated FT with A-275." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 53 FT /note="L->A: Does not affect selectivity; when associated FT with A-278." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 241 FT /note="S->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with A- FT 338." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 271 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 271 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-46." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 271 FT /note="I->W: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->A: Decreased selectivity for potassium ion. FT Abolished proton and potassium channel activity. Decreased FT selectivity for potassium ion; when associated with 45-A-- FT A-49." FT /evidence="ECO:0000269|PubMed:32267231, FT ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 275 FT /note="L->A: Does not affect selectivity; when associated FT with A-50." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 278 FT /note="L->A: Does not affect selectivity; when associated FT with A-53." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 279 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 279 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 309 FT /note="R->A,Q: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 327 FT /note="H->A: Reduced potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 328 FT /note="H->A: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 338 FT /note="T->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with A- FT 241." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 345 FT /note="N->L: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 360 FT /note="Q->L: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 393 FT /note="M->I: Does not affect potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 393 FT /note="M->W: Reduced potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 395 FT /note="T->W: Abolished interaction with LAMP1 and FT subsequent inhibition." FT /evidence="ECO:0000269|PubMed:37390818" FT MUTAGEN 449 FT /note="H->A: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT HELIX 34..48 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 49..52 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 53..56 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 67..101 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 107..120 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 123..132 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:8DHM" FT HELIX 138..163 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 165..167 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 170..172 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 181..204 FT /evidence="ECO:0007829|PDB:6W8N" FT TURN 208..211 FT /evidence="ECO:0007829|PDB:7LF6" FT HELIX 212..223 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:6W8O" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:8FYF" FT HELIX 258..283 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 290..293 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 294..297 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 299..304 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 307..331 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 333..335 FT /evidence="ECO:0007829|PDB:6WC9" FT HELIX 339..352 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 355..361 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 364..367 FT /evidence="ECO:0007829|PDB:7UNM" FT HELIX 369..398 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 401..404 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 416..439 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 441..460 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 462..475 FT /evidence="ECO:0007829|PDB:7UNL" SQ SEQUENCE 504 AA; 55615 MW; 7FEE4C22CA248094 CRC64; MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVTV AWAAHTRLFQ VVGKTDDTLA LLNLACMMTI TFLPYTFSLM VTFPDVPLGI FLFCVCVIAI GVVQALIVGY AFHFPHLLSP QIQRSAHRAL YRRHVLGIVL QGPALCFAAA IFSLFFVPLS YLLMVTVILL PYVSKVTGWC RDRLLGHREP SAHPVEVFSF DLHEPLSKER VEAFSDGVYA IVATLLILDI CEDNVPDPKD VKERFSGSLV AALSATGPRF LAYFGSFATV GLLWFAHHSL FLHVRKATRA MGLLNTLSLA FVGGLPLAYQ QTSAFARQPR DELERVRVSC TIIFLASIFQ LAMWTTALLH QAETLQPSVW FGGREHVLMF AKLALYPCAS LLAFASTCLL SRFSVGIFHL MQIAVPCAFL LLRLLVGLAL ATLRVLRGLA RPEHPPPAPT GQDDPQSQLL PAPC // ID TM230_HUMAN Reviewed; 120 AA. AC Q96A57; B2RDM8; D3DVZ9; Q0VGC8; Q5TDS5; Q96ES2; Q9P0A7; DT 02-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 171. DE RecName: Full=Transmembrane protein 230; GN Name=TMEM230; Synonyms=C20orf30; ORFNames=HSPC274, UNQ2432/PRO4992; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Umbilical cord blood; RA Ye M., Zhang Q.-H., Zhou J., Shen Y., Wu X.-Y., Guan Z.Q., Wang L., RA Fan H.-Y., Mao Y.-F., Dai M., Huang Q.-H., Chen S.-J., Chen Z.; RT "Human partial CDS from CD34+ stem cells."; RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skeletal muscle; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Bone marrow, Brain, Duodenum, Gall bladder, Lung, Ovary, and RC Prostate; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15 AND SER-24, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, POSSIBLE INVOLVEMENT IN PARK, VARIANTS PARK RP CYS-29 AND LEU-78, VARIANT CYS-108, VARIANT THR-64 (ISOFORM 1), AND RP CHARACTERIZATION OF VARIANTS PARK CYS-29 AND LEU-78. RX PubMed=27270108; DOI=10.1038/ng.3589; RA Deng H.X., Shi Y., Yang Y., Ahmeti K.B., Miller N., Huang C., Cheng L., RA Zhai H., Deng S., Nuytemans K., Corbett N.J., Kim M.J., Deng H., Tang B., RA Yang Z., Xu Y., Chan P., Huang B., Gao X.P., Song Z., Liu Z., Fecto F., RA Siddique N., Foroud T., Jankovic J., Ghetti B., Nicholson D.A., Krainc D., RA Melen O., Vance J.M., Pericak-Vance M.A., Ma Y.C., Rajput A.H., RA Siddique T.; RT "Identification of TMEM230 mutations in familial Parkinson's disease."; RL Nat. Genet. 48:733-739(2016). CC -!- FUNCTION: Involved in trafficking and recycling of synaptic vesicles. CC {ECO:0000269|PubMed:27270108}. CC -!- INTERACTION: CC Q96A57-2; O43765: SGTA; NbExp=3; IntAct=EBI-17546822, EBI-347996; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane CC protein {ECO:0000305}. Golgi apparatus, trans-Golgi network CC {ECO:0000269|PubMed:27270108}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle {ECO:0000269|PubMed:27270108}. Early endosome CC {ECO:0000269|PubMed:27270108}. Recycling endosome CC {ECO:0000269|PubMed:27270108}. Late endosome CC {ECO:0000269|PubMed:27270108}. Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:27270108}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=2; CC IsoId=Q96A57-1; Sequence=Displayed; CC Name=1; CC IsoId=Q96A57-2; Sequence=VSP_018155; CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:27270108}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC Genetic variants in TMEM230 and DNAJC13 have been found in the same CC large multigenerational family with adult-onset Parkinson disease. The CC pathological role of each gene and therefore the exact molecular basis CC of the disease is unclear. {ECO:0000305|PubMed:27270108}. CC -!- SIMILARITY: Belongs to the TMEM134/TMEM230 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: [Isoform 1]: CC Sequence=AAF28952.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF161392; AAF28952.1; ALT_FRAME; mRNA. DR EMBL; AY359115; AAQ89473.1; -; mRNA. DR EMBL; AK315606; BAG37975.1; -; mRNA. DR EMBL; AL121890; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL121924; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471133; EAX10431.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10432.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10433.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10434.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10437.1; -; Genomic_DNA. DR EMBL; BC070212; AAH70212.1; -; mRNA. DR EMBL; BC009768; AAH09768.1; -; mRNA. DR EMBL; BC009769; AAH09769.1; -; mRNA. DR EMBL; BC009770; AAH09770.1; -; mRNA. DR EMBL; BC011990; AAH11990.1; -; mRNA. DR EMBL; BC015113; AAH15113.1; -; mRNA. DR EMBL; BC110408; AAI10409.2; -; mRNA. DR CCDS; CCDS13086.1; -. [Q96A57-1] DR RefSeq; NP_001009924.1; NM_001009924.2. [Q96A57-1] DR RefSeq; NP_001009925.1; NM_001009925.2. [Q96A57-1] DR RefSeq; NP_001317913.1; NM_001330984.2. [Q96A57-1] DR RefSeq; NP_001317914.1; NM_001330985.2. [Q96A57-1] DR RefSeq; NP_001317915.1; NM_001330986.2. [Q96A57-1] DR RefSeq; NP_001410909.1; NM_001423980.1. [Q96A57-1] DR RefSeq; NP_054864.3; NM_014145.4. [Q96A57-1] DR AlphaFoldDB; Q96A57; -. DR BioGRID; 118834; 60. DR FunCoup; Q96A57; 1851. DR IntAct; Q96A57; 28. DR MINT; Q96A57; -. DR STRING; 9606.ENSP00000341364; -. DR TCDB; 9.B.232.1.1; the parkinson's disease tmem230 (tmem230) family. DR iPTMnet; Q96A57; -. DR PhosphoSitePlus; Q96A57; -. DR BioMuta; TMEM230; -. DR DMDM; 74751737; -. DR CPTAC; CPTAC-960; -. DR jPOST; Q96A57; -. DR MassIVE; Q96A57; -. DR PaxDb; 9606-ENSP00000341364; -. DR PeptideAtlas; Q96A57; -. DR ProteomicsDB; 75916; -. [Q96A57-1] DR ProteomicsDB; 75917; -. [Q96A57-2] DR Pumba; Q96A57; -. DR TopDownProteomics; Q96A57-1; -. [Q96A57-1] DR TopDownProteomics; Q96A57-2; -. [Q96A57-2] DR Antibodypedia; 2275; 190 antibodies from 23 providers. DR DNASU; 29058; -. DR Ensembl; ENST00000202834.12; ENSP00000202834.7; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000342308.11; ENSP00000341364.6; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379277.7; ENSP00000368579.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379279.6; ENSP00000368581.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379283.6; ENSP00000368585.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379286.6; ENSP00000368588.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379299.6; ENSP00000368601.2; ENSG00000089063.17. [Q96A57-1] DR GeneID; 29058; -. DR KEGG; hsa:29058; -. DR MANE-Select; ENST00000202834.12; ENSP00000202834.7; NM_001009925.2; NP_001009925.1. DR UCSC; uc002wlk.4; human. [Q96A57-1] DR AGR; HGNC:15876; -. DR ClinPGx; PA25746; -. DR CTD; 29058; -. DR DisGeNET; 29058; -. DR GeneCards; TMEM230; -. DR HGNC; HGNC:15876; TMEM230. DR HPA; ENSG00000089063; Low tissue specificity. DR MalaCards; TMEM230; -. DR MIM; 168600; phenotype. DR MIM; 617019; gene. DR OpenTargets; ENSG00000089063; -. DR VEuPathDB; HostDB:ENSG00000089063; -. DR eggNOG; KOG4753; Eukaryota. DR GeneTree; ENSGT00390000008694; -. DR HOGENOM; CLU_126638_1_0_1; -. DR InParanoid; Q96A57; -. DR OMA; AYYAYYK; -. DR OrthoDB; 5597044at2759; -. DR PAN-GO; Q96A57; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q96A57; -. DR PathwayCommons; Q96A57; -. DR SignaLink; Q96A57; -. DR Agora; ENSG00000089063; -. DR BioGRID-ORCS; 29058; 77 hits in 1128 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; TMEM230; human. DR GenomeRNAi; 29058; -. DR Pharos; Q96A57; Tbio. DR PRO; PR:Q96A57; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; Q96A57; protein. DR Bgee; ENSG00000089063; Expressed in gall bladder and 104 other cell types or tissues. DR ExpressionAtlas; Q96A57; baseline and differential. DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell. DR GO; GO:0030424; C:axon; IEA:GOC. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0012505; C:endomembrane system; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0098930; P:axonal transport; IDA:SynGO. DR GO; GO:0048489; P:synaptic vesicle transport; IMP:UniProtKB. DR InterPro; IPR044234; TMEM230. DR InterPro; IPR008590; TMEM_230/134. DR PANTHER; PTHR15664; C20ORF30 PROTEIN; 1. DR PANTHER; PTHR15664:SF6; TRANSMEMBRANE PROTEIN 230; 1. DR Pfam; PF05915; TMEM_230_134; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasmic vesicle; Disease variant; Endosome; KW Golgi apparatus; Membrane; Neurodegeneration; Parkinson disease; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Synapse; Transmembrane; Transmembrane helix. FT CHAIN 1..120 FT /note="Transmembrane protein 230" FT /id="PRO_0000233892" FT TRANSMEM 46..66 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 79..99 FT /note="Helical" FT /evidence="ECO:0000255" FT MOD_RES 15 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 23 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 1 FT /note="M -> MQPWALPTVGELWVCGRPGAALRWSLVLSPRLEPSGVISAHCNLHLL FT ASSDSSASASRLCQRVM (in isoform 1)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_018155" FT VARIANT 29 FT /note="Y -> C (in PARK; uncertain significance; sporadic FT case; results in decreased synaptic vesicle trafficking; FT dbSNP:rs1056737920)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076713" FT VARIANT 78 FT /note="R -> L (in PARK; uncertain significance; results in FT decreased synaptic vesicle trafficking; dbSNP:rs764786986)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076714" FT VARIANT 108 FT /note="R -> C (in dbSNP:rs143571424)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076715" FT CONFLICT 59..61 FT /note="LII -> SY (in Ref. 1; AAF28952)" FT /evidence="ECO:0000305" FT CONFLICT 109 FT /note="G -> A (in Ref. 6; AAH11990)" FT /evidence="ECO:0000305" FT VARIANT Q96A57-2:64 FT /note="M -> T (in dbSNP:rs141394228)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_082923" SQ SEQUENCE 120 AA; 13188 MW; 18A4A556330D77CE CRC64; MMPSRTNLAT GIPSSKVKYS RLSSTDDGYI DLQFKKTPPK IPYKAIALAT VLFLIGAFLI IIGSLLLSGY ISKGGADRAV PVLIIGILVF LPGFYHLRIA YYASKGYRGY SYDDIPDFDD // ID TRIM9_HUMAN Reviewed; 710 AA. AC Q9C026; D3DSB7; D3DSB8; Q92557; Q96D24; Q96NI4; Q9C025; Q9C027; DT 04-AUG-2003, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 216. DE RecName: Full=E3 ubiquitin-protein ligase TRIM9; DE EC=2.3.2.27 {ECO:0000269|PubMed:20085810}; DE AltName: Full=RING finger protein 91; DE AltName: Full=RING-type E3 ubiquitin transferase TRIM9 {ECO:0000305}; DE AltName: Full=Tripartite motif-containing protein 9; GN Name=TRIM9; Synonyms=KIAA0282, RNF91; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT PHE-653. RX PubMed=11331580; DOI=10.1093/emboj/20.9.2140; RA Reymond A., Meroni G., Fantozzi A., Merla G., Cairo S., Luzi L., RA Riganelli D., Zanaria E., Messali S., Cainarca S., Guffanti A., Minucci S., RA Pelicci P.G., Ballabio A.; RT "The tripartite motif family identifies cell compartments."; RL EMBO J. 20:2140-2151(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PHE-653. RC TISSUE=Brain; RX PubMed=9179496; DOI=10.1093/dnares/4.1.53; RA Ohara O., Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., RA Nomura N.; RT "Construction and characterization of human brain cDNA libraries suitable RT for analysis of cDNA clones encoding relatively large proteins."; RL DNA Res. 4:53-59(1997). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Fetal brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5), AND VARIANT RP PHE-653. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCALIZATION, TISSUE RP SPECIFICITY, AND AUTOUBIQUITINATION. RX PubMed=20085810; DOI=10.1016/j.nbd.2010.01.007; RA Tanji K., Kamitani T., Mori F., Kakita A., Takahashi H., Wakabayashi K.; RT "TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the RT brain of Parkinson's disease and dementia with Lewy bodies."; RL Neurobiol. Dis. 38:210-218(2010). RN [8] RP STRUCTURE BY NMR OF 437-534. RG RIKEN structural genomics initiative (RSGI); RT "Solution structures of the FN3 domain of human tripartite motif protein RT 9."; RL Submitted (JUN-2006) to the PDB data bank. CC -!- FUNCTION: E3 ubiquitin-protein ligase which ubiquitinates itself in CC cooperation with an E2 enzyme UBE2D2/UBC4 and serves as a targeting CC signal for proteasomal degradation. May play a role in regulation of CC neuronal functions and may also participate in the formation or CC breakdown of abnormal inclusions in neurodegenerative disorders. May CC act as a regulator of synaptic vesicle exocytosis by controlling the CC availability of SNAP25 for the SNARE complex formation. CC {ECO:0000269|PubMed:20085810}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:20085810}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:20085810}. CC -!- SUBUNIT: Interacts with SNAP25. {ECO:0000250|UniProtKB:Q91ZY8}. CC -!- INTERACTION: CC Q9C026; Q9Y2T2: AP3M1; NbExp=3; IntAct=EBI-720828, EBI-2371151; CC Q9C026; P05067: APP; NbExp=3; IntAct=EBI-720828, EBI-77613; CC Q9C026; P54253: ATXN1; NbExp=6; IntAct=EBI-720828, EBI-930964; CC Q9C026; B7Z3H4: BTRC; NbExp=3; IntAct=EBI-720828, EBI-16429269; CC Q9C026; Q9Y297: BTRC; NbExp=8; IntAct=EBI-720828, EBI-307461; CC Q9C026; P48730: CSNK1D; NbExp=3; IntAct=EBI-720828, EBI-751621; CC Q9C026; Q2TBE0: CWF19L2; NbExp=6; IntAct=EBI-720828, EBI-5453285; CC Q9C026; Q9UI08: EVL; NbExp=3; IntAct=EBI-720828, EBI-346653; CC Q9C026; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-720828, EBI-6448852; CC Q9C026; Q9H5Z6-2: FAM124B; NbExp=3; IntAct=EBI-720828, EBI-11986315; CC Q9C026; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-720828, EBI-6658203; CC Q9C026; Q969S9: GFM2; NbExp=3; IntAct=EBI-720828, EBI-2371750; CC Q9C026; O60333-2: KIF1B; NbExp=3; IntAct=EBI-720828, EBI-10975473; CC Q9C026; Q969V5: MUL1; NbExp=3; IntAct=EBI-720828, EBI-744120; CC Q9C026; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-720828, EBI-10271199; CC Q9C026; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-720828, EBI-741158; CC Q9C026; Q9NZD8: SPG21; NbExp=6; IntAct=EBI-720828, EBI-742688; CC Q9C026; Q13148: TARDBP; NbExp=6; IntAct=EBI-720828, EBI-372899; CC Q9C026; Q96PN8: TSSK3; NbExp=3; IntAct=EBI-720828, EBI-3918381; CC Q9C026; Q68CQ4: UTP25; NbExp=3; IntAct=EBI-720828, EBI-747711; CC Q9C026; P50552: VASP; NbExp=4; IntAct=EBI-720828, EBI-748201; CC Q9C026; P62258: YWHAE; NbExp=2; IntAct=EBI-720828, EBI-356498; CC Q9C026-5; A0A0S2Z507: BTRC; NbExp=3; IntAct=EBI-16437499, EBI-16429247; CC Q9C026-5; B7Z3H4: BTRC; NbExp=3; IntAct=EBI-16437499, EBI-16429269; CC Q9C026-5; Q9Y297: BTRC; NbExp=4; IntAct=EBI-16437499, EBI-307461; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20085810}. Cell CC projection, dendrite {ECO:0000269|PubMed:20085810}. Cytoplasmic CC vesicle, secretory vesicle, synaptic vesicle CC {ECO:0000250|UniProtKB:Q91ZY8}. Synapse {ECO:0000250|UniProtKB:Q91ZY8}. CC Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q91ZY8}. Note=Enriched CC at synaptic terminals where it exists in a soluble form and a synaptic CC vesicle-associated form. Associated with the cytoskeleton (By CC similarity). Found in proximal dendrites of pyramidal neurons in the CC cerebral cortex and hippocampus, and Purkinje cells in the cerebellum CC (PubMed:20085810). {ECO:0000250|UniProtKB:Q91ZY8, CC ECO:0000269|PubMed:20085810}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Beta; CC IsoId=Q9C026-1; Sequence=Displayed; CC Name=4; CC IsoId=Q9C026-4; Sequence=VSP_007922, VSP_007923, VSP_007924; CC Name=5; CC IsoId=Q9C026-5; Sequence=VSP_007925, VSP_007926; CC -!- TISSUE SPECIFICITY: Brain. Highly expressed in the cerebral cortex (at CC protein level). Severely decreased in the affected brain areas in CC Parkinson disease and dementia with Lewy bodies. CC {ECO:0000269|PubMed:20085810}. CC -!- DOMAIN: The coiled coil domain mediates the interaction with the N- CC terminal t-SNARE domain of SNAP25. {ECO:0000250|UniProtKB:Q91ZY8}. CC -!- PTM: Auto-ubiquitinated. Poly-ubiquitinated in cultured cells, whereas CC it is monoubiquitinated in vitro. {ECO:0000269|PubMed:20085810}. CC -!- MISCELLANEOUS: [Isoform 4]: May be due to a competing donor splice CC site, to exon inclusion and to intron retention. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be due to intron retention. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the TRIM/RBCC family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG53490.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAG53492.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA13398.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA13398.2; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF220036; AAG53490.1; ALT_FRAME; mRNA. DR EMBL; AF220037; AAG53491.1; -; mRNA. DR EMBL; AF220038; AAG53492.1; ALT_FRAME; mRNA. DR EMBL; D87458; BAA13398.2; ALT_SEQ; mRNA. DR EMBL; AK055388; BAB70913.1; -; mRNA. DR EMBL; CH471078; EAW65680.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65681.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65682.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65684.1; -; Genomic_DNA. DR EMBL; BC013414; AAH13414.1; -; mRNA. DR EMBL; BC063872; AAH63872.1; -; mRNA. DR CCDS; CCDS45105.1; -. [Q9C026-5] DR CCDS; CCDS9703.1; -. [Q9C026-1] DR RefSeq; NP_055978.4; NM_015163.5. [Q9C026-1] DR RefSeq; NP_443210.1; NM_052978.5. [Q9C026-5] DR RefSeq; XP_011534691.1; XM_011536389.3. [Q9C026-4] DR RefSeq; XP_054231290.1; XM_054375315.1. [Q9C026-4] DR RefSeq; XP_054231294.1; XM_054375319.1. [Q9C026-1] DR RefSeq; XP_054231300.1; XM_054375325.1. [Q9C026-5] DR PDB; 2DB8; NMR; -; A=439-534. DR PDB; 7B2S; X-ray; 1.50 A; A=535-710. DR PDBsum; 2DB8; -. DR PDBsum; 7B2S; -. DR AlphaFoldDB; Q9C026; -. DR BMRB; Q9C026; -. DR SMR; Q9C026; -. DR BioGRID; 125280; 412. DR FunCoup; Q9C026; 729. DR IntAct; Q9C026; 65. DR MINT; Q9C026; -. DR STRING; 9606.ENSP00000298355; -. DR iPTMnet; Q9C026; -. DR PhosphoSitePlus; Q9C026; -. DR BioMuta; TRIM9; -. DR DMDM; 33516964; -. DR REPRODUCTION-2DPAGE; Q9C026; -. DR jPOST; Q9C026; -. DR MassIVE; Q9C026; -. DR PaxDb; 9606-ENSP00000298355; -. DR PeptideAtlas; Q9C026; -. DR ProteomicsDB; 79943; -. [Q9C026-1] DR ProteomicsDB; 79944; -. [Q9C026-4] DR ProteomicsDB; 79945; -. [Q9C026-5] DR Pumba; Q9C026; -. DR Antibodypedia; 10667; 507 antibodies from 25 providers. DR DNASU; 114088; -. DR Ensembl; ENST00000298355.7; ENSP00000298355.3; ENSG00000100505.15. [Q9C026-1] DR Ensembl; ENST00000338969.9; ENSP00000342970.5; ENSG00000100505.15. [Q9C026-4] DR Ensembl; ENST00000360392.4; ENSP00000353561.4; ENSG00000100505.15. [Q9C026-5] DR GeneID; 114088; -. DR KEGG; hsa:114088; -. DR UCSC; uc001wyx.5; human. [Q9C026-1] DR AGR; HGNC:16288; -. DR ClinPGx; PA38116; -. DR CTD; 114088; -. DR DisGeNET; 114088; -. DR GeneCards; TRIM9; -. DR HGNC; HGNC:16288; TRIM9. DR HPA; ENSG00000100505; Tissue enriched (brain). DR MIM; 606555; gene. DR OpenTargets; ENSG00000100505; -. DR VEuPathDB; HostDB:ENSG00000100505; -. DR eggNOG; KOG4367; Eukaryota. DR GeneTree; ENSGT00940000154071; -. DR HOGENOM; CLU_013137_19_2_1; -. DR InParanoid; Q9C026; -. DR OMA; PDTICTI; -. DR OrthoDB; 295536at2759; -. DR PAN-GO; Q9C026; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q9C026; -. DR PathwayCommons; Q9C026; -. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9C026; -. DR SIGNOR; Q9C026; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000100505; -. DR BioGRID-ORCS; 114088; 32 hits in 1186 CRISPR screens. DR ChiTaRS; TRIM9; human. DR EvolutionaryTrace; Q9C026; -. DR GeneWiki; TRIM9; -. DR GenomeRNAi; 114088; -. DR Pharos; Q9C026; Tbio. DR PRO; PR:Q9C026; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9C026; protein. DR Bgee; ENSG00000100505; Expressed in right hemisphere of cerebellum and 145 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR CDD; cd19843; Bbox1_TRIM9_C-I; 1. DR CDD; cd19826; Bbox2_TRIM9_C-I; 1. DR CDD; cd00063; FN3; 1. DR CDD; cd16755; RING-HC_TRIM9; 1. DR CDD; cd12889; SPRY_PRY_TRIM67_9; 1. DR FunFam; 2.60.120.920:FF:000009; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 2.60.40.10:FF:000178; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 3.30.40.10:FF:000168; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 4.10.830.40:FF:000001; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 3.30.160.60:FF:000329; E3 ubiquitin-protein ligase TRIM9 isoform X2; 1. DR FunFam; 1.20.5.170:FF:000017; Putative E3 ubiquitin-protein ligase TRIM9; 1. DR Gene3D; 1.20.5.170; -; 1. DR Gene3D; 2.60.120.920; -; 1. DR Gene3D; 4.10.830.40; -; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR001870; B30.2/SPRY. DR InterPro; IPR043136; B30.2/SPRY_sf. DR InterPro; IPR003649; Bbox_C. DR InterPro; IPR013320; ConA-like_dom_sf. DR InterPro; IPR017903; COS_domain. DR InterPro; IPR050617; E3_ligase_FN3/SPRY. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR003877; SPRY_dom. DR InterPro; IPR049582; TRIM9_Bbox1. DR InterPro; IPR000315; Znf_B-box. DR InterPro; IPR018957; Znf_C3HC4_RING-type. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR PANTHER; PTHR24099; E3 UBIQUITIN-PROTEIN LIGASE TRIM36-RELATED; 1. DR PANTHER; PTHR24099:SF13; E3 UBIQUITIN-PROTEIN LIGASE TRIM9; 1. DR Pfam; PF22586; ANCHR-like_BBOX; 1. DR Pfam; PF00041; fn3; 1. DR Pfam; PF00622; SPRY; 1. DR Pfam; PF00643; zf-B_box; 1. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00502; BBC; 1. DR SMART; SM00336; BBOX; 2. DR SMART; SM00060; FN3; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00449; SPRY; 1. DR SUPFAM; SSF57845; B-box zinc-binding domain; 1. DR SUPFAM; SSF49899; Concanavalin A-like lectins/glucanases; 1. DR SUPFAM; SSF49265; Fibronectin type III; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR PROSITE; PS50188; B302_SPRY; 1. DR PROSITE; PS51262; COS; 1. DR PROSITE; PS50853; FN3; 1. DR PROSITE; PS50119; ZF_BBOX; 2. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell projection; Coiled coil; KW Cytoplasm; Cytoplasmic vesicle; Cytoskeleton; Metal-binding; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW Synapse; Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; KW Zinc-finger. FT CHAIN 1..710 FT /note="E3 ubiquitin-protein ligase TRIM9" FT /id="PRO_0000056208" FT DOMAIN 374..432 FT /note="COS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00586" FT DOMAIN 440..535 FT /note="Fibronectin type-III" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 533..702 FT /note="B30.2/SPRY" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00548" FT ZN_FING 10..50 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT ZN_FING 163..212 FT /note="B box-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT ZN_FING 224..266 FT /note="B box-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT COILED 273..340 FT /evidence="ECO:0000255" FT BINDING 168 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 171 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 193 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 198 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 229 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 232 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 252 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 258 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT MOD_RES 41 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 44 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 46 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 49 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT VAR_SEQ 436..439 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007922" FT VAR_SEQ 534 FT /note="E -> EDTDSEEQTLPFPVPSERLPLRRMSPFSSTLNLQPSFPGRSYFDFRS FT SPHQLSLHSSLQSLNAPGCNFETQSAPYSQLVDIKKLLA (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007923" FT VAR_SEQ 535..550 FT /note="VAWFAFDPGSAHSDII -> GKALQQYPSERELRGI (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_007925" FT VAR_SEQ 551..710 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_007926" FT VAR_SEQ 692..710 FT /note="TLHTGLPVPDFYSSRASIA -> STLPLRLNSCCWLPVQRLPRAVQSNRREG FT S (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007924" FT VARIANT 653 FT /note="L -> F (in dbSNP:rs2275462)" FT /evidence="ECO:0000269|PubMed:11331580, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9179496" FT /id="VAR_016202" FT CONFLICT 314 FT /note="A -> V (in Ref. 2; BAB70913)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="Q -> R (in Ref. 2; BAB70913)" FT /evidence="ECO:0000305" FT STRAND 454..460 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 473..479 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 482..485 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 488..494 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 498..501 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 505..507 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 510..516 FT /evidence="ECO:0007829|PDB:2DB8" FT HELIX 542..544 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 549..552 FT /evidence="ECO:0007829|PDB:7B2S" FT TURN 553..556 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 557..564 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 566..571 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 576..588 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 595..599 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 605..607 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 615..620 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 622..629 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 632..638 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 646..652 FT /evidence="ECO:0007829|PDB:7B2S" FT TURN 653..656 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 657..662 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 679..685 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 689..694 FT /evidence="ECO:0007829|PDB:7B2S" SQ SEQUENCE 710 AA; 79177 MW; AEAB24807C89D0E2 CRC64; MEEMEEELKC PVCGSFYREP IILPCSHNLC QACARNILVQ TPESESPQSH RAAGSGVSDY DYLDLDKMSL YSEADSGYGS YGGFASAPTT PCQKSPNGVR VFPPAMPPPA THLSPALAPV PRNSCITCPQ CHRSLILDDR GLRGFPKNRV LEGVIDRYQQ SKAAALKCQL CEKAPKEATV MCEQCDVFYC DPCRLRCHPP RGPLAKHRLV PPAQGRVSRR LSPRKVSTCT DHELENHSMY CVQCKMPVCY QCLEEGKHSS HEVKALGAMW KLHKSQLSQA LNGLSDRAKE AKEFLVQLRN MVQQIQENSV EFEACLVAQC DALIDALNRR KAQLLARVNK EHEHKLKVVR DQISHCTVKL RQTTGLMEYC LEVIKENDPS GFLQISDALI RRVHLTEDQW GKGTLTPRMT TDFDLSLDNS PLLQSIHQLD FVQVKASSPV PATPILQLEE CCTHNNSATL SWKQPPLSTV PADGYILELD DGNGGQFREV YVGKETMCTV DGLHFNSTYN ARVKAFNKTG VSPYSKTLVL QTSEVAWFAF DPGSAHSDII LSNDNLTVTC SSYDDRVVLG KTGFSKGIHY WELTVDRYDN HPDPAFGVAR MDVMKDVMLG KDDKAWAMYV DNNRSWFMHN NSHTNRTEGG ITKGATIGVL LDLNRKNLTF FINDEQQGPI AFDNVEGLFF PAVSLNRNVQ VTLHTGLPVP DFYSSRASIA // ID TRPM7_HUMAN Reviewed; 1865 AA. AC Q96QT4; Q6ZMF5; Q86VJ4; Q8NBW2; Q9BXB2; Q9NXQ2; DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 188. DE RecName: Full=Transient receptor potential cation channel subfamily M member 7; DE EC=2.7.11.1 {ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, ECO:0000269|PubMed:18394644}; DE AltName: Full=Channel-kinase 1; DE AltName: Full=Long transient receptor potential channel 7 {ECO:0000303|PubMed:11385574}; DE Short=LTrpC-7; DE Short=LTrpC7; DE Contains: DE RecName: Full=TRPM7 kinase, cleaved form {ECO:0000250|UniProtKB:Q923J1}; DE Short=M7CK; DE Contains: DE RecName: Full=TRPM7 channel, cleaved form {ECO:0000250|UniProtKB:Q923J1}; GN Name=TRPM7; Synonyms=CHAK1, LTRPC7 {ECO:0000303|PubMed:11385574}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY RP REGULATION. RX PubMed=11385574; DOI=10.1038/35079092; RA Nadler M.J.S., Hermosura M.C., Inabe K., Perraud A.-L., Zhu Q., RA Stokes A.J., Kurosaki T., Kinet J.-P., Penner R., Scharenberg A.M., RA Fleig A.; RT "LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell RT viability."; RL Nature 411:590-595(2001). RN [2] RP ERRATUM OF PUBMED:11385574. RA Nadler M.J.S., Hermosura M.C., Inabe K., Perraud A.-L., Zhu Q., RA Stokes A.J., Kurosaki T., Kinet J.-P., Penner R., Scharenberg A.M., RA Fleig A.; RL Nature 412:660-660(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION. RX PubMed=14594813; DOI=10.1074/jbc.m308820200; RA Ryazanova L.V., Dorovkov M.V., Ansari A., Ryazanov A.G.; RT "Characterization of the protein kinase activity of TRPM7/ChaK1, a protein RT kinase fused to the transient receptor potential ion channel."; RL J. Biol. Chem. 279:3708-3716(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-575 AND 1096-1865, AND VARIANT RP ILE-1482. RC TISSUE=Colon, and Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 464-998. RC TISSUE=Liver; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF LYS-1648 AND GLY-1799. RX PubMed=12887921; DOI=10.1016/s0092-8674(03)00556-7; RA Schmitz C., Perraud A.-L., Johnson C.O., Inabe K., Smith M.K., Penner R., RA Kurosaki T., Fleig A., Scharenberg A.M.; RT "Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7."; RL Cell 114:191-200(2003). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15485879; DOI=10.1074/jbc.c400441200; RA Dorovkov M.V., Ryazanov A.G.; RT "Phosphorylation of annexin I by TRPM7 channel-kinase."; RL J. Biol. Chem. 279:50643-50646(2004). RN [8] RP INTERACTION WITH TRPM6. RX PubMed=14976260; DOI=10.1073/pnas.0305252101; RA Chubanov V., Waldegger S., Mederos y Schnitzler M., Vitzthum H., RA Sassen M.C., Seyberth H.W., Konrad M., Gudermann T.; RT "Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 RT gene causes hypomagnesemia with secondary hypocalcemia."; RL Proc. Natl. Acad. Sci. U.S.A. 101:2894-2899(2004). RN [9] RP INTERACTION WITH TRPM6. RX PubMed=16636202; DOI=10.1085/jgp.200609502; RA Li M., Jiang J., Yue L.; RT "Functional characterization of homo- and heteromeric channel kinases TRPM6 RT and TRPM7."; RL J. Gen. Physiol. 127:525-537(2006). RN [10] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=18394644; DOI=10.1016/j.jmb.2008.02.057; RA Clark K., Middelbeek J., Lasonder E., Dulyaninova N.G., Morrice N.A., RA Ryazanov A.G., Bresnick A.R., Figdor C.G., van Leeuwen F.N.; RT "TRPM7 regulates myosin IIA filament stability and protein localization by RT heavy chain phosphorylation."; RL J. Mol. Biol. 378:790-803(2008). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND PHOSPHORYLATION AT RP THR-1163; SER-1191; SER-1193; SER-1255; SER-1258; THR-1265; SER-1287; RP SER-1358; SER-1361; SER-1387; SER-1390; SER-1396; SER-1404; THR-1405; RP SER-1407; THR-1435; SER-1446; THR-1455; SER-1456; SER-1463; SER-1468; RP THR-1471; SER-1476; SER-1477; THR-1482; SER-1493; SER-1504; THR-1508; RP SER-1513; SER-1527; SER-1533; THR-1537; THR-1542; SER-1543; THR-1551; RP SER-1567; SER-1569; THR-1583; SER-1598; SER-1615; SER-1660; THR-1685; RP SER-1779; THR-1830 AND SER-1860. RX PubMed=18365021; DOI=10.1371/journal.pone.0001876; RA Clark K., Middelbeek J., Morrice N.A., Figdor C.G., Lasonder E., RA van Leeuwen F.N.; RT "Massive autophosphorylation of the Ser/Thr-rich domain controls protein RT kinase activity of TRPM6 and TRPM7."; RL PLoS ONE 3:e1876-e1876(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1477, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [14] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-101; SER-1387; SER-1390; RP SER-1395; SER-1404; SER-1477; SER-1527 AND SER-1569, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [16] RP FUNCTION. RX PubMed=24316671; DOI=10.1038/ncb2883; RA Cai Z., Jitkaew S., Zhao J., Chiang H.C., Choksi S., Liu J., Ward Y., RA Wu L.G., Liu Z.G.; RT "Plasma membrane translocation of trimerized MLKL protein is required for RT TNF-induced necroptosis."; RL Nat. Cell Biol. 16:55-65(2014). RN [17] RP PALMITOYLATION AT CYS-1143; CYS-1144 AND CYS-1146, FUNCTION, AND RP TRANSPORTER ACTIVITY. RX PubMed=36027648; DOI=10.1016/j.ceca.2022.102639; RA Gao X., Kuo C.W., Main A., Brown E., Rios F.J., Camargo L.L., Mary S., RA Wypijewski K., Goek C., Touyz R.M., Fuller W.; RT "Palmitoylation regulates cellular distribution of and transmembrane Ca RT flux through TrpM7."; RL Cell Calcium 106:102639-102639(2022). RN [18] RP VARIANT ILE-1482, CHARACTERIZATION OF VARIANT ILE-1482, AND ACTIVITY RP REGULATION. RX PubMed=16051700; DOI=10.1073/pnas.0505149102; RA Hermosura M.C., Nayakanti H., Dorovkov M.V., Calderon F.R., Ryazanov A.G., RA Haymer D.S., Garruto R.M.; RT "A TRPM7 variant shows altered sensitivity to magnesium that may contribute RT to the pathogenesis of two Guamanian neurodegenerative disorders."; RL Proc. Natl. Acad. Sci. U.S.A. 102:11510-11515(2005). RN [19] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-68; CYS-406; THR-459; ASN-574; SER-720; RP VAL-830; TYR-949; ARG-1064; THR-1211; VAL-1254; GLU-1306; LYS-1444 AND RP ILE-1482. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [20] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, VARIANT ASP-1046, RP CHARACTERIZATION OF VARIANT ASP-1046, AND INVOLVEMENT IN HYPOMAGNESEMIA RP WITH SECONDARY HYPOCALCEMIA. RX PubMed=35561741; DOI=10.1093/ndt/gfac182; RA Vargas-Poussou R., Claverie-Martin F., Prot-Bertoye C., Carotti V., RA van der Wijst J., Perdomo-Ramirez A., Fraga-Rodriguez G.M., Hureaux M., RA Bos C., Latta F., Houillier P., Hoenderop J., de Baaij J.; RT "Possible role for rare TRPM7 variants in patients with hypomagnesemia with RT secondary hypocalcemia."; RL Nephrol. Dial. Transplant. 0:0-0(2022). CC -!- FUNCTION: Bifunctional protein that combines an ion channel with an CC intrinsic kinase domain, enabling it to modulate cellular functions CC either by conducting ions through the pore or by phosphorylating CC downstream proteins via its kinase domain. The channel is highly CC permeable to divalent cations, specifically calcium (Ca2+), magnesium CC (Mg2+) and zinc (Zn2+) and mediates their influx (PubMed:11385574, CC PubMed:12887921, PubMed:15485879, PubMed:24316671, PubMed:35561741, CC PubMed:36027648). Controls a wide range of biological processes such as CC Ca2(+), Mg(2+) and Zn(2+) homeostasis, vesicular Zn(2+) release channel CC and intracellular Ca(2+) signaling, embryonic development, immune CC responses, cell motility, proliferation and differentiation (By CC similarity). The C-terminal alpha-kinase domain autophosphorylates CC cytoplasmic residues of TRPM7 (PubMed:18365021). In vivo, TRPM7 CC phosphorylates SMAD2, suggesting that TRPM7 kinase may play a role in CC activating SMAD signaling pathways. In vitro, TRPM7 kinase CC phosphorylates ANXA1 (annexin A1), myosin II isoforms and a variety of CC proteins with diverse cellular functions (PubMed:15485879, CC PubMed:18394644). {ECO:0000250|UniProtKB:Q923J1, CC ECO:0000269|PubMed:11385574, ECO:0000269|PubMed:12887921, CC ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, CC ECO:0000269|PubMed:18394644, ECO:0000269|PubMed:24316671, CC ECO:0000269|PubMed:35561741, ECO:0000269|PubMed:36027648}. CC -!- FUNCTION: [TRPM7 channel, cleaved form]: The cleaved channel exhibits CC substantially higher current and potentiates Fas receptor signaling. CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- FUNCTION: [TRPM7 kinase, cleaved form]: The C-terminal kinase domain CC can be cleaved from the channel segment in a cell-type-specific CC fashion. In immune cells, the TRPM7 kinase domain is clipped from the CC channel domain by caspases in response to Fas-receptor stimulation. The CC cleaved kinase fragments can translocate to the nucleus, and bind CC chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to CC ultimately phosphorylate specific Ser/Thr residues of histones known to CC be functionally important for cell differentiation and embryonic CC development. {ECO:0000250|UniProtKB:Q923J1}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, CC ECO:0000269|PubMed:18394644}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18365021, ECO:0000269|PubMed:18394644}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Mg(2+)(in) = Mg(2+)(out); Xref=Rhea:RHEA:29827, CC ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:11385574, CC ECO:0000269|PubMed:12887921, ECO:0000269|PubMed:35561741}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671, CC ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:11385574, CC ECO:0000269|PubMed:36027648}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000250|UniProtKB:Q923J1}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:Q923J1}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:Q923J1}; CC -!- ACTIVITY REGULATION: Channel displays constitutive activity. Channel CC activity is negatively regulated by cytosolic Mg(2+) and Mg-ATP CC (PubMed:11385574, PubMed:16051700). Channel activity is negatively CC regulated by low intracellular pH (By similarity). Resting free CC cytosolic Mg(2+) and Mg-ATP concentrations seem to be sufficient to CC block native TRPM7 channel activity (By similarity). TRPM7 channel CC activity is highly dependent on membrane levels of phosphatidylinositol CC 4,5 bisphosphate (PIP2). PIP2 hydrolysis negatively regulates TRPM7 CC channel activity (By similarity). TRPM7 kinase activity does not affect CC channel activity (By similarity). The kinase activity is controlled CC through the autophosphorylation of a serine/threonine-rich region CC located N-terminal to the catalytic domain (PubMed:18365021). CC {ECO:0000250|UniProtKB:Q923J1, ECO:0000250|UniProtKB:Q925B3, CC ECO:0000269|PubMed:11385574, ECO:0000269|PubMed:16051700, CC ECO:0000269|PubMed:18365021}. CC -!- SUBUNIT: Homotetramer (By similarity). Interacts with PLCB1 (By CC similarity). Forms heteromers with TRPM6; heteromeric channels are CC functionally different from the homomeric channels (PubMed:14976260, CC PubMed:16636202). {ECO:0000250|UniProtKB:Q923J1, CC ECO:0000250|UniProtKB:Q925B3, ECO:0000269|PubMed:14976260, CC ECO:0000269|PubMed:16636202}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24316671, CC ECO:0000269|PubMed:35561741}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q923J1}. Cytoplasmic vesicle membrane CC {ECO:0000250|UniProtKB:Q923J1}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q923J1}. Note=Localized largely in intracellular CC Zn(2+)-storage vesicles. {ECO:0000250|UniProtKB:Q923J1}. CC -!- SUBCELLULAR LOCATION: [TRPM7 kinase, cleaved form]: Nucleus CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- PTM: Palmitoylated; palmitoylation at Cys-1143, Cys-1144 and Cys-1146 CC promotes TRPM7 trafficking from the Golgi to the surface membrane. CC {ECO:0000269|PubMed:36027648}. CC -!- PTM: Autophosphorylated; autophosphorylation of C-terminus regulates CC TRPM7 kinase activity towards its substrates. CC {ECO:0000269|PubMed:18365021}. CC -!- PTM: The C-terminal kinase domain can be cleaved from the channel CC segment in a cell-type-specific fashion. TRPM7 is cleaved by caspase-8, CC dissociating the kinase from the ion-conducting pore. The cleaved CC kinase fragments (M7CKs) can translocate to the cell nucleus and binds CC chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to CC ultimately phosphorylate specific Ser/Thr residues of histones. CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- DISEASE: Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1 CC (ALS-PDC1) [MIM:105500]: A neurodegenerative disorder characterized by CC chronic, progressive and uniformly fatal amyotrophic lateral sclerosis CC and parkinsonism-dementia. Both diseases are known to occur in the same CC kindred, the same sibship and even the same individual. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Note=TRPM7 variants have been identified as a potential cause CC of disease in patients suffering from seizures and muscle cramps due to CC magnesium deficiency and episodes of hypocalcemia. CC {ECO:0000269|PubMed:35561741}. CC -!- SIMILARITY: In the C-terminal section; belongs to the protein kinase CC superfamily. Alpha-type protein kinase family. ALPK subfamily. CC {ECO:0000305}. CC -!- SIMILARITY: In the N-terminal section; belongs to the transient CC receptor (TC 1.A.4) family. LTrpC subfamily. TRPM7 sub-subfamily. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC11462.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=BAD18773.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY032950; AAK44211.1; -; mRNA. DR EMBL; AF346629; AAK19738.2; -; mRNA. DR EMBL; AK000124; BAA90958.1; -; mRNA. DR EMBL; AK172800; BAD18773.1; ALT_INIT; mRNA. DR EMBL; AK075193; BAC11462.1; ALT_INIT; mRNA. DR EMBL; BC051024; AAH51024.1; -; mRNA. DR CCDS; CCDS42035.1; -. DR RefSeq; NP_001288141.1; NM_001301212.1. DR RefSeq; NP_060142.3; NM_017672.5. DR AlphaFoldDB; Q96QT4; -. DR SMR; Q96QT4; -. DR BioGRID; 120177; 153. DR CORUM; Q96QT4; -. DR FunCoup; Q96QT4; 1775. DR IntAct; Q96QT4; 44. DR MINT; Q96QT4; -. DR STRING; 9606.ENSP00000495860; -. DR BindingDB; Q96QT4; -. DR ChEMBL; CHEMBL1250412; -. DR DrugBank; DB04447; 1,4-Dithiothreitol. DR DrugBank; DB14513; Magnesium. DR DrugBank; DB09481; Magnesium carbonate. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB00179; Masoprocol. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR GuidetoPHARMACOLOGY; 499; -. DR TCDB; 1.A.4.5.1; the transient receptor potential ca2+/cation channel (trp-cc) family. DR CarbonylDB; Q96QT4; -. DR iPTMnet; Q96QT4; -. DR PhosphoSitePlus; Q96QT4; -. DR SwissPalm; Q96QT4; -. DR BioMuta; TRPM7; -. DR DMDM; 56404941; -. DR jPOST; Q96QT4; -. DR MassIVE; Q96QT4; -. DR PaxDb; 9606-ENSP00000320239; -. DR PeptideAtlas; Q96QT4; -. DR ProteomicsDB; 77898; -. DR Pumba; Q96QT4; -. DR Antibodypedia; 24755; 465 antibodies from 40 providers. DR DNASU; 54822; -. DR Ensembl; ENST00000646667.1; ENSP00000495860.1; ENSG00000092439.16. DR GeneID; 54822; -. DR KEGG; hsa:54822; -. DR MANE-Select; ENST00000646667.1; ENSP00000495860.1; NM_017672.6; NP_060142.3. DR UCSC; uc001zyt.5; human. DR AGR; HGNC:17994; -. DR ClinPGx; PA38273; -. DR CTD; 54822; -. DR DisGeNET; 54822; -. DR GeneCards; TRPM7; -. DR HGNC; HGNC:17994; TRPM7. DR HPA; ENSG00000092439; Tissue enriched (parathyroid). DR MalaCards; TRPM7; -. DR MIM; 105500; phenotype. DR MIM; 605692; gene. DR OpenTargets; ENSG00000092439; -. DR Orphanet; 140957; Autosomal dominant macrothrombocytopenia. DR Orphanet; 90020; Parkinson-dementia complex of Guam. DR VEuPathDB; HostDB:ENSG00000092439; -. DR eggNOG; KOG3614; Eukaryota. DR GeneTree; ENSGT00940000157091; -. DR InParanoid; Q96QT4; -. DR OMA; SSKDPHX; -. DR OrthoDB; 301415at2759; -. DR PAN-GO; Q96QT4; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q96QT4; -. DR PathwayCommons; Q96QT4; -. DR Reactome; R-HSA-3295583; TRP channels. DR SignaLink; Q96QT4; -. DR SIGNOR; Q96QT4; -. DR Agora; ENSG00000092439; -. DR BioGRID-ORCS; 54822; 406 hits in 1198 CRISPR screens. DR ChiTaRS; TRPM7; human. DR GeneWiki; TRPM7; -. DR GenomeRNAi; 54822; -. DR Pharos; Q96QT4; Tchem. DR PRO; PR:Q96QT4; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q96QT4; protein. DR Bgee; ENSG00000092439; Expressed in left ventricle myocardium and 179 other cell types or tissues. DR ExpressionAtlas; Q96QT4; baseline and differential. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB. DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0001726; C:ruffle; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005262; F:calcium channel activity; IDA:UniProtKB. DR GO; GO:0015095; F:magnesium ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0017022; F:myosin binding; IEA:Ensembl. DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IEA:Ensembl. DR GO; GO:0031032; P:actomyosin structure organization; IEA:Ensembl. DR GO; GO:0070588; P:calcium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:0006816; P:calcium ion transport; IBA:GO_Central. DR GO; GO:0016340; P:calcium-dependent cell-matrix adhesion; IEA:Ensembl. DR GO; GO:0010961; P:intracellular magnesium ion homeostasis; ISS:UniProtKB. DR GO; GO:0010960; P:magnesium ion homeostasis; IDA:UniProtKB. DR GO; GO:0015693; P:magnesium ion transport; IDA:UniProtKB. DR GO; GO:0098655; P:monoatomic cation transmembrane transport; IBA:GO_Central. DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0006829; P:zinc ion transport; ISS:UniProtKB. DR CDD; cd16971; Alpha_kinase_ChaK1_TRMP7; 1. DR FunFam; 1.20.5.1010:FF:000002; Transient receptor potential cation channel subfamily M member 7; 1. DR FunFam; 3.20.200.10:FF:000001; Transient receptor potential cation channel, subfamily M, member 7; 1. DR FunFam; 3.30.200.20:FF:000129; Transient receptor potential cation channel, subfamily M, member 7; 1. DR Gene3D; 3.20.200.10; MHCK/EF2 kinase; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.20.5.1010; TRPM, tetramerisation domain; 1. DR InterPro; IPR004166; a-kinase_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR050927; TRPM. DR InterPro; IPR057366; TRPM-like. DR InterPro; IPR029601; TRPM7_a-kinase_dom. DR InterPro; IPR041491; TRPM_SLOG. DR InterPro; IPR032415; TRPM_tetra. DR InterPro; IPR037162; TRPM_tetra_sf. DR PANTHER; PTHR13800:SF8; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY M MEMBER 7; 1. DR PANTHER; PTHR13800; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 6; 1. DR Pfam; PF02816; Alpha_kinase; 1. DR Pfam; PF18139; LSDAT_euk; 1. DR Pfam; PF25508; TRPM2; 2. DR Pfam; PF16519; TRPM_tetra; 1. DR SMART; SM00811; Alpha_kinase; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS51158; ALPHA_KINASE; 1. PE 1: Evidence at protein level; KW Acetylation; Amyotrophic lateral sclerosis; ATP-binding; Calcium; KW Calcium channel; Calcium transport; Cell membrane; Coiled coil; KW Cytoplasmic vesicle; Disease variant; Ion channel; Ion transport; Kinase; KW Lipoprotein; Membrane; Metal-binding; Necrosis; Neurodegeneration; KW Nucleotide-binding; Nucleus; Palmitate; Parkinsonism; Phosphoprotein; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Transmembrane; KW Transmembrane helix; Transport; Zinc. FT CHAIN 1..1865 FT /note="Transient receptor potential cation channel FT subfamily M member 7" FT /id="PRO_0000215331" FT CHAIN 1..? FT /note="TRPM7 channel, cleaved form" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT /id="PRO_0000461294" FT CHAIN ?..1865 FT /note="TRPM7 kinase, cleaved form" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT /id="PRO_0000461295" FT TOPO_DOM 1..850 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 851..876 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 877..882 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 883..904 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 905..923 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 924..943 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 944..956 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 957..980 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 981..999 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 1000..1023 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1024..1025 FT /note="Extracellular" FT /evidence="ECO:0000305" FT INTRAMEM 1026..1066 FT /note="Pore-forming" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1067..1069 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 1070..1098 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1099..1865 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT DOMAIN 1594..1824 FT /note="Alpha-type protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00501" FT REGION 544..575 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1386..1407 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1492..1511 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1524..1543 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1836..1865 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 1198..1250 FT /evidence="ECO:0000250" FT COMPBIAS 544..555 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 560..573 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1386..1398 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1494..1511 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1844..1865 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 1767 FT /note="Proton acceptor" FT /evidence="ECO:0000250" FT BINDING 1621 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1622 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1623 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1624 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1648 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1720 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1721 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1723 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1753 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1777 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1810 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1812 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1816 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 101 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1163 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1191 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1193 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1224 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1255 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1258 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1265 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1287 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1301 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1358 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1361 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1386 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1387 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1390 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1395 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1396 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1404 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1405 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1407 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1435 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1446 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1455 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1456 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1463 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1467 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1468 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1471 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1476 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1477 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 1482 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1493 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1500 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1504 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1508 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1513 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1527 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1533 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1537 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1542 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1543 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1551 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1567 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1569 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1583 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1598 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1615 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1660 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1685 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1779 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1830 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1851 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1860 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT LIPID 1143 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT LIPID 1144 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT LIPID 1146 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT VARIANT 68 FT /note="G -> V (in dbSNP:rs56064201)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042395" FT VARIANT 406 FT /note="S -> C (in an ovarian serous carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042396" FT VARIANT 459 FT /note="I -> T (in dbSNP:rs55924090)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042397" FT VARIANT 574 FT /note="K -> N (in dbSNP:rs56040619)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042398" FT VARIANT 720 FT /note="T -> S (in a breast infiltrating ductal carcinoma FT sample; somatic mutation; dbSNP:rs1040254222)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042399" FT VARIANT 830 FT /note="M -> V (in a gastric adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042400" FT VARIANT 949 FT /note="F -> Y (in dbSNP:rs55681028)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042401" FT VARIANT 1033 FT /note="A -> G (in dbSNP:rs34530969)" FT /id="VAR_052381" FT VARIANT 1046 FT /note="G -> D (found in a patient with hypomagnesemia and FT secondary hypocalcemia; likely pathogenic; de novo variant; FT causes severely reduced Mg(2+) uptake in transfected cells; FT dbSNP:rs2059709974)" FT /evidence="ECO:0000269|PubMed:35561741" FT /id="VAR_086707" FT VARIANT 1064 FT /note="Q -> R (in dbSNP:rs56298128)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042402" FT VARIANT 1145 FT /note="I -> V (in dbSNP:rs34711809)" FT /id="VAR_052382" FT VARIANT 1211 FT /note="I -> T (in dbSNP:rs56090496)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042403" FT VARIANT 1254 FT /note="A -> V (in dbSNP:rs56288221)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042404" FT VARIANT 1306 FT /note="D -> E (in dbSNP:rs55970334)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042405" FT VARIANT 1444 FT /note="R -> K (in dbSNP:rs55840070)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042406" FT VARIANT 1482 FT /note="T -> I (mutant channels are functional but show FT increased susceptibility to inhibition by intracellular FT Mg(2+) concentrations compared to wild-type channels; FT dbSNP:rs8042919)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:16051700, ECO:0000269|PubMed:17344846" FT /id="VAR_019967" FT MUTAGEN 1648 FT /note="K->R: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:12887921" FT MUTAGEN 1799 FT /note="G->D: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:12887921" FT CONFLICT 573..575 FT /note="EKM -> KKK (in Ref. 4; BAD18773)" FT /evidence="ECO:0000305" FT CONFLICT 998 FT /note="A -> S (in Ref. 5)" FT /evidence="ECO:0000305" FT CONFLICT 1496 FT /note="Missing (in Ref. 3; AAK19738)" FT /evidence="ECO:0000305" FT CONFLICT 1520 FT /note="D -> V (in Ref. 3; AAK19738)" FT /evidence="ECO:0000305" SQ SEQUENCE 1865 AA; 212697 MW; BE732674D52D7485 CRC64; MSQKSWIEST LTKRECVYII PSSKDPHRCL PGCQICQQLV RCFCGRLVKQ HACFTASLAM KYSDVKLGDH FNQAIEEWSV EKHTEQSPTD AYGVINFQGG SHSYRAKYVR LSYDTKPEVI LQLLLKEWQM ELPKLVISVH GGMQKFELHP RIKQLLGKGL IKAAVTTGAW ILTGGVNTGV AKHVGDALKE HASRSSRKIC TIGIAPWGVI ENRNDLVGRD VVAPYQTLLN PLSKLNVLNN LHSHFILVDD GTVGKYGAEV RLRRELEKTI NQQRIHARIG QGVPVVALIF EGGPNVILTV LEYLQESPPV PVVVCEGTGR AADLLAYIHK QTEEGGNLPD AAEPDIISTI KKTFNFGQNE ALHLFQTLME CMKRKELITV FHIGSDEHQD IDVAILTALL KGTNASAFDQ LILTLAWDRV DIAKNHVFVY GQQWLVGSLE QAMLDALVMD RVAFVKLLIE NGVSMHKFLT IPRLEELYNT KQGPTNPMLF HLVRDVKQGN LPPGYKITLI DIGLVIEYLM GGTYRCTYTR KRFRLIYNSL GGNNRRSGRN TSSSTPQLRK SHESFGNRAD KKEKMRHNHF IKTAQPYRPK IDTVMEEGKK KRTKDEIVDI DDPETKRFPY PLNELLIWAC LMKRQVMARF LWQHGEESMA KALVACKIYR SMAYEAKQSD LVDDTSEELK QYSNDFGQLA VELLEQSFRQ DETMAMKLLT YELKNWSNST CLKLAVSSRL RPFVAHTCTQ MLLSDMWMGR LNMRKNSWYK VILSILVPPA ILLLEYKTKA EMSHIPQSQD AHQMTMDDSE NNFQNITEEI PMEVFKEVRI LDSNEGKNEM EIQMKSKKLP ITRKFYAFYH APIVKFWFNT LAYLGFLMLY TFVVLVQMEQ LPSVQEWIVI AYIFTYAIEK VREIFMSEAG KVNQKIKVWF SDYFNISDTI AIISFFIGFG LRFGAKWNFA NAYDNHVFVA GRLIYCLNII FWYVRLLDFL AVNQQAGPYV MMIGKMVANM FYIVVIMALV LLSFGVPRKA ILYPHEAPSW TLAKDIVFHP YWMIFGEVYA YEIDVCANDS VIPQICGPGT WLTPFLQAVY LFVQYIIMVN LLIAFFNNVY LQVKAISNIV WKYQRYHFIM AYHEKPVLPP PLIILSHIVS LFCCICKRRK KDKTSDGPKL FLTEEDQKKL HDFEEQCVEM YFNEKDDKFH SGSEERIRVT FERVEQMCIQ IKEVGDRVNY IKRSLQSLDS QIGHLQDLSA LTVDTLKTLT AQKASEASKV HNEITRELSI SKHLAQNLID DGPVRPSVWK KHGVVNTLSS SLPQGDLESN NPFHCNILMK DDKDPQCNIF GQDLPAVPQR KEFNFPEAGS SSGALFPSAV SPPELRQRLH GVELLKIFNK NQKLGSSSTS IPHLSSPPTK FFVSTPSQPS CKSHLETGTK DQETVCSKAT EGDNTEFGAF VGHRDSMDLQ RFKETSNKIK ILSNNNTSEN TLKRVSSLAG FTDCHRTSIP VHSKQAEKIS RRPSTEDTHE VDSKAALIPD WLQDRPSNRE MPSEEGTLNG LTSPFKPAMD TNYYYSAVER NNLMRLSQSI PFTPVPPRGE PVTVYRLEES SPNILNNSMS SWSQLGLCAK IEFLSKEEMG GGLRRAVKVQ CTWSEHDILK SGHLYIIKSF LPEVVNTWSS IYKEDTVLHL CLREIQQQRA AQKLTFAFNQ MKPKSIPYSP RFLEVFLLYC HSAGQWFAVE ECMTGEFRKY NNNNGDEIIP TNTLEEIMLA FSHWTYEYTR GELLVLDLQG VGENLTDPSV IKAEEKRSCD MVFGPANLGE DAIKNFRAKH HCNSCCRKLK LPDLKRNDYT PDKIIFPQDE PSDLNLQPGN STKESESTNS VRLML // ID UCHL1_HUMAN Reviewed; 223 AA. AC P09936; Q4W5K6; Q71UM0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 2. DT 28-JAN-2026, entry version 248. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1; DE Short=UCH-L1; DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; DE AltName: Full=Neuron cytoplasmic protein 9.5; DE AltName: Full=PGP 9.5; DE Short=PGP9.5; DE AltName: Full=Ubiquitin thioesterase L1; DE Flags: Precursor; GN Name=UCHL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15. RX PubMed=2163617; DOI=10.1042/bj2680521; RA Day I.N.M., Hinks L.J., Thompson R.J.; RT "The structure of the human gene encoding protein gene product 9.5 RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase."; RL Biochem. J. 268:521-524(1990). RN [5] RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=14722078; DOI=10.1074/jbc.m314124200; RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., RA Li L.; RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's RT diseases."; RL J. Biol. Chem. 279:13256-13264(2004). RN [6] RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3; RA Day I.N.M., Thompson R.J.; RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel RT cytoplasmic marker for neurones and neuroendocrine cells."; RL FEBS Lett. 210:157-160(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION RP OF VARIANT PARK5 MET-93. RX PubMed=9774100; DOI=10.1038/26652; RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.; RT "The ubiquitin pathway in Parkinson's disease."; RL Nature 395:451-452(1998). RN [9] RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151. RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r; RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.; RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in RT their SV40 transformed counterparts."; RL FEBS Lett. 280:235-240(1991). RN [10] RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151. RX PubMed=1286667; DOI=10.1002/elps.11501301199; RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., RA Vandekerckhove J.; RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein RT database of normal human epidermal keratinocytes."; RL Electrophoresis 13:960-969(1992). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8639624; DOI=10.1021/bi960099f; RA Larsen C.N., Price J.S., Wilkinson K.D.; RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: RT identification of two active site residues."; RL Biochemistry 35:6735-6744(1996). RN [12] RP TISSUE SPECIFICITY. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND RP CHARACTERIZATION OF VARIANT TYR-18. RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7; RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.; RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect RT alpha-synuclein degradation and Parkinson's disease susceptibility."; RL Cell 111:209-218(2002). RN [14] RP INTERACTION WITH COPS5. RX PubMed=12082530; DOI=10.1038/sj.onc.1205390; RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., RA Yochem R., Ratovitski E., Sidransky D., Jen J.; RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)."; RL Oncogene 21:3003-3010(2002). RN [15] RP CATALYTIC ACTIVITY, AND ACTIVE SITE. RX PubMed=16475834; DOI=10.1021/bi052135t; RA Case A., Stein R.L.; RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1."; RL Biochemistry 45:2443-2452(2006). RN [16] RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220. RX PubMed=19261853; DOI=10.1073/pnas.0806474106; RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R., RA Liu Y., Logan T., Lansbury P.T. Jr.; RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein RT neurotoxicity and is a therapeutic target for Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP FUNCTION. RX PubMed=22212137; DOI=10.1111/j.1471-4159.2011.07644.x; RA Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.; RT "Control of BACE1 degradation and APP processing by ubiquitin carboxyl- RT terminal hydrolase L1."; RL J. Neurochem. 120:1129-1138(2012). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93, RP CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90. RX PubMed=23359680; DOI=10.1073/pnas.1222732110; RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M., RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C., RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A., RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.; RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads RT to early-onset progressive neurodegeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT RP MET-1 (ISOFORMS 1; 2 AND 3). RX PubMed=37316325; DOI=10.26508/lsa.202301972; RA Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M., RA Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.; RT "N-terminal proteoforms may engage in different protein complexes."; RL Life. Sci Alliance 6:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT. RX PubMed=16537382; DOI=10.1073/pnas.0510403103; RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S., RA Lansbury P.T., Ringe D., Petsko G.A.; RT "Structural basis for conformational plasticity of the Parkinson's disease- RT associated ubiquitin hydrolase UCH-L1."; RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF RP CYS-90 AND PHE-204. RX PubMed=20439756; DOI=10.1073/pnas.0910870107; RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.; RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of RT the ubiquitin hydrolase UCHL1 into productive conformation."; RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010). RN [25] RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2; RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.; RT "Alterations of structure and hydrolase activity of parkinsonism-associated RT human ubiquitin carboxyl-terminal hydrolase L1 variants."; RL Biochem. Biophys. Res. Commun. 304:176-183(2003). RN [26] RP VARIANT MET-93. RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6; RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.; RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene RT is not observed in European cases with familial Parkinson's disease."; RL Neurosci. Lett. 270:1-4(1999). RN [27] RP VARIANT TYR-18. RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040; RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., RA Lynch T., Hardy J., Farrer M.; RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal RT hydrolase gene in familial Parkinson's disease."; RL NeuroReport 10:427-429(1999). RN [28] RP VARIANT TYR-18. RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x; RA Mellick G.D., Silburn P.A.; RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does RT not confer protection against idiopathic Parkinson's disease."; RL Neurosci. Lett. 293:127-130(2000). RN [29] RP VARIANT TYR-18. RX PubMed=15048890; DOI=10.1002/ana.20017; RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RT "UCHL1 is a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 55:512-521(2004). RN [30] RP ERRATUM OF PUBMED:15048890. RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RL Ann. Neurol. 55:899-899(2004). RN [31] RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON RP DISEASE. RX PubMed=16450370; DOI=10.1002/ana.20757; RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T., RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P., RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.; RT "UCHL-1 is not a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 59:627-633(2006). RN [32] RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL RP CELLS. RX PubMed=18411255; DOI=10.1093/hmg/ddn115; RA Kyratzi E., Pavlaki M., Stefanis L.; RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to RT neuronal cells."; RL Hum. Mol. Genet. 17:2160-2171(2008). RN [33] RP VARIANT TYR-18. RX PubMed=21268678; DOI=10.3109/13816810.2010.544360; RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N., RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.; RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in RT patients with cataracts."; RL Ophthalmic Genet. 32:75-79(2011). RN [34] RP VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS RP SPG79B GLN-178 AND ASP-216. RX PubMed=28007905; DOI=10.1093/hmg/ddw391; RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y., RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M., RA Tallaksen C.M., Selmer K.K.; RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing."; RL Hum. Mol. Genet. 26:1031-1040(2017). RN [35] RP VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS; RP 178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A. RX PubMed=35986737; DOI=10.1016/j.gim.2022.07.006; RG Genomics England Research Consortium; RA Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J., RA Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L., RA Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A., RA Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y., RA Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N., RA Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K., RA Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B., RA Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O., RA Schoels L., Houlden H., Haack T.B., Hengel H.; RT "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative RT disorder with spasticity, ataxia, neuropathy, and optic atrophy."; RL Genet. Med. 24:2079-2090(2022). CC -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several CC processes such as maintenance of synaptic function, cardiac function, CC inflammatory response or osteoclastogenesis (PubMed:22212137, CC PubMed:23359680). Abrogates the ubiquitination of multiple proteins CC including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor CC protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In CC addition, recognizes and hydrolyzes a peptide bond at the C-terminal CC glycine of ubiquitin to maintain a stable pool of monoubiquitin that is CC a key requirement for the ubiquitin-proteasome and the autophagy- CC lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100). CC Regulates amyloid precursor protein/APP processing by promoting BACE1 CC degradation resulting in decreased amyloid beta production CC (PubMed:22212137). Plays a role in the immune response by regulating CC the ability of MHC I molecules to reach cross-presentation compartments CC competent for generating Ag-MHC I complexes (By similarity). Mediates CC the 'Lys-48'-linked deubiquitination of the transcriptional coactivator CC WWTR1/TAZ leading to its stabilization and inhibition of CC osteoclastogenesis (By similarity). Deubiquitinates and stabilizes CC epidermal growth factor receptor EGFR to prevent its degradation and to CC activate its downstream mediators (By similarity). Modulates oxidative CC activity in skeletal muscle by regulating key mitochondrial oxidative CC proteins (By similarity). Enhances the activity of hypoxia-inducible CC factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated CC ubiquitination and consequently inhibiting its degradation CC (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9, CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137, CC ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865, CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity). CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530, CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}. CC -!- INTERACTION: CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439; CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613; CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467; CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449; CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767; CC P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414; CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823; CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444; CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129; CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644; CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567; CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590; CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661; CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353; CC P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343; CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952; CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852; CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242; CC P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369; CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304; CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629; CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415; CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377; CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779; CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407; CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247; CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082; CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354; CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063; CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642; CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555; CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984; CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535; CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109; CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083; CC P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276; CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290; CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370; CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829; CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850; CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242; CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid- CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is CC associated with membranes in brain. Localizes near and/or within CC mitochondria to potentially interact with mitochondrial proteins. CC {ECO:0000250|UniProtKB:Q9R0P9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; CC IsoId=P09936-1; Sequence=Displayed; CC Name=2; CC IsoId=P09936-2; Sequence=VSP_062524; CC Name=3; CC IsoId=P09936-3; Sequence=VSP_062523; CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes CC throughout the neocortex (at protein level). Expressed in neurons and CC cells of the diffuse neuroendocrine system and their tumors. Weakly CC expressed in ovary. Down-regulated in brains from Parkinson disease and CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078, CC ECO:0000269|PubMed:9790970}. CC -!- PTM: O-glycosylated. {ECO:0000250}. CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex CC neurodegenerative disorder with manifestations ranging from typical CC Parkinson disease to dementia with Lewy bodies. Clinical features CC include parkinsonian symptoms (resting tremor, rigidity, postural CC instability and bradykinesia), dementia, diffuse Lewy body pathology, CC autonomic dysfunction, hallucinations and paranoia. CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia CC (SPG79A) [MIM:620221]: A form of spastic paraplegia, a CC neurodegenerative disorder characterized by a slow, gradual, CC progressive weakness and spasticity of the lower limbs. Rate of CC progression and the severity of symptoms are quite variable. Initial CC symptoms may include difficulty with balance, weakness and stiffness in CC the legs, muscle spasms, and dragging the toes when walking. In some CC forms of the disorder, bladder symptoms (such as incontinence) may CC appear, or the weakness and stiffness may spread to other parts of the CC body. SPG79A is a slowly progressive form characterized by late-onset CC spastic ataxia, neuropathy, and often optic atrophy. CC {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG79B is CC characterized by childhood onset blindness, cerebellar ataxia, CC nystagmus, dorsal column dysfunction, and spasticity with upper motor CC neuron dysfunction. {ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic CC acid have been observed in brains from Alzheimer disease (AD) and CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be CC associated with neurofibrillary tangles. In contrast to UCHL3, does not CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8. CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}. CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met CC with Parkinson disease. However, according to PubMed:16450370 this CC association is uncertain and UCHL1 is not a susceptibility gene for CC Parkinson disease. {ECO:0000305}. CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 CC and Cys-220 are subject of controversy and could be the artifactual CC results of sample handling. {ECO:0000305|PubMed:14722078}. CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase CC activity (PubMed:12408865). However, in another study, UCHL1 was shown CC to lack ubiquitin ligase activity (PubMed:23359680). CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase CC L1 entry; CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AC095043; AAY40923.1; -; Genomic_DNA. DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA. DR EMBL; BC000332; AAH00332.1; -; mRNA. DR EMBL; BC005117; AAH05117.1; -; mRNA. DR EMBL; BC006305; AAH06305.1; -; mRNA. DR EMBL; X17377; CAA35249.1; -; Genomic_DNA. DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA. DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA. DR CCDS; CCDS3462.1; -. [P09936-1] DR PIR; A25856; A25856. DR RefSeq; NP_004172.2; NM_004181.4. [P09936-1] DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223. DR PDB; 2LEN; NMR; -; A=1-223. DR PDB; 3IFW; X-ray; 2.40 A; A=1-223. DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223. DR PDB; 3KVF; X-ray; 2.80 A; A=1-223. DR PDB; 3KW5; X-ray; 2.83 A; A=1-223. DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223. DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223. DR PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8DY8; X-ray; 2.10 A; A/B=1-223. DR PDB; 8EDE; X-ray; 1.80 A; A/B=1-223. DR PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8XI7; X-ray; 1.95 A; A/B=1-223. DR PDB; 9O4M; X-ray; 2.00 A; A/B=1-223. DR PDBsum; 2ETL; -. DR PDBsum; 2LEN; -. DR PDBsum; 3IFW; -. DR PDBsum; 3IRT; -. DR PDBsum; 3KVF; -. DR PDBsum; 3KW5; -. DR PDBsum; 4DM9; -. DR PDBsum; 4JKJ; -. DR PDBsum; 7ZM0; -. DR PDBsum; 8DY8; -. DR PDBsum; 8EDE; -. DR PDBsum; 8PW1; -. DR PDBsum; 8XI7; -. DR PDBsum; 9O4M; -. DR AlphaFoldDB; P09936; -. DR BMRB; P09936; -. DR SASBDB; P09936; -. DR SMR; P09936; -. DR BioGRID; 113192; 258. DR CORUM; P09936; -. DR DIP; DIP-36620N; -. DR FunCoup; P09936; 1475. DR IntAct; P09936; 199. DR MINT; P09936; -. DR STRING; 9606.ENSP00000284440; -. DR BindingDB; P09936; -. DR ChEMBL; CHEMBL6159; -. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR GuidetoPHARMACOLOGY; 2426; -. DR MEROPS; C12.001; -. DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09936; -. DR MetOSite; P09936; -. DR PhosphoSitePlus; P09936; -. DR SwissPalm; P09936; -. DR BioMuta; UCHL1; -. DR DMDM; 136681; -. DR CPTAC; CPTAC-601; -. DR CPTAC; CPTAC-602; -. DR jPOST; P09936; -. DR MassIVE; P09936; -. DR PaxDb; 9606-ENSP00000284440; -. DR PeptideAtlas; P09936; -. DR ProteomicsDB; 52282; -. DR Pumba; P09936; -. DR Antibodypedia; 1062; 2368 antibodies from 53 providers. DR DNASU; 7345; -. DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1] DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1] DR GeneID; 7345; -. DR KEGG; hsa:7345; -. DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2. DR AGR; HGNC:12513; -. DR ClinPGx; PA37160; -. DR CTD; 7345; -. DR DisGeNET; 7345; -. DR GeneCards; UCHL1; -. DR HGNC; HGNC:12513; UCHL1. DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland). DR MalaCards; UCHL1; -. DR MIM; 191342; gene. DR MIM; 613643; phenotype. DR MIM; 615491; phenotype. DR MIM; 620221; phenotype. DR OpenTargets; ENSG00000154277; -. DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000154277; -. DR eggNOG; KOG1415; Eukaryota. DR GeneTree; ENSGT00940000157306; -. DR HOGENOM; CLU_054406_2_0_1; -. DR InParanoid; P09936; -. DR OMA; AQTYSKH; -. DR OrthoDB; 427186at2759; -. DR PAN-GO; P09936; 3 GO annotations based on evolutionary models. DR PhylomeDB; P09936; -. DR BRENDA; 3.4.19.12; 2681. DR PathwayCommons; P09936; -. DR Reactome; R-HSA-5689603; UCH proteinases. DR SABIO-RK; P09936; -. DR SignaLink; P09936; -. DR SIGNOR; P09936; -. DR Agora; ENSG00000154277; -. DR BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UCHL1; human. DR EvolutionaryTrace; P09936; -. DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -. DR GenomeRNAi; 7345; -. DR Pharos; P09936; Tchem. DR PRO; PR:P09936; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P09936; protein. DR Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues. DR ExpressionAtlas; P09936; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB. DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl. DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IBA:GO_Central. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1. DR FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1. DR Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001578; Peptidase_C12_UCH. DR InterPro; IPR036959; Peptidase_C12_UCH_sf. DR InterPro; IPR057254; UCH_AS. DR PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1. DR Pfam; PF01088; Peptidase_C12; 1. DR PRINTS; PR00707; UBCTHYDRLASE. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00140; UCH_1; 1. DR PROSITE; PS52048; UCH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Cytoplasm; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; KW Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; KW Phosphoprotein; Prenylation; Protease; Proteomics identification; KW Reference proteome; Thiol protease; Ubl conjugation pathway. FT CHAIN 1..220 FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1" FT /id="PRO_0000211055" FT PROPEP 221..223 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000414311" FT DOMAIN 2..221 FT /note="UCH catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT REGION 5..10 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT REGION 211..216 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT ACT_SITE 90 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT ACT_SITE 161 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT SITE 1 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 6 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 12 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 84 FT /note="Transition state stabilizer" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:8639624" FT SITE 124 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 176 FT /note="Important for enzyme activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT SITE 179 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 220 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES 125 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00981" FT LIPID 220 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:19261853" FT VAR_SEQ 1..11 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062523" FT VAR_SEQ 1..5 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062524" FT VARIANT 2..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087898" FT VARIANT 7 FT /note="E -> A (in SPG79B; has decreased binding to FT ubiquitin and significantly decreased hydrolase activity FT compared to wild-type; dbSNP:rs397515634)" FT /evidence="ECO:0000269|PubMed:23359680" FT /id="VAR_070875" FT VARIANT 18 FT /note="S -> Y (it confers protection from oxidative stress FT when expressed at physiological levels in neuroblastoma FT cells and primary cortical neurons; loss of dimerization FT ability; impaired ligase activity; dbSNP:rs5030732)" FT /evidence="ECO:0000269|PubMed:10203348, FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865, FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890, FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255, FT ECO:0000269|PubMed:21268678" FT /id="VAR_015677" FT VARIANT 25..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087899" FT VARIANT 52 FT /note="L -> LL (in SPG79A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087900" FT VARIANT 93 FT /note="I -> M (in PARK5; impaired enzymatic hydrolase FT activity; has about a 50% reduction in catalytic activity FT compared to wild-type protein; dbSNP:rs121917767)" FT /evidence="ECO:0000269|PubMed:10454131, FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100" FT /id="VAR_015678" FT VARIANT 178..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087901" FT VARIANT 178 FT /note="R -> Q (in SPG79B; increased hydrolase activity; FT decreased protein abundance; dbSNP:rs768996179)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078119" FT VARIANT 211..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087902" FT VARIANT 216 FT /note="A -> D (in SPG79B; decreased protein abundance; FT dbSNP:rs1057519600)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078120" FT MUTAGEN 73 FT /note="Q->R: No effect on enzymatic parameters." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 90 FT /note="C->S: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, FT ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624" FT MUTAGEN 97 FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin FT ethyl ester, slight reduction in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->D: 10000-fold decrease in enzymatic activity; no FT change in affinity for ubiquitin ethyl ester." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->K,Q,N,Y: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 176 FT /note="D->N: 6-fold decrease in affinity for ubiquitin FT ethyl ester; 97.5% decrease in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 204 FT /note="F->A: Almost complete loss of activity." FT /evidence="ECO:0000269|PubMed:20439756" FT HELIX 10..19 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 22..25 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 27..31 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 36..41 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 46..54 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 57..70 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 71..74 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:2LEN" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 101..105 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 113..120 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 121..123 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 126..135 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 137..147 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 160..168 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 183..187 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 193..207 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2LEN" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:8EDE" FT MOD_RES P09936-2:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES P09936-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" SQ SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64; MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA // ID WIPI4_HUMAN Reviewed; 360 AA. AC Q9Y484; A6NGH5; B7WPI2; Q5MNZ5; Q6IBS7; Q6NT94; Q96H03; DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 187. DE RecName: Full=WD repeat domain phosphoinositide-interacting protein 4; DE Short=WIPI-4; DE AltName: Full=WD repeat-containing protein 45; GN Name=WDR45; Synonyms=WDRX1, WDRXI4, WIPI4; ORFNames=JM5; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Testis; RX PubMed=15602573; DOI=10.1038/sj.onc.1208331; RA Proikas-Cezanne T., Waddell S., Gaugel A., Frickey T., Lupas A., RA Nordheim A.; RT "WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, RT is aberrantly expressed in human cancer and is linked to starvation-induced RT autophagy."; RL Oncogene 23:9314-9325(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Strom T.M., Nyakatura G., Hellebrand H., Drescher B., Rosenthal A., RA Meindl A.; RT "Transcription map in Xp11.23."; RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 69-360 (ISOFORM 2). RC TISSUE=Brain, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP SUBCELLULAR LOCATION. RX PubMed=21802374; DOI=10.1016/j.devcel.2011.06.024; RA Lu Q., Yang P., Huang X., Hu W., Guo B., Wu F., Lin L., Kovacs A.L., Yu L., RA Zhang H.; RT "The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of RT omegasomes to autophagosomes."; RL Dev. Cell 21:343-357(2011). RN [8] RP INVOLVEMENT IN NBIA5, AND FUNCTION. RX PubMed=23435086; DOI=10.1038/ng.2562; RA Saitsu H., Nishimura T., Muramatsu K., Kodera H., Kumada S., Sugai K., RA Kasai-Yoshida E., Sawaura N., Nishida H., Hoshino A., Ryujin F., RA Yoshioka S., Nishiyama K., Kondo Y., Tsurusaki Y., Nakashima M., Miyake N., RA Arakawa H., Kato M., Mizushima N., Matsumoto N.; RT "De novo mutations in the autophagy gene WDR45 cause static encephalopathy RT of childhood with neurodegeneration in adulthood."; RL Nat. Genet. 45:445-449(2013). RN [9] RP INTERACTION WITH ATG2A AND ATG2B. RX PubMed=28820312; DOI=10.1080/15548627.2017.1359381; RA Zheng J.X., Li Y., Ding Y.H., Liu J.J., Zhang M.J., Dong M.Q., Wang H.W., RA Yu L.; RT "Architecture of the ATG2B-WDR45 complex and an aromatic Y/HF motif crucial RT for complex formation."; RL Autophagy 13:1870-1883(2017). RN [10] RP FUNCTION, PHOSPHOINOSITIDES-BINDING, ACTIVITY REGULATION, INTERACTION WITH RP AMPK; ATG2A; NUDC; ULK1; WIPI1 AND WIPI2, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF ASN-15; GLN-16; ASP-17; GLU-55; ARG-109; ARG-111; HIS-112; RP ASP-113; LYS-114 AND 232-ARG-ARG-233. RX PubMed=28561066; DOI=10.1038/ncomms15637; RA Bakula D., Mueller A.J., Zuleger T., Takacs Z., Franz-Wachtel M., RA Thost A.K., Brigger D., Tschan M.P., Frickey T., Robenek H., Macek B., RA Proikas-Cezanne T.; RT "WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling RT circuits in the control of autophagy."; RL Nat. Commun. 8:15637-15637(2017). RN [11] RP FUNCTION. RX PubMed=31271352; DOI=10.7554/elife.45777; RA Maeda S., Otomo C., Otomo T.; RT "The autophagic membrane tether ATG2A transfers lipids between membranes."; RL Elife 8:0-0(2019). RN [12] RP INTERACTION WITH ATG2A. RX PubMed=32483132; DOI=10.1038/s41467-020-16523-y; RA Ren J., Liang R., Wang W., Zhang D., Yu L., Feng W.; RT "Multi-site-mediated entwining of the linear WIR-motif around WIPI beta- RT propellers for autophagy."; RL Nat. Commun. 11:2702-2702(2020). RN [13] RP VARIANT NBIA5 7-ARG--PHE-360 DEL. RX PubMed=25356899; DOI=10.1371/journal.pgen.1004772; RA Hamdan F.F., Srour M., Capo-Chichi J.M., Daoud H., Nassif C., Patry L., RA Massicotte C., Ambalavanan A., Spiegelman D., Diallo O., Henrion E., RA Dionne-Laporte A., Fougerat A., Pshezhetsky A.V., Venkateswaran S., RA Rouleau G.A., Michaud J.L.; RT "De novo mutations in moderate or severe intellectual disability."; RL PLoS Genet. 10:E1004772-E1004772(2014). RN [14] RP VARIANT NBIA5 ASP-208. RX PubMed=25592411; DOI=10.1016/j.jns.2014.12.036; RA Tschentscher A., Dekomien G., Ross S., Cremer K., Kukuk G.M., Epplen J.T., RA Hoffjan S.; RT "Analysis of the C19orf12 and WDR45 genes in patients with RT neurodegeneration with brain iron accumulation."; RL J. Neurol. Sci. 349:105-109(2015). CC -!- FUNCTION: Component of the autophagy machinery that controls the major CC intracellular degradation process by which cytoplasmic materials are CC packaged into autophagosomes and delivered to lysosomes for degradation CC (PubMed:23435086, PubMed:28561066). Binds phosphatidylinositol 3- CC phosphate (PtdIns3P) (PubMed:28561066). Activated by the STK11/AMPK CC signaling pathway upon starvation, WDR45 is involved in autophagosome CC assembly downstream of WIPI2, regulating the size of forming CC autophagosomes (PubMed:28561066). Together with WIPI1, promotes ATG2 CC (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association CC with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes CC (PubMed:31271352). Probably recruited to membranes through its PtdIns3P CC activity (PubMed:28561066). {ECO:0000269|PubMed:23435086, CC ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:31271352}. CC -!- ACTIVITY REGULATION: Activated upon amino-acid starvation. CC {ECO:0000269|PubMed:28561066}. CC -!- SUBUNIT: Interacts with WIPI1 (PubMed:28561066). Interacts with WIPI2 CC (PubMed:28561066). Interacts with ATG2A and ATG2B (PubMed:28561066, CC PubMed:28820312, PubMed:32483132). Interacts with ULK1 CC (PubMed:28561066). May interact with the PRKAA1, PRKAA2, PRKAB1 and CC PRKAG1 subunits of the AMPK kinase (PubMed:28561066). May interact with CC NUDC (PubMed:28561066). {ECO:0000269|PubMed:28561066, CC ECO:0000269|PubMed:28820312, ECO:0000269|PubMed:32483132}. CC -!- SUBCELLULAR LOCATION: Preautophagosomal structure CC {ECO:0000269|PubMed:21802374, ECO:0000269|PubMed:28561066}. Cytoplasm CC {ECO:0000269|PubMed:21802374}. Note=Diffusely localized in the CC cytoplasm under nutrient-rich conditions. Localizes to autophagic CC structures during starvation-induced autophagy. CC {ECO:0000269|PubMed:21802374}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9Y484-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9Y484-2; Sequence=VSP_016976; CC Name=3; CC IsoId=Q9Y484-3; Sequence=VSP_016975; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with high expression in CC skeletal muscle and heart. Weakly expressed in liver and placenta. CC Expression is down-regulated in pancreatic and in kidney tumors. CC {ECO:0000269|PubMed:15602573}. CC -!- DOMAIN: The L/FRRG motif is required for recruitment to PtdIns3P. CC {ECO:0000250|UniProtKB:Q9Y4P8}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 5 (NBIA5) CC [MIM:300894]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. NBIA5 is CC characterized by global developmental delay in early childhood that is CC essentially static, with slow motor and cognitive gains until CC adolescence or early adulthood. In young adulthood, affected CC individuals develop progressive dystonia, parkinsonism, extrapyramidal CC signs, and dementia resulting in severe disability. CC {ECO:0000269|PubMed:23435086, ECO:0000269|PubMed:25356899, CC ECO:0000269|PubMed:25592411}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the WD repeat PROPPIN family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY691428; AAV80764.1; -; mRNA. DR EMBL; AJ005897; CAA06754.1; -; mRNA. DR EMBL; CR456725; CAG33006.1; -; mRNA. DR EMBL; AF196779; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471224; EAW50697.1; -; Genomic_DNA. DR EMBL; CH471224; EAW50702.1; -; Genomic_DNA. DR EMBL; BC000464; AAH00464.1; -; mRNA. DR EMBL; BC003037; AAH03037.1; -; mRNA. DR EMBL; BC009027; AAH09027.1; -; mRNA. DR EMBL; BC069206; AAH69206.1; -; mRNA. DR CCDS; CCDS14318.1; -. [Q9Y484-3] DR CCDS; CCDS35250.1; -. [Q9Y484-1] DR RefSeq; NP_001025067.1; NM_001029896.2. [Q9Y484-1] DR RefSeq; NP_009006.2; NM_007075.3. [Q9Y484-3] DR PDB; 8KBX; EM; 3.23 A; A=1-360. DR PDB; 8KC3; EM; 7.00 A; D=1-360. DR PDB; 8Y1L; EM; 7.05 A; A=1-360. DR PDBsum; 8KBX; -. DR PDBsum; 8KC3; -. DR PDBsum; 8Y1L; -. DR AlphaFoldDB; Q9Y484; -. DR EMDB; EMD-37086; -. DR EMDB; EMD-37091; -. DR EMDB; EMD-38839; -. DR SMR; Q9Y484; -. DR BioGRID; 116323; 52. DR CORUM; Q9Y484; -. DR FunCoup; Q9Y484; 883. DR STRING; 9606.ENSP00000348848; -. DR TCDB; 9.A.15.2.1; the autophagy-related phagophore-formation transporter (apt) family. DR GlyGen; Q9Y484; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9Y484; -. DR PhosphoSitePlus; Q9Y484; -. DR SwissPalm; Q9Y484; -. DR BioMuta; WDR45; -. DR DMDM; 74762056; -. DR jPOST; Q9Y484; -. DR MassIVE; Q9Y484; -. DR PaxDb; 9606-ENSP00000348848; -. DR PeptideAtlas; Q9Y484; -. DR ProteomicsDB; 86126; -. [Q9Y484-1] DR ProteomicsDB; 86127; -. [Q9Y484-2] DR ProteomicsDB; 86128; -. [Q9Y484-3] DR Pumba; Q9Y484; -. DR ABCD; Q9Y484; 2 sequenced antibodies. DR Antibodypedia; 34945; 170 antibodies from 21 providers. DR DNASU; 11152; -. DR Ensembl; ENST00000322995.13; ENSP00000365543.5; ENSG00000196998.20. [Q9Y484-2] DR Ensembl; ENST00000356463.7; ENSP00000348848.3; ENSG00000196998.20. [Q9Y484-3] DR Ensembl; ENST00000376368.7; ENSP00000365546.2; ENSG00000196998.20. [Q9Y484-3] DR Ensembl; ENST00000376372.9; ENSP00000365551.3; ENSG00000196998.20. [Q9Y484-1] DR Ensembl; ENST00000634944.1; ENSP00000488972.1; ENSG00000196998.20. [Q9Y484-1] DR Ensembl; ENST00000710219.1; ENSP00000518130.1; ENSG00000292221.1. [Q9Y484-1] DR Ensembl; ENST00000710220.1; ENSP00000518131.1; ENSG00000292221.1. [Q9Y484-1] DR Ensembl; ENST00000710225.1; ENSP00000518136.1; ENSG00000292221.1. [Q9Y484-2] DR Ensembl; ENST00000710226.1; ENSP00000518137.1; ENSG00000292221.1. [Q9Y484-3] DR Ensembl; ENST00000710231.1; ENSP00000518141.1; ENSG00000292221.1. [Q9Y484-3] DR GeneID; 11152; -. DR KEGG; hsa:11152; -. DR MANE-Select; ENST00000376372.9; ENSP00000365551.3; NM_001029896.2; NP_001025067.1. DR UCSC; uc004dmk.2; human. [Q9Y484-1] DR AGR; HGNC:28912; -. DR ClinPGx; PA134927673; -. DR CTD; 11152; -. DR DisGeNET; 11152; -. DR GeneCards; WDR45; -. DR GeneReviews; WDR45; -. DR HGNC; HGNC:28912; WDR45. DR HPA; ENSG00000196998; Low tissue specificity. DR MalaCards; WDR45; -. DR MIM; 300526; gene. DR MIM; 300894; phenotype. DR OpenTargets; ENSG00000196998; -. DR Orphanet; 329284; Beta-propeller protein-associated neurodegeneration. DR Orphanet; 697160; Infantile epileptic spasms syndrome. DR VEuPathDB; HostDB:ENSG00000196998; -. DR eggNOG; KOG2111; Eukaryota. DR GeneTree; ENSGT00940000155657; -. DR InParanoid; Q9Y484; -. DR OMA; YAVCENG; -. DR OrthoDB; 1667587at2759; -. DR PAN-GO; Q9Y484; 9 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y484; -. DR PathwayCommons; Q9Y484; -. DR Reactome; R-HSA-1632852; Macroautophagy. DR SignaLink; Q9Y484; -. DR SIGNOR; Q9Y484; -. DR Agora; ENSG00000196998; -. DR BioGRID-ORCS; 11152; 21 hits in 778 CRISPR screens. DR ChiTaRS; WDR45; human. DR GeneWiki; WDR45; -. DR GenomeRNAi; 11152; -. DR Pharos; Q9Y484; Tbio. DR PRO; PR:Q9Y484; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q9Y484; protein. DR Bgee; ENSG00000196998; Expressed in apex of heart and 209 other cell types or tissues. DR ExpressionAtlas; Q9Y484; baseline and differential. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0000407; C:phagophore assembly site; IDA:UniProtKB. DR GO; GO:0034045; C:phagophore assembly site membrane; IBA:GO_Central. DR GO; GO:1901981; F:phosphatidylinositol phosphate binding; IDA:UniProtKB. DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IBA:GO_Central. DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IBA:GO_Central. DR GO; GO:0000045; P:autophagosome assembly; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; IBA:GO_Central. DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB. DR GO; GO:0061723; P:glycophagy; IBA:GO_Central. DR GO; GO:0044804; P:nucleophagy; IBA:GO_Central. DR GO; GO:0000425; P:pexophagy; IBA:GO_Central. DR GO; GO:2000786; P:positive regulation of autophagosome assembly; IDA:UniProtKB. DR GO; GO:0034497; P:protein localization to phagophore assembly site; IBA:GO_Central. DR FunFam; 2.130.10.10:FF:000154; WD repeat domain phosphoinositide-interacting protein 4; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR048720; PROPPIN. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR InterPro; IPR036322; WD40_repeat_dom_sf. DR InterPro; IPR001680; WD40_rpt. DR PANTHER; PTHR11227; WD-REPEAT PROTEIN INTERACTING WITH PHOSPHOINOSIDES WIPI -RELATED; 1. DR Pfam; PF21032; PROPPIN; 1. DR SMART; SM00320; WD40; 4. DR SUPFAM; SSF50978; WD40 repeat-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cytoplasm; Disease variant; KW Lipid-binding; Neurodegeneration; Proteomics identification; KW Reference proteome; Repeat; WD repeat. FT CHAIN 1..360 FT /note="WD repeat domain phosphoinositide-interacting FT protein 4" FT /id="PRO_0000051452" FT REPEAT 1..34 FT /note="WD 1" FT REPEAT 40..84 FT /note="WD 2" FT REPEAT 92..128 FT /note="WD 3" FT REPEAT 133..174 FT /note="WD 4" FT REPEAT 183..222 FT /note="WD 5" FT REPEAT 227..266 FT /note="WD 6" FT REPEAT 284..329 FT /note="WD 7" FT MOTIF 231..234 FT /note="L/FRRG motif" FT /evidence="ECO:0000250|UniProtKB:Q9Y4P8" FT VAR_SEQ 78 FT /note="S -> SA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_016975" FT VAR_SEQ 145 FT /note="K -> KAAHPTPHLHTL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_016976" FT VARIANT 7..360 FT /note="Missing (in NBIA5)" FT /evidence="ECO:0000269|PubMed:25356899" FT /id="VAR_078645" FT VARIANT 208 FT /note="A -> D (in NBIA5; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25592411" FT /id="VAR_080430" FT MUTAGEN 15 FT /note="N->A: Decreased interaction with ATG2A. Loss of FT interaction with ATG2A; when associated with A-17." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 16 FT /note="Q->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 17 FT /note="D->A: Decreased interaction with ATG2A. Loss of FT interaction with ATG2A; when associated with A-15." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 55 FT /note="E->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 109 FT /note="R->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 111 FT /note="R->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 112 FT /note="H->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 113 FT /note="D->A: Loss of interaction with AMPK. No effect on FT interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 114 FT /note="K->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 232..233 FT /note="RR->AA: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT CONFLICT 217 FT /note="I -> T (in Ref. 3; CAG33006)" FT /evidence="ECO:0000305" FT CONFLICT 300..302 FT /note="FTV -> YTA (in Ref. 1; AAV80764)" FT /evidence="ECO:0000305" FT HELIX 6..8 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 9..14 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 18..25 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 28..33 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 34..37 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 38..43 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 45..48 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 49..56 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 60..74 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 78..83 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 91..94 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 95..100 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 105..111 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 114..127 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 134..139 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 158..162 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 168..173 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 174..176 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 186..189 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 195..200 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 204..211 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 215..221 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 222..224 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 227..232 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 240..245 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 249..256 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 257..259 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 260..268 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 269..271 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 272..274 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 276..278 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 288..291 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 297..301 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 308..312 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 320..327 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 330..337 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 343..350 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 351..353 FT /evidence="ECO:0007829|PDB:8KBX" SQ SEQUENCE 360 AA; 39868 MW; E1A6746277182AF9 CRC64; MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS NLLALVGGGS SPKFSEISVL IWDDAREGKD SKEKLVLEFT FTKPVLSVRM RHDKIVIVLK NRIYVYSFPD NPRKLFEFDT RDNPKGLCDL CPSLEKQLLV FPGHKCGSLQ LVDLASTKPG TSSAPFTINA HQSDIACVSL NQPGTVVASA SQKGTLIRLF DTQSKEKLVE LRRGTDPATL YCINFSHDSS FLCASSDKGT VHIFALKDTR LNRRSALARV GKVGPMIGQY VDSQWSLASF TVPAESACIC AFGRNTSKNV NSVIAICVDG TFHKYVFTPD GNCNREAFDV YLDICDDDDF //