ID ACBD6_HUMAN Reviewed; 282 AA. AC Q9BR61; DT 18-APR-2006, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 182. DE RecName: Full=Acyl-CoA-binding domain-containing protein 6; GN Name=ACBD6; 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=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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=18268358; DOI=10.1194/jlr.m800007-jlr200; RA Soupene E., Serikov V., Kuypers F.A.; RT "Characterization of an acyl-coenzyme A binding protein predominantly RT expressed in human primitive progenitor cells."; RL J. Lipid Res. 49:1103-1112(2008). RN [4] 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 [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-106, 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 [6] 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 [7] 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 [8] RP INVOLVEMENT IN NEDPM. RX PubMed=36457943; DOI=10.1212/nxg.0000000000200046; RA Yeetong P., Tanpowpong N., Rakwongkhachon S., Suphapeetiporn K., RA Shotelersuk V.; RT "Neurodevelopmental Disorder, Obesity, Pancytopenia, Diabetes Mellitus, RT Cirrhosis, and Renal Failure in ACBD6-Associated Syndrome: A Case Report."; RL Neurol. Genet. 9:e200046-e200046(2023). RN [9] RP STRUCTURE BY NMR OF 42-137. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of RSGI RUH-040, an ACBP domain from human cDNA."; RL Submitted (NOV-2005) to the PDB data bank. RN [10] RP VARIANTS NEDPM 54-GLN--ALA-282 DEL; 63-GLU--ALA-282 DEL; 72-TYR--ALA-282 RP DEL; 73-LYS--ALA-282 DEL; 94-GLN--ALA-282 DEL; 180-SER--ALA-282 DEL; RP 198-TRP--ALA-282 DEL; GLY-201; ASN-219 INS AND 254-ARG--ALA-282 DEL, RP INVOLVEMENT IN NEDPM, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=37951597; DOI=10.1093/brain/awad380; RA Kaiyrzhanov R., Rad A., Lin S.J., Bertoli-Avella A., Kallemeijn W.W., RA Godwin A., Zaki M.S., Huang K., Lau T., Petree C., Efthymiou S., RA Karimiani E.G., Hempel M., Normand E.A., Rudnik-Schoeneborn S., RA Schatz U.A., Baggelaar M.P., Ilyas M., Sultan T., Alvi J.R., Ganieva M., RA Fowler B., Aanicai R., Tayfun G.A., Al Saman A., Alswaid A., Amiri N., RA Asilova N., Shotelersuk V., Yeetong P., Azam M., Babaei M., Monajemi G.B., RA Mohammadi P., Samie S., Banu S.H., Pinto Basto J., Kortuem F., Bauer M., RA Bauer P., Beetz C., Garshasbi M., Issa A.H., Eyaid W., Ahmed H., RA Hashemi N., Hassanpour K., Herman I., Ibrohimov S., Abdul-Majeed B.A., RA Imdad M., Isrofilov M., Kaiyal Q., Khan S., Kirmse B., Koster J., RA Lourenco C.M., Mitani T., Moldovan O., Murphy D., Najafi M., Pehlivan D., RA Rocha M.E., Salpietro V., Schmidts M., Shalata A., Mahroum M., RA Talbeya J.K., Taylor R.W., Vazquez D., Vetro A., Waterham H.R., Zaman M., RA Schrader T.A., Chung W.K., Guerrini R., Lupski J.R., Gleeson J., Suri M., RA Jamshidi Y., Bhatia K.P., Vona B., Schrader M., Severino M., Guille M., RA Tate E.W., Varshney G.K., Houlden H., Maroofian R.; RT "Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with RT progressive and complex movement disorders."; RL Brain 147:1436-1456(2024). CC -!- FUNCTION: Binds long-chain acyl-coenzyme A molecules with a strong CC preference for unsaturated C18:1-CoA, lower affinity for unsaturated CC C20:4-CoA, and very weak affinity for saturated C16:0-CoA. Does not CC bind fatty acids. Plays a role in protein N-myristoylation CC (PubMed:37951597). {ECO:0000269|PubMed:18268358, CC ECO:0000269|PubMed:37951597}. CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:18268358}. CC -!- INTERACTION: CC Q9BR61; P30419: NMT1; NbExp=7; IntAct=EBI-2848793, EBI-5280164; CC Q9BR61; O60551: NMT2; NbExp=18; IntAct=EBI-2848793, EBI-3920273; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18268358, CC ECO:0000269|PubMed:37951597}. Nucleus {ECO:0000269|PubMed:37951597}. CC -!- TISSUE SPECIFICITY: Detected in placenta and spleen (at protein level). CC Detected in placenta, umbilical cord blood, CD34-positive hematopoietic CC progenitor cells and bone marrow. {ECO:0000269|PubMed:18268358}. CC -!- DISEASE: Neurodevelopmental disorder with progressive movement CC abnormalities (NEDPM) [MIM:620785]: An autosomal recessive, progressive CC disorder characterized by global developmental delay, intellectual CC disability, significant expressive language impairment, behavioral CC abnormalities, and movement disorders including dystonia, spasticity CC and cerebellar ataxia associated with gait impairment. Additional CC features include facial dysmorphism, oculomotor anomalies, CC microcephaly, seizures and brain imaging abnormalities. Parkinsonism CC may develop in older patients. {ECO:0000269|PubMed:36457943, CC ECO:0000269|PubMed:37951597}. Note=The disease is caused by variants CC affecting the gene represented in this entry. 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; AL445469; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL139141; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL358354; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC006505; AAH06505.1; -; mRNA. DR CCDS; CCDS1339.1; -. DR RefSeq; NP_115736.1; NM_032360.4. DR RefSeq; XP_047288036.1; XM_047432080.1. DR RefSeq; XP_047288037.1; XM_047432081.1. DR RefSeq; XP_047288038.1; XM_047432082.1. DR RefSeq; XP_047288039.1; XM_047432083.1. DR RefSeq; XP_047288040.1; XM_047432084.1. DR RefSeq; XP_047288041.1; XM_047432085.1. DR RefSeq; XP_054195160.1; XM_054339185.1. DR RefSeq; XP_054195161.1; XM_054339186.1. DR RefSeq; XP_054195162.1; XM_054339187.1. DR RefSeq; XP_054195163.1; XM_054339188.1. DR RefSeq; XP_054195164.1; XM_054339189.1. DR RefSeq; XP_054195165.1; XM_054339190.1. DR PDB; 2COP; NMR; -; A=42-137. DR PDBsum; 2COP; -. DR AlphaFoldDB; Q9BR61; -. DR SMR; Q9BR61; -. DR BioGRID; 124046; 20. DR FunCoup; Q9BR61; 1398. DR IntAct; Q9BR61; 20. DR STRING; 9606.ENSP00000495710; -. DR iPTMnet; Q9BR61; -. DR MetOSite; Q9BR61; -. DR PhosphoSitePlus; Q9BR61; -. DR BioMuta; ACBD6; -. DR DMDM; 74762703; -. DR jPOST; Q9BR61; -. DR MassIVE; Q9BR61; -. DR PaxDb; 9606-ENSP00000356567; -. DR PeptideAtlas; Q9BR61; -. DR ProteomicsDB; 78745; -. DR Pumba; Q9BR61; -. DR Antibodypedia; 72484; 198 antibodies from 28 providers. DR DNASU; 84320; -. DR Ensembl; ENST00000367595.4; ENSP00000356567.3; ENSG00000230124.9. DR Ensembl; ENST00000642319.1; ENSP00000495710.1; ENSG00000230124.9. DR GeneID; 84320; -. DR KEGG; hsa:84320; -. DR MANE-Select; ENST00000367595.4; ENSP00000356567.3; NM_032360.4; NP_115736.1. DR UCSC; uc001gog.4; human. DR AGR; HGNC:23339; -. DR ClinPGx; PA134925459; -. DR CTD; 84320; -. DR DisGeNET; 84320; -. DR GeneCards; ACBD6; -. DR HGNC; HGNC:23339; ACBD6. DR HPA; ENSG00000230124; Low tissue specificity. DR MalaCards; ACBD6; -. DR MIM; 616352; gene. DR MIM; 620785; phenotype. DR OpenTargets; ENSG00000230124; -. DR VEuPathDB; HostDB:ENSG00000230124; -. DR eggNOG; KOG0817; Eukaryota. DR GeneTree; ENSGT00940000157458; -. DR HOGENOM; CLU_050309_1_0_1; -. DR InParanoid; Q9BR61; -. DR OMA; ARSKWQA; -. DR OrthoDB; 10254927at2759; -. DR PAN-GO; Q9BR61; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q9BR61; -. DR PathwayCommons; Q9BR61; -. DR Reactome; R-HSA-77289; Mitochondrial Fatty Acid Beta-Oxidation. DR SignaLink; Q9BR61; -. DR Agora; ENSG00000230124; -. DR BioGRID-ORCS; 84320; 15 hits in 1158 CRISPR screens. DR ChiTaRS; ACBD6; human. DR EvolutionaryTrace; Q9BR61; -. DR GenomeRNAi; 84320; -. DR Pharos; Q9BR61; Tbio. DR PRO; PR:Q9BR61; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9BR61; protein. DR Bgee; ENSG00000230124; Expressed in cortical plate and 162 other cell types or tissues. DR ExpressionAtlas; Q9BR61; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000062; F:fatty-acyl-CoA binding; IMP:UniProtKB. DR GO; GO:0008289; F:lipid binding; IMP:UniProtKB. DR FunFam; 1.20.80.10:FF:000022; acyl-CoA-binding domain-containing protein 6 isoform X1; 1. DR FunFam; 1.25.40.20:FF:000252; acyl-CoA-binding domain-containing protein 6 isoform X2; 1. DR Gene3D; 1.20.80.10; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 2. DR InterPro; IPR000582; Acyl-CoA-binding_protein. DR InterPro; IPR035984; Acyl-CoA-binding_sf. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_sf. DR PANTHER; PTHR24119; ACYL-COA-BINDING DOMAIN-CONTAINING PROTEIN 6; 1. DR PANTHER; PTHR24119:SF0; ACYL-COA-BINDING DOMAIN-CONTAINING PROTEIN 6; 1. DR Pfam; PF00887; ACBP; 1. DR Pfam; PF12796; Ank_2; 1. DR PRINTS; PR00689; ACOABINDINGP. DR PRINTS; PR01415; ANKYRIN. DR SMART; SM00248; ANK; 2. DR SUPFAM; SSF47027; Acyl-CoA binding protein; 1. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS51228; ACB_2; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 2. PE 1: Evidence at protein level; KW 3D-structure; ANK repeat; Autism spectrum disorder; Cytoplasm; KW Disease variant; Dystonia; Intellectual disability; Lipid-binding; Nucleus; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat. FT CHAIN 1..282 FT /note="Acyl-CoA-binding domain-containing protein 6" FT /id="PRO_0000232879" FT DOMAIN 42..127 FT /note="ACB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00573" FT REPEAT 191..220 FT /note="ANK 1" FT REPEAT 224..253 FT /note="ANK 2" FT REGION 1..31 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 69..73 FT /ligand="an acyl-CoA" FT /ligand_id="ChEBI:CHEBI:58342" FT /evidence="ECO:0000250" FT BINDING 95 FT /ligand="an acyl-CoA" FT /ligand_id="ChEBI:CHEBI:58342" FT /evidence="ECO:0000250" FT BINDING 114 FT /ligand="an acyl-CoA" FT /ligand_id="ChEBI:CHEBI:58342" FT /evidence="ECO:0000250" FT MOD_RES 106 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT VARIANT 54..282 FT /note="Missing (in NEDPM; pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089637" FT VARIANT 63..282 FT /note="Missing (in NEDPM; pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089638" FT VARIANT 72..282 FT /note="Missing (in NEDPM; pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089639" FT VARIANT 73..282 FT /note="Missing (in NEDPM; pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089640" FT VARIANT 94..282 FT /note="Missing (in NEDPM; pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089641" FT VARIANT 180..282 FT /note="Missing (in NEDPM; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089642" FT VARIANT 198..282 FT /note="Missing (in NEDPM; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089643" FT VARIANT 201 FT /note="D -> G (in NEDPM; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089644" FT VARIANT 219 FT /note="N -> NN (in NEDPM; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089645" FT VARIANT 254..282 FT /note="Missing (in NEDPM; uncertain significance)" FT /evidence="ECO:0000269|PubMed:37951597" FT /id="VAR_089646" FT HELIX 43..53 FT /evidence="ECO:0007829|PDB:2COP" FT TURN 57..59 FT /evidence="ECO:0007829|PDB:2COP" FT HELIX 62..76 FT /evidence="ECO:0007829|PDB:2COP" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:2COP" FT HELIX 107..121 FT /evidence="ECO:0007829|PDB:2COP" SQ SEQUENCE 282 AA; 31151 MW; 0EA01CFDB5C5ECB2 CRC64; MASSFLPAGA ITGDSGGELS SGDDSGEVEF PHSPEIEETS CLAELFEKAA AHLQGLIQVA SREQLLYLYA RYKQVKVGNC NTPKPSFFDF EGKQKWEAWK ALGDSSPSQA MQEYIAVVKK LDPGWNPQIP EKKGKEANTG FGGPVISSLY HEETIREEDK NIFDYCRENN IDHITKAIKS KNVDVNVKDE EGRALLHWAC DRGHKELVTV LLQHRADINC QDNEGQTALH YASACEFLDI VELLLQSGAD PTLRDQDGCL PEEVTGCKTV SLVLQRHTTG KA // 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 CNR1_HUMAN Reviewed; 472 AA. AC P21554; B2R9T4; E1P512; Q13949; Q495Z0; Q4PLI4; Q4VBM6; Q5JVL5; Q5UB37; AC Q9UNN0; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 1. DT 28-JAN-2026, entry version 234. DE RecName: Full=Cannabinoid receptor 1; DE Short=CB-R; DE Short=CB1; DE AltName: Full=CANN6; GN Name=CNR1; Synonyms=CNR; 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). RC TISSUE=Brain stem; RX PubMed=2263478; DOI=10.1093/nar/18.23.7142; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Nucleotide sequence of a human cannabinoid receptor cDNA."; RL Nucleic Acids Res. 18:7142-7142(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RC TISSUE=Brain stem; RX PubMed=1718258; DOI=10.1042/bj2790129; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Molecular cloning of a human cannabinoid receptor which is also expressed RT in testis."; RL Biochem. J. 279:129-134(1991). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lung; RX PubMed=7876112; DOI=10.1074/jbc.270.8.3726; RA Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M., RA Le Fur G., Caput D., Ferrara P.; RT "An amino-terminal variant of the central cannabinoid receptor resulting RT from alternative splicing."; RL J. Biol. Chem. 270:3726-3731(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION (ISOFORMS 1; 2 AND 3), AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=15620723; DOI=10.1016/j.febslet.2004.11.085; RA Ryberg E., Vu H.K., Larsson N., Groblewski T., Hjorth S., Elebring T., RA Sjoegren S., Greasley P.J.; RT "Identification and characterisation of a novel splice variant of the human RT CB1 receptor."; RL FEBS Lett. 579:259-264(2005). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RA Kathmann M., Schlicker E.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Bonner T.I.; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain tumor; RA Kumar S., Gupta S., Sharma G.; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; 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 [10] 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 [11] 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 [12] 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 [13] RP REVIEW ON INVOLVEMENT IN NERVOUS SYSTEM DISORDERS. RX PubMed=32549916; DOI=10.1007/s13167-020-00203-4; RA Reddy V., Grogan D., Ahluwalia M., Salles E.L., Ahluwalia P., Khodadadi H., RA Alverson K., Nguyen A., Raju S.P., Gaur P., Braun M., Vale F.L., RA Costigliola V., Dhandapani K., Baban B., Vaibhav K.; RT "Targeting the endocannabinoid system: a predictive, preventive, and RT personalized medicine-directed approach to the management of brain RT pathologies."; RL EPMA J. 11:217-250(2020). RN [14] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=8255419; DOI=10.1016/0306-4522(93)90352-g; RA Glass M., Faull R.L., Dragunow M.; RT "Loss of cannabinoid receptors in the substantia nigra in Huntington's RT disease."; RL Neuroscience 56:523-527(1993). RN [15] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=10828533; DOI=10.1016/s0306-4522(00)00008-7; RA Glass M., Dragunow M., Faull R.L.; RT "The pattern of neurodegeneration in Huntington's disease: a comparative RT study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations RT in the human basal ganglia in Huntington's disease."; RL Neuroscience 97:505-519(2000). RN [16] RP FUNCTION, AND INTERACTION WITH CNRIP1. RC TISSUE=Brain; RX PubMed=17895407; DOI=10.1124/mol.107.039263; RA Niehaus J.L., Liu Y., Wallis K.T., Egertova M., Bhartur S.G., RA Mukhopadhyay S., Shi S., He H., Selley D.E., Howlett A.C., Elphick M.R., RA Lewis D.L.; RT "CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor RT interacting protein CRIP 1a."; RL Mol. Pharmacol. 72:1557-1566(2007). RN [17] RP ACTIVITY REGULATION. RX PubMed=18077343; DOI=10.1073/pnas.0706980105; RA Heimann A.S., Gomes I., Dale C.S., Pagano R.L., Gupta A., de Souza L.L., RA Luchessi A.D., Castro L.M., Giorgi R., Rioli V., Ferro E.S., Devi L.A.; RT "Hemopressin is an inverse agonist of CB1 cannabinoid receptors."; RL Proc. Natl. Acad. Sci. U.S.A. 104:20588-20593(2007). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-415, AND MUTAGENESIS RP OF CYS-415. RX PubMed=21895628; DOI=10.1111/j.1476-5381.2011.01658.x; RA Oddi S., Dainese E., Sandiford S., Fezza F., Lanuti M., Chiurchiu V., RA Totaro A., Catanzaro G., Barcaroli D., De Laurenzi V., Centonze D., RA Mukhopadhyay S., Selent J., Howlett A.C., Maccarrone M.; RT "Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid RT receptor on membrane localization and signalling."; RL Br. J. Pharmacol. 165:2635-2651(2012). RN [19] RP INVOLVEMENT IN OBESITY. RX PubMed=18177726; DOI=10.1016/j.cmet.2007.11.012; RA Addy C., Wright H., Van Laere K., Gantz I., Erondu N., Musser B.J., Lu K., RA Yuan J., Sanabria-Bohorquez S.M., Stoch A., Stevens C., Fong T.M., RA De Lepeleire I., Cilissen C., Cote J., Rosko K., Gendrano I.N. III, RA Nguyen A.M., Gumbiner B., Rothenberg P., de Hoon J., Bormans G., Depre M., RA Eng W.S., Ravussin E., Klein S., Blundell J., Herman G.A., Burns H.D., RA Hargreaves R.J., Wagner J., Gottesdiener K., Amatruda J.M., RA Heymsfield S.B.; RT "The acyclic CB1R inverse agonist taranabant mediates weight loss by RT increasing energy expenditure and decreasing caloric intake."; RL Cell Metab. 7:68-78(2008). RN [20] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=19524019; DOI=10.1016/j.neuroscience.2009.06.014; RA Dowie M.J., Bradshaw H.B., Howard M.L., Nicholson L.F., Faull R.L., RA Hannan A.J., Glass M.; RT "Altered CB1 receptor and endocannabinoid levels precede motor symptom RT onset in a transgenic mouse model of Huntington's disease."; RL Neuroscience 163:456-465(2009). RN [21] RP FUNCTION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE. RX PubMed=23955712; DOI=10.1038/nm.3265; RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J., RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P., RA Kunos G.; RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by RT endocannabinoids mediates beta cell loss in type 2 diabetes."; RL Nat. Med. 19:1132-1140(2013). RN [22] RP INVOLVEMENT IN ALZHEIMER DISEASE. RX PubMed=30096288; DOI=10.1016/j.bcp.2018.08.007; RA Aso E., Andres-Benito P., Ferrer I.; RT "Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer- RT like symptoms in a transgenic animal model."; RL Biochem. Pharmacol. 157:210-216(2018). RN [23] RP INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=31342135; DOI=10.1007/s00259-019-04445-x; RA Ceccarini J., Casteels C., Ahmad R., Crabbe M., Van de Vliet L., RA Vanhaute H., Vandenbulcke M., Vandenberghe W., Van Laere K.; RT "Regional changes in the type 1 cannabinoid receptor are associated with RT cognitive dysfunction in Parkinson's disease."; RL Eur. J. Nucl. Med. Mol. Imaging 46:2348-2357(2019). RN [24] RP STRUCTURE BY NMR OF 338-346, INTERACTION WITH GNAI1, AND MUTAGENESIS OF RP 341-LEU-ALA-342. RX PubMed=12237474; DOI=10.1110/ps.0218402; RA Ulfers A.L., McMurry J.L., Miller A., Wang L., Kendall D.A., Mierke D.F.; RT "Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures RT of IC3 and a mutant with altered G protein specificity."; RL Protein Sci. 11:2526-2531(2002). RN [25] {ECO:0007744|PDB:5TGZ} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 99-306 AND 332-414, FUNCTION, AND RP TOPOLOGY. RX PubMed=27768894; DOI=10.1016/j.cell.2016.10.004; RA Hua T., Vemuri K., Pu M., Qu L., Han G.W., Wu Y., Zhao S., Shui W., Li S., RA Korde A., Laprairie R.B., Stahl E.L., Ho J.H., Zvonok N., Zhou H., RA Kufareva I., Wu B., Zhao Q., Hanson M.A., Bohn L.M., Makriyannis A., RA Stevens R.C., Liu Z.J.; RT "Crystal structure of the human cannabinoid receptor CB1."; RL Cell 167:750-762(2016). RN [26] {ECO:0007744|PDB:5U09} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-301 AND 334-421 IN COMPLEX RP WITH INVERSE AGONIST TARANABANT, MUTAGENESIS OF THR-210, TOPOLOGY, AND RP FUNCTION. RX PubMed=27851727; DOI=10.1038/nature20613; RA Shao Z., Yin J., Chapman K., Grzemska M., Clark L., Wang J., RA Rosenbaum D.M.; RT "High-resolution crystal structure of the human CB1 cannabinoid receptor."; RL Nature 540:602-606(2016). RN [27] {ECO:0007744|PDB:7FEE, ECO:0007744|PDB:7WV9} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 74-305 AND 333-414, INTERACTION RP WITH GNAI2, FUNCTION, AND MUTAGENESIS OF PHE-155. RX PubMed=35637350; DOI=10.1038/s41589-022-01038-y; RA Yang X., Wang X., Xu Z., Wu C., Zhou Y., Wang Y., Lin G., Li K., Wu M., RA Xia A., Liu J., Cheng L., Zou J., Yan W., Shao Z., Yang S.; RT "Molecular mechanism of allosteric modulation for the cannabinoid receptor RT CB1."; RL Nat. Chem. Biol. 18:831-840(2022). CC -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids CC (eCBs), including N-arachidonoylethanolamide (also called anandamide or CC AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, CC such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, CC PubMed:27768894, PubMed:27851727, PubMed:35637350). Mediates many CC cannabinoid-induced effects, acting, among others, on food intake, CC memory loss, gastrointestinal motility, catalepsy, ambulatory activity, CC anxiety, chronic pain. Signaling typically involves reduction in cyclic CC AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the CC hypothalamus, may have a dual effect on mitochondrial respiration CC depending upon the agonist dose and possibly upon the cell type. CC Increases respiration at low doses, while decreases respiration at high CC doses. At high doses, CNR1 signal transduction involves G-protein CC alpha-i protein activation and subsequent inhibition of mitochondrial CC soluble adenylate cyclase, decrease in cyclic AMP concentration, CC inhibition of protein kinase A (PKA)-dependent phosphorylation of CC specific subunits of the mitochondrial electron transport system, CC including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive CC oxygen species (ROS) formation and mediates cannabinoid-induced CC increase in SREBF1 and FASN gene expression. In response to CC cannabinoids, drives the release of orexigenic beta-endorphin, but not CC that of melanocyte-stimulating hormone alpha/alpha-MSH, from CC hypothalamic POMC neurons, hence promoting food intake. In the CC hippocampus, regulates cellular respiration and energy production in CC response to cannabinoids. Involved in cannabinoid-dependent CC depolarization-induced suppression of inhibition (DSI), a process in CC which depolarization of CA1 postsynaptic pyramidal neurons mobilizes CC eCBs, which retrogradely activate presynaptic CB1 receptors, CC transiently decreasing GABAergic inhibitory neurotransmission. Also CC reduces excitatory synaptic transmission (By similarity). In superior CC cervical ganglions and cerebral vascular smooth muscle cells, inhibits CC voltage-gated Ca(2+) channels in a constitutive, as well as agonist- CC dependent manner (PubMed:17895407). In cerebral vascular smooth muscle CC cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels CC leads to vasodilation and decreased vascular tone (By similarity). CC Induces leptin production in adipocytes and reduces LRP2-mediated CC leptin clearance in the kidney, hence participating in hyperleptinemia. CC In adipose tissue, CNR1 signaling leads to increased expression of CC SREBF1, ACACA and FASN genes (By similarity). In the liver, activation CC by endocannabinoids leads to increased de novo lipogenesis and reduced CC fatty acid catabolism, associated with increased expression of CC SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de CC novo cholesterol synthesis and HDL-cholesteryl ether uptake. CC Peripherally modulates energy metabolism (By similarity). In high CC carbohydrate diet-induced obesity, may decrease the expression of CC mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as CC well as that of selected glucose/ pyruvate metabolic enzymes, hence CC affecting energy expenditure through mitochondrial metabolism (By CC similarity). In response to cannabinoid anandamide, elicits a pro- CC inflammatory response in macrophages, which involves NLRP3 inflammasome CC activation and IL1B and IL18 secretion (By similarity). In macrophages CC infiltrating pancreatic islets, this process may participate in the CC progression of type-2 diabetes and associated loss of pancreatic beta- CC cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777, CC ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723, CC ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712, CC ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727, CC ECO:0000269|PubMed:35637350}. CC -!- FUNCTION: [Isoform 1]: Binds both 2-arachidonoylglycerol (2-AG) and CC anandamide. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 2]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 2 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 3]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 3 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin CC subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: CC hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and CC subsequent signaling. {ECO:0000269|PubMed:18077343}. CC -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction CC attenuates constitutive, but not agonist-dependent, inhibition of CC voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates CC with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) CC alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation CC is important for interaction with GNAI3 and GNAO1 (PubMed:12237474). CC {ECO:0000269|PubMed:12237474, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:35637350}. CC -!- INTERACTION: CC P21554; P29274: ADORA2A; NbExp=8; IntAct=EBI-2909859, EBI-2902702; CC P21554; P21554: CNR1; NbExp=8; IntAct=EBI-2909859, EBI-2909859; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21895628}; CC Multi-pass membrane protein {ECO:0000269|PubMed:27768894, CC ECO:0000269|PubMed:27851727}. Membrane raft CC {ECO:0000269|PubMed:21895628}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:P47746}. Cell projection, axon CC {ECO:0000250|UniProtKB:P20272}. Presynapse CC {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria, CC the C-terminus is located in the mitochondrial intermembrane space, a CC compartment topologically considered as extracellular. In canonical CC seven-transmembrane G-protein coupled receptors, the C-terminus is CC cytosolic (By similarity). Found on presynaptic axon terminals in some CC GABAergic neurons in the somatosensory cortex (By similarity). CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=P21554-1; Sequence=Displayed; CC Name=2; Synonyms=CB1a {ECO:0000303|PubMed:15620723}, Short; CC IsoId=P21554-2; Sequence=VSP_001868; CC Name=3; Synonyms=CB1b {ECO:0000303|PubMed:15620723}; CC IsoId=P21554-3; Sequence=VSP_016529; CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in fetal and CC adult brain. Expression levels of isoform 2 and isoform 3 are much CC lower than those of isoform 1. {ECO:0000269|PubMed:15620723}. CC -!- INDUCTION: Up-regulated by endocannabinoid anandamide. CC {ECO:0000269|PubMed:23955712}. CC -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma CC membrane and lipid rafts and association with G protein alpha subunits. CC {ECO:0000269|PubMed:21895628}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in CC this entry may be involved in disease pathogenesis. May contribute to CC the development of diet-induced obesity and several obesity-associated CC features, such as dyslipidemia and liver steatosis, regulating CC peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 CC inverse agonists have been shown to reduce body weight and improve CC metabolic abnormalities in obese subjects, although adverse CC neuropsychiatric effects, including anxiety, irritability, and CC depressed mood, halted their therapeutic development (PubMed:18177726). CC In obese mice, peripherally restricted CNR1 inverse agonists have been CC shown to normalize metabolic abnormalities, including insulin CC resistance and fatty liver, and to reverse leptin resistance. CC {ECO:0000269|PubMed:18177726}. CC -!- DISEASE: Note=Dysfunction of the endogenous cannabinoid system CC including CNR1 has been implicated in the pathogenesis of a number of CC central nervous system disorders, including Huntington disease, CC Parkinson disease, and Alzheimer disease (PubMed:32549916). In post- CC mortem brains from Huntington disease patients, a progressive CNR1 loss CC has been observed in the caudate nucleus, putamen, and substantia nigra CC pars reticulata, and altered expression and abnormal endocannabinoid CC levels precede motor symptoms in a disease mouse model CC (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson CC disease, low CNR1 expression in mid-superior frontal gyrus and mid- CC cingulate cortex has been associated with poor mind, poor executive CC functioning and poor episode memory, while patients with more severe CC visuospatial dysfunction showed decreased receptor availability in the CC precuneus, mid-cingulate, supplementary motor cortex, inferior CC orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model CC for Alzheimer disease, CNR1 heterozygous deletion has been associated CC with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) CC and accelerated memory impairment, suggesting synaptic dysfunction and CC a crucial role for CNR1 in the progression of disease symptoms CC (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, CC PubMed:8255419). {ECO:0000269|PubMed:10828533, CC ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288, CC ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916, CC ECO:0000269|PubMed:8255419}. CC -!- MISCELLANEOUS: High-fat diet also increases the hepatic levels of CNR1 CC ligand anandamide, but not that of 2-arachidonoylglycerol. CC {ECO:0000250|UniProtKB:P47746}. CC -!- MISCELLANEOUS: [Isoform 2]: Dubious isoform. A putative downstream CC initiation AUG is used to produce isoform 2 (PubMed:1718258). The use CC of the first AUG (same as isoform 1) gives a truncated protein of 36 CC AA. {ECO:0000305|PubMed:1718258}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. 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; X54937; CAA38699.1; -; mRNA. DR EMBL; X81120; CAA57018.1; -; mRNA. DR EMBL; X81121; CAA57019.1; -; mRNA. DR EMBL; AY766182; AAV35030.1; -; mRNA. DR EMBL; AF107262; AAD34320.1; -; mRNA. DR EMBL; U73304; AAB18200.1; -; Genomic_DNA. DR EMBL; DQ067455; AAY68486.1; -; mRNA. DR EMBL; AY225225; AAO67710.1; -; Genomic_DNA. DR EMBL; AL136096; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK313908; BAG36631.1; -; mRNA. DR EMBL; CH471051; EAW48574.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48575.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48576.1; -; Genomic_DNA. DR EMBL; BC074811; AAH74811.1; -; mRNA. DR EMBL; BC074812; AAH74812.1; -; mRNA. DR EMBL; BC095513; AAH95513.1; -; mRNA. DR EMBL; BC100968; AAI00969.1; -; mRNA. DR EMBL; BC100969; AAI00970.1; -; mRNA. DR EMBL; BC100970; AAI00971.1; -; mRNA. DR EMBL; BC100971; AAI00972.1; -; mRNA. DR CCDS; CCDS5015.1; -. [P21554-1] DR CCDS; CCDS5016.2; -. [P21554-3] DR PIR; S17595; S17595. DR RefSeq; NP_001153698.1; NM_001160226.3. [P21554-1] DR RefSeq; NP_001153730.1; NM_001160258.3. [P21554-1] DR RefSeq; NP_001153731.1; NM_001160259.3. [P21554-1] DR RefSeq; NP_001352798.1; NM_001365869.2. [P21554-1] DR RefSeq; NP_001352799.1; NM_001365870.2. [P21554-1] DR RefSeq; NP_001352801.1; NM_001365872.2. [P21554-1] DR RefSeq; NP_001352803.1; NM_001365874.3. [P21554-1] DR RefSeq; NP_001357474.1; NM_001370545.1. [P21554-1] DR RefSeq; NP_001357475.1; NM_001370546.1. [P21554-1] DR RefSeq; NP_001357476.1; NM_001370547.1. [P21554-1] DR RefSeq; NP_001411023.1; NM_001424094.1. [P21554-1] DR RefSeq; NP_001411024.1; NM_001424095.1. [P21554-1] DR RefSeq; NP_001411025.1; NM_001424096.1. [P21554-1] DR RefSeq; NP_001411026.1; NM_001424097.1. [P21554-1] DR RefSeq; NP_001411027.1; NM_001424098.1. [P21554-1] DR RefSeq; NP_057167.2; NM_016083.4. [P21554-1] DR RefSeq; NP_149421.2; NM_033181.4. [P21554-3] DR RefSeq; XP_047274127.1; XM_047418171.1. [P21554-1] DR RefSeq; XP_047274128.1; XM_047418172.1. [P21554-1] DR RefSeq; XP_047274129.1; XM_047418173.1. [P21554-1] DR RefSeq; XP_054210179.1; XM_054354204.1. [P21554-1] DR RefSeq; XP_054210180.1; XM_054354205.1. [P21554-1] DR RefSeq; XP_054210181.1; XM_054354206.1. [P21554-1] DR PDB; 1LVQ; NMR; -; A=338-346. DR PDB; 1LVR; NMR; -; A=338-346. DR PDB; 2B0Y; NMR; -; A=400-414. DR PDB; 2KOE; NMR; -; A=377-414. DR PDB; 2MZ2; NMR; -; A=400-414. DR PDB; 2MZ3; NMR; -; A=400-414. DR PDB; 2MZA; NMR; -; A=400-414. DR PDB; 5TGZ; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 5U09; X-ray; 2.60 A; A=90-301, A=333-421. DR PDB; 5XR8; X-ray; 2.95 A; A=99-306, A=332-414. DR PDB; 5XRA; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 6KPG; EM; 3.00 A; R=71-425. DR PDB; 6KQI; X-ray; 3.25 A; A=94-301, A=334-413. DR PDB; 6N4B; EM; 3.00 A; R=1-472. DR PDB; 7FEE; X-ray; 2.70 A; A=74-305, A=333-414. DR PDB; 7V3Z; X-ray; 3.29 A; A=102-306, A=336-414. DR PDB; 7WV9; EM; 3.36 A; R=1-472. DR PDB; 8GAG; EM; 3.30 A; R=1-472. DR PDB; 8GHV; EM; 2.80 A; D=1-472. DR PDB; 8IKG; EM; 3.40 A; R=99-408. DR PDB; 8IKH; EM; 3.30 A; R=99-408. DR PDB; 8K8J; EM; 2.88 A; R=71-425. DR PDB; 8WRZ; EM; 3.60 A; R=71-432. DR PDB; 8WU1; EM; 3.20 A; R=1-413. DR PDB; 9B54; EM; 2.86 A; R=1-472. DR PDB; 9B65; EM; 3.03 A; R=1-472. DR PDB; 9B9Y; EM; 3.50 A; R=96-301, R=334-416. DR PDB; 9B9Z; EM; 3.30 A; R=96-301, R=334-416. DR PDB; 9BA0; EM; 3.13 A; R=96-301, R=334-416. DR PDB; 9DGI; EM; 3.35 A; R=1-472. DR PDB; 9EGO; EM; 3.20 A; R=1-472. DR PDB; 9ERX; EM; 2.90 A; R=2-472. DR PDBsum; 1LVQ; -. DR PDBsum; 1LVR; -. DR PDBsum; 2B0Y; -. DR PDBsum; 2KOE; -. DR PDBsum; 2MZ2; -. DR PDBsum; 2MZ3; -. DR PDBsum; 2MZA; -. DR PDBsum; 5TGZ; -. DR PDBsum; 5U09; -. DR PDBsum; 5XR8; -. DR PDBsum; 5XRA; -. DR PDBsum; 6KPG; -. DR PDBsum; 6KQI; -. DR PDBsum; 6N4B; -. DR PDBsum; 7FEE; -. DR PDBsum; 7V3Z; -. DR PDBsum; 7WV9; -. DR PDBsum; 8GAG; -. DR PDBsum; 8GHV; -. DR PDBsum; 8IKG; -. DR PDBsum; 8IKH; -. DR PDBsum; 8K8J; -. DR PDBsum; 8WRZ; -. DR PDBsum; 8WU1; -. DR PDBsum; 9B54; -. DR PDBsum; 9B65; -. DR PDBsum; 9B9Y; -. DR PDBsum; 9B9Z; -. DR PDBsum; 9BA0; -. DR PDBsum; 9DGI; -. DR PDBsum; 9EGO; -. DR PDBsum; 9ERX; -. DR AlphaFoldDB; P21554; -. DR EMDB; EMD-0339; -. DR EMDB; EMD-0745; -. DR EMDB; EMD-19929; -. DR EMDB; EMD-29898; -. DR EMDB; EMD-32850; -. DR EMDB; EMD-35511; -. DR EMDB; EMD-35512; -. DR EMDB; EMD-36951; -. DR EMDB; EMD-37795; -. DR EMDB; EMD-40052; -. DR EMDB; EMD-44199; -. DR EMDB; EMD-44247; -. DR EMDB; EMD-44392; -. DR EMDB; EMD-44393; -. DR EMDB; EMD-44394; -. DR EMDB; EMD-46828; -. DR EMDB; EMD-47992; -. DR SMR; P21554; -. DR BioGRID; 107668; 11. DR CORUM; P21554; -. DR DIP; DIP-61575N; -. DR FunCoup; P21554; 1275. DR IntAct; P21554; 12. DR STRING; 9606.ENSP00000358513; -. DR BindingDB; P21554; -. DR ChEMBL; CHEMBL218; -. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB14737; Cannabinol. DR DrugBank; DB05750; Drinabant. DR DrugBank; DB00470; Dronabinol. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB00486; Nabilone. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB16495; Oleic monoethanolamide. DR DrugBank; DB01083; Orlistat. DR DrugBank; DB11745; Otenabant. DR DrugBank; DB13495; Paraoxon. DR DrugBank; DB09288; Propacetamol. DR DrugBank; DB02955; Ricinoleic acid. DR DrugBank; DB06155; Rimonabant. DR DrugBank; DB05077; SLV319. DR DrugBank; DB13070; Surinabant. DR DrugBank; DB06624; Taranabant. DR DrugBank; DB11755; Tetrahydrocannabivarin. DR DrugBank; DB05201; V24343. DR DrugBank; DB13950; WIN 55212-2. DR DrugCentral; P21554; -. DR GuidetoPHARMACOLOGY; 56; -. DR SwissLipids; SLP:000001607; -. DR TCDB; 9.A.14.2.2; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P21554; 2 sites, No reported glycans. DR GlyGen; P21554; 2 sites. DR iPTMnet; P21554; -. DR PhosphoSitePlus; P21554; -. DR SwissPalm; P21554; -. DR BioMuta; CNR1; -. DR DMDM; 115562; -. DR MassIVE; P21554; -. DR PaxDb; 9606-ENSP00000358513; -. DR PeptideAtlas; P21554; -. DR ProteomicsDB; 53875; -. [P21554-1] DR ProteomicsDB; 53876; -. [P21554-2] DR ProteomicsDB; 53877; -. [P21554-3] DR ABCD; P21554; 62 sequenced antibodies. DR Antibodypedia; 3355; 718 antibodies from 42 providers. DR DNASU; 1268; -. DR Ensembl; ENST00000369499.3; ENSP00000358511.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000369501.3; ENSP00000358513.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000428600.3; ENSP00000412192.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000468898.2; ENSP00000420188.1; ENSG00000118432.14. [P21554-3] DR Ensembl; ENST00000549890.2; ENSP00000446819.1; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000551417.2; ENSP00000446702.2; ENSG00000118432.14. [P21554-1] DR GeneID; 1268; -. DR KEGG; hsa:1268; -. DR MANE-Select; ENST00000369501.3; ENSP00000358513.2; NM_016083.6; NP_057167.2. DR AGR; HGNC:2159; -. DR ClinPGx; PA26681; -. DR CTD; 1268; -. DR DisGeNET; 1268; -. DR GeneCards; CNR1; -. DR HGNC; HGNC:2159; CNR1. DR HPA; ENSG00000118432; Tissue enhanced (adipose tissue, pituitary gland). DR MIM; 114610; gene. DR MIM; 601665; phenotype. DR OpenTargets; ENSG00000118432; -. DR VEuPathDB; HostDB:ENSG00000118432; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01140000282530; -. DR HOGENOM; CLU_009579_7_0_1; -. DR InParanoid; P21554; -. DR OMA; HKHANSA; -. DR OrthoDB; 5966748at2759; -. DR PAN-GO; P21554; 6 GO annotations based on evolutionary models. DR PhylomeDB; P21554; -. DR PathwayCommons; P21554; -. DR Reactome; R-HSA-373076; Class A/1 (Rhodopsin-like receptors). DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR SignaLink; P21554; -. DR SIGNOR; P21554; -. DR Agora; ENSG00000118432; -. DR BioGRID-ORCS; 1268; 19 hits in 1157 CRISPR screens. DR ChiTaRS; CNR1; human. DR EvolutionaryTrace; P21554; -. DR GeneWiki; Cannabinoid_receptor_type_1; -. DR GenomeRNAi; 1268; -. DR Pharos; P21554; Tclin. DR PRO; PR:P21554; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P21554; protein. DR Bgee; ENSG00000118432; Expressed in ganglionic eminence and 150 other cell types or tissues. DR ExpressionAtlas; P21554; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0004949; F:cannabinoid receptor activity; IDA:UniProtKB. DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl. DR GO; GO:0038171; P:cannabinoid signaling pathway; IDA:UniProtKB. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc. DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl. DR GO; GO:0099509; P:regulation of presynaptic cytosolic calcium ion concentration; IEA:Ensembl. DR GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IEA:Ensembl. DR CDD; cd15340; 7tmA_CB1; 1. DR FunFam; 1.20.1070.10:FF:000072; Cannabinoid receptor 1; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000810; Canbinoid_rcpt_1. DR InterPro; IPR002230; Cnbnoid_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PIRSF; PIRSF037995; Cnoid_rcpt_1; 1. DR PRINTS; PR00522; CANABINOID1R. DR PRINTS; PR00362; CANNABINOIDR. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity; KW Palmitate; Phosphoprotein; Proteomics identification; Receptor; KW Reference proteome; Synapse; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..472 FT /note="Cannabinoid receptor 1" FT /id="PRO_0000069314" FT TOPO_DOM 1..116 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 117..142 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 143..154 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 155..175 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 176..187 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 188..212 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 213..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 233..255 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 256..273 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 274..299 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 300..344 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 345..365 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 366..377 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 378..399 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 400..472 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT REGION 2..23 FT /note="Required for mitochondrial localization" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 425 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 429 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT LIPID 415 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:21895628" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 83 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..89 FT /note="MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS FT FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF -> MALQIPPSAPSPLTSCTW FT AQMTFSTKTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7876112" FT /id="VSP_001868" FT VAR_SEQ 22..54 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15620723" FT /id="VSP_016529" FT MUTAGEN 155 FT /note="F->V: Enhanced G(i) signaling activation ability." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 155 FT /note="F->W: Reduced agonist-induced receptor activation." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 210 FT /note="T->A: 7-fold lower affinity for a synthetic agonist, FT CP55940, possibly due the stabilization of an inactive FT conformation." FT /evidence="ECO:0000269|PubMed:27851727" FT MUTAGEN 341..342 FT /note="LA->AL: Loss of activity, when assayed for GNAI1 FT GTPase stimulatory activity." FT /evidence="ECO:0000269|PubMed:12237474" FT MUTAGEN 415 FT /note="C->A: Loss of palmitoylation, marked loss of FT association with lipid rafts on the plasma membrane and FT loss of activity, when assayed for downstream GTP-binding FT and reduction in cAMP levels." FT /evidence="ECO:0000269|PubMed:21895628" FT CONFLICT 94 FT /note="E -> G (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="M -> I (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="C -> R (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 200 FT /note="F -> L (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 216 FT /note="I -> V (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 246 FT /note="V -> A (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="L -> P (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 332 FT /note="P -> S (in Ref. 12; AAI00972)" FT /evidence="ECO:0000305" FT STRAND 100..102 FT /evidence="ECO:0007829|PDB:7FEE" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 113..143 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 145..148 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 154..178 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 186..219 FT /evidence="ECO:0007829|PDB:5U09" FT TURN 221..223 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 230..249 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 250..253 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 257..260 FT /evidence="ECO:0007829|PDB:5U09" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 273..300 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 302..305 FT /evidence="ECO:0007829|PDB:6KPG" FT HELIX 306..309 FT /evidence="ECO:0007829|PDB:8K8J" FT HELIX 334..367 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 375..400 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 402..409 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 411..415 FT /evidence="ECO:0007829|PDB:2B0Y" SQ SEQUENCE 472 AA; 52858 MW; 1D2E49061D12ABF2 CRC64; MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL // ID CPLX1_HUMAN Reviewed; 134 AA. AC O14810; A6NI80; B2R4R5; D3DVN3; F1T0G1; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 28-JAN-2026, entry version 175. DE RecName: Full=Complexin-1; DE AltName: Full=Complexin I; DE Short=CPX I; DE AltName: Full=Synaphin-2; GN Name=CPLX1; 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]. RC TISSUE=Brain; RX PubMed=7553862; DOI=10.1016/0092-8674(95)90239-2; RA McMahon H.T., Missler M., Li C., Suedhof T.C.; RT "Complexins: cytosolic proteins that regulate SNAP receptor function."; RL Cell 83:111-119(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fetal brain; RX PubMed=24722188; DOI=10.1038/ncomms4650; RA Corominas R., Yang X., Lin G.N., Kang S., Shen Y., Ghamsari L., Broly M., RA Rodriguez M., Tam S., Wanamaker S.A., Fan C., Yi S., Tasan M., Lemmens I., RA Kuang X., Zhao N., Malhotra D., Michaelson J.J., Vacic V., Calderwood M.A., RA Roth F.P., Tavernier J., Horvath S., Salehi-Ashtiani K., Korkin D., RA Sebat J., Hill D.E., Hao T., Vidal M., Iakoucheva L.M.; RT "Protein interaction network of alternatively spliced isoforms from brain RT links genetic risk factors for autism."; RL Nat. Commun. 5:3650-3650(2014). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=21697133; DOI=10.1167/iovs.11-7479; RA Oshikawa M., Tsutsui C., Ikegami T., Fuchida Y., Matsubara M., Toyama S., RA Usami R., Ohtoko K., Kato S.; RT "Full-length transcriptome analysis of human retina-derived cell lines RT ARPE-19 and Y79 using the vector-capping method."; RL Invest. Ophthalmol. Vis. Sci. 52:6662-6670(2011). RN [5] 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 [6] 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 [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]. RC TISSUE=Eye; 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 TISSUE SPECIFICITY. RX PubMed=9853440; DOI=10.1016/s0140-6736(98)03341-8; RA Harrison P.J., Eastwood S.L.; RT "Preferential involvement of excitatory neurons in medial temporal lobe in RT schizophrenia."; RL Lancet 352:1669-1673(1998). RN [10] RP TISSUE SPECIFICITY. RX PubMed=11483314; DOI=10.1016/s0306-4522(01)00141-5; RA Eastwood S.L., Cotter D., Harrison P.J.; RT "Cerebellar synaptic protein expression in schizophrenia."; RL Neuroscience 105:219-229(2001). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=15526345; DOI=10.1002/pmic.200400848; RA Basso M., Giraudo S., Corpillo D., Bergamasco B., Lopiano L., Fasano M.; RT "Proteome analysis of human substantia nigra in Parkinson's disease."; RL Proteomics 4:3943-3952(2004). RN [12] RP INVOLVEMENT IN DEE63, AND VARIANT DEE63 108-GLU--LYS-134 DEL. RX PubMed=26539891; DOI=10.1016/j.neuron.2015.09.048; RA Karaca E., Harel T., Pehlivan D., Jhangiani S.N., Gambin T., RA Coban Akdemir Z., Gonzaga-Jauregui C., Erdin S., Bayram Y., Campbell I.M., RA Hunter J.V., Atik M.M., Van Esch H., Yuan B., Wiszniewski W., Isikay S., RA Yesil G., Yuregir O.O., Tug Bozdogan S., Aslan H., Aydin H., Tos T., RA Aksoy A., De Vivo D.C., Jain P., Geckinli B.B., Sezer O., Gul D., RA Durmaz B., Cogulu O., Ozkinay F., Topcu V., Candan S., Cebi A.H., Ikbal M., RA Yilmaz Gulec E., Gezdirici A., Koparir E., Ekici F., Coskun S., Cicek S., RA Karaer K., Koparir A., Duz M.B., Kirat E., Fenercioglu E., Ulucan H., RA Seven M., Guran T., Elcioglu N., Yildirim M.S., Aktas D., Alikasifoglu M., RA Ture M., Yakut T., Overton J.D., Yuksel A., Ozen M., Muzny D.M., RA Adams D.R., Boerwinkle E., Chung W.K., Gibbs R.A., Lupski J.R.; RT "Genes that affect brain structure and function identified by rare variant RT analyses of mendelian neurologic disease."; RL Neuron 88:499-513(2015). RN [13] RP INVOLVEMENT IN DEE63, AND VARIANTS DEE63 105-CYS--LYS-134 DEL AND MET-128. RX PubMed=28422131; DOI=10.1038/ejhg.2017.52; RA Redler S., Strom T.M., Wieland T., Cremer K., Engels H., Distelmaier F., RA Schaper J., Kuechler A., Lemke J.R., Jeschke S., Schreyer N., Sticht H., RA Koch M., Luedecke H.J., Wieczorek D.; RT "Variants in CPLX1 in two families with autosomal-recessive severe RT infantile myoclonic epilepsy and ID."; RL Eur. J. Hum. Genet. 25:889-893(2017). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 28-83 ALONE AND IN COMPLEX WITH RP SNAP25; VAMP2 AND RAT STX1A, SUBUNIT, AND FUNCTION. RX PubMed=21785414; DOI=10.1038/nsmb.2101; RA Kummel D., Krishnakumar S.S., Radoff D.T., Li F., Giraudo C.G., Pincet F., RA Rothman J.E., Reinisch K.M.; RT "Complexin cross-links prefusion SNAREs into a zigzag array."; RL Nat. Struct. Mol. Biol. 18:927-933(2011). CC -!- FUNCTION: Positively regulates a late step in exocytosis of various CC cytoplasmic vesicles, such as synaptic vesicles and other secretory CC vesicles (PubMed:21785414). Organizes the SNAREs into a cross-linked CC zigzag topology that, when interposed between the vesicle and plasma CC membranes, is incompatible with fusion, thereby preventing SNAREs from CC releasing neurotransmitters until an action potential arrives at the CC synapse (PubMed:21785414). Also involved in glucose-induced secretion CC of insulin by pancreatic beta-cells. Essential for motor behavior. CC {ECO:0000250|UniProtKB:P63040, ECO:0000269|PubMed:21785414}. CC -!- SUBUNIT: Binds to the SNARE core complex containing SNAP25, VAMP2 and CC STX1A. {ECO:0000269|PubMed:21785414}. CC -!- INTERACTION: CC O14810; P60880-2: SNAP25; NbExp=6; IntAct=EBI-2691813, EBI-12177361; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:P63040}. Perikaryon CC {ECO:0000250|UniProtKB:P63040}. Presynapse CC {ECO:0000250|UniProtKB:P63040}. Note=Enriched at synaptic-releasing CC sites in mature neurons. {ECO:0000250|UniProtKB:P63040}. CC -!- TISSUE SPECIFICITY: Nervous system. In hippocampus and cerebellum, CC expressed mainly by inhibitory neurons. Overexpressed in substantia CC nigra from patients with Parkinson disease. CC {ECO:0000269|PubMed:11483314, ECO:0000269|PubMed:15526345, CC ECO:0000269|PubMed:9853440}. CC -!- DISEASE: Developmental and epileptic encephalopathy 63 (DEE63) CC [MIM:617976]: A form of epileptic encephalopathy, a heterogeneous group CC of severe early-onset epilepsies characterized by refractory seizures, CC neurodevelopmental impairment, and poor prognosis. Development is CC normal prior to seizure onset, after which cognitive and motor delays CC become apparent. DEE63 is an autosomal recessive disease with onset in CC infancy. {ECO:0000269|PubMed:26539891, ECO:0000269|PubMed:28422131}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the complexin/synaphin 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; AF022383; AAB72108.1; -; mRNA. DR EMBL; KJ534815; AHW56455.1; -; mRNA. DR EMBL; BT007029; AAP35676.1; -; mRNA. DR EMBL; AB593095; BAJ84035.1; -; mRNA. DR EMBL; AK311921; BAG34862.1; -; mRNA. DR EMBL; AC139887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471131; EAW82648.1; -; Genomic_DNA. DR EMBL; CH471131; EAW82649.1; -; Genomic_DNA. DR EMBL; BC002471; AAH02471.1; -; mRNA. DR CCDS; CCDS46995.1; -. DR RefSeq; NP_006642.1; NM_006651.4. DR PDB; 3RK3; X-ray; 3.50 A; E=26-83. DR PDB; 3RL0; X-ray; 3.80 A; g/h/i/j/k/l/m/n=26-83. DR PDBsum; 3RK3; -. DR PDBsum; 3RL0; -. DR AlphaFoldDB; O14810; -. DR SMR; O14810; -. DR BioGRID; 116028; 42. DR CORUM; O14810; -. DR DIP; DIP-56109N; -. DR FunCoup; O14810; 335. DR IntAct; O14810; 13. DR MINT; O14810; -. DR STRING; 9606.ENSP00000305613; -. DR iPTMnet; O14810; -. DR PhosphoSitePlus; O14810; -. DR BioMuta; CPLX1; -. DR jPOST; O14810; -. DR MassIVE; O14810; -. DR PaxDb; 9606-ENSP00000305613; -. DR PeptideAtlas; O14810; -. DR ProteomicsDB; 48251; -. DR Antibodypedia; 22160; 175 antibodies from 25 providers. DR DNASU; 10815; -. DR Ensembl; ENST00000304062.11; ENSP00000305613.6; ENSG00000168993.16. DR GeneID; 10815; -. DR KEGG; hsa:10815; -. DR MANE-Select; ENST00000304062.11; ENSP00000305613.6; NM_006651.4; NP_006642.1. DR UCSC; uc003gbi.4; human. DR AGR; HGNC:2309; -. DR ClinPGx; PA26826; -. DR CTD; 10815; -. DR DisGeNET; 10815; -. DR GeneCards; CPLX1; -. DR HGNC; HGNC:2309; CPLX1. DR HPA; ENSG00000168993; Tissue enriched (brain). DR MalaCards; CPLX1; -. DR MIM; 605032; gene. DR MIM; 617976; phenotype. DR OpenTargets; ENSG00000168993; -. DR Orphanet; 352582; Familial infantile myoclonic epilepsy. DR Orphanet; 280; Wolf-Hirschhorn syndrome. DR VEuPathDB; HostDB:ENSG00000168993; -. DR eggNOG; ENOG502S3I2; Eukaryota. DR GeneTree; ENSGT00950000182938; -. DR InParanoid; O14810; -. DR OMA; RVHESHA; -. DR OrthoDB; 5972090at2759; -. DR PAN-GO; O14810; 5 GO annotations based on evolutionary models. DR PhylomeDB; O14810; -. DR PathwayCommons; O14810; -. DR Reactome; R-HSA-181429; Serotonin Neurotransmitter Release Cycle. DR Reactome; R-HSA-181430; Norepinephrine Neurotransmitter Release Cycle. DR Reactome; R-HSA-210500; Glutamate Neurotransmitter Release Cycle. DR Reactome; R-HSA-212676; Dopamine Neurotransmitter Release Cycle. DR Reactome; R-HSA-264642; Acetylcholine Neurotransmitter Release Cycle. DR Reactome; R-HSA-888590; GABA synthesis, release, reuptake and degradation. DR SignaLink; O14810; -. DR Agora; ENSG00000168993; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 10815; 7 hits in 1142 CRISPR screens. DR EvolutionaryTrace; O14810; -. DR GeneWiki; CPLX1; -. DR GenomeRNAi; 10815; -. DR Pharos; O14810; Tbio. DR PRO; PR:O14810; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; O14810; protein. DR Bgee; ENSG00000168993; Expressed in lateral nuclear group of thalamus and 124 other cell types or tissues. DR ExpressionAtlas; O14810; baseline and differential. DR GO; GO:0044305; C:calyx of Held; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0098794; C:postsynapse; IEA:Ensembl. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl. DR GO; GO:0031201; C:SNARE complex; IBA:GO_Central. DR GO; GO:0070032; C:synaptobrevin 2-SNAP-25-syntaxin-1a-complexin I complex; IEA:Ensembl. DR GO; GO:0070554; C:synaptobrevin 2-SNAP-25-syntaxin-3-complexin complex; TAS:ParkinsonsUK-UCL. DR GO; GO:0043195; C:terminal bouton; IBA:GO_Central. DR GO; GO:0000149; F:SNARE binding; IBA:GO_Central. DR GO; GO:0017075; F:syntaxin-1 binding; IEA:Ensembl. DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc. DR GO; GO:0006887; P:exocytosis; TAS:ProtInc. DR GO; GO:0030073; P:insulin secretion; IEA:Ensembl. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0099145; P:regulation of exocytic insertion of neurotransmitter receptor to postsynaptic membrane; IEA:Ensembl. DR GO; GO:0017157; P:regulation of exocytosis; TAS:ParkinsonsUK-UCL. DR GO; GO:0031630; P:regulation of synaptic vesicle fusion to presynaptic active zone membrane; IBA:GO_Central. DR GO; GO:0016079; P:synaptic vesicle exocytosis; IBA:GO_Central. DR CDD; cd22740; Complexin_NTD; 1. DR DisProt; DP02360; -. DR FunFam; 1.20.5.580:FF:000001; Complexin 2; 1. DR Gene3D; 1.20.5.580; Single Helix bin; 1. DR InterPro; IPR008849; Synaphin. DR PANTHER; PTHR16705; COMPLEXIN; 1. DR PANTHER; PTHR16705:SF6; COMPLEXIN-1; 1. DR Pfam; PF05835; Synaphin; 1. DR SUPFAM; SSF58038; SNARE fusion complex; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell projection; Coiled coil; Cytoplasm; Disease variant; KW Epilepsy; Exocytosis; Neurotransmitter transport; KW Proteomics identification; Reference proteome; Synapse; Transport. FT CHAIN 1..134 FT /note="Complexin-1" FT /id="PRO_0000144870" FT REGION 1..60 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 48..70 FT /note="Interaction with the SNARE complex" FT /evidence="ECO:0000250" FT REGION 74..113 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 29..69 FT /evidence="ECO:0000255" FT COMPBIAS 15..60 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 105..134 FT /note="Missing (in DEE63)" FT /evidence="ECO:0000269|PubMed:28422131" FT /id="VAR_080795" FT VARIANT 108..134 FT /note="Missing (in DEE63)" FT /evidence="ECO:0000269|PubMed:26539891" FT /id="VAR_080796" FT VARIANT 128 FT /note="L -> M (in DEE63; uncertain significance; FT dbSNP:rs371709824)" FT /evidence="ECO:0000269|PubMed:28422131" FT /id="VAR_080797" FT HELIX 29..70 FT /evidence="ECO:0007829|PDB:3RK3" SQ SEQUENCE 134 AA; 15030 MW; A7A52F17F10D28A4 CRC64; MEFVMKQALG GATKDMGKML GGDEEKDPDA AKKEEERQEA LRQAEEERKA KYAKMEAERE AVRQGIRDKY GIKKKEEREA EAQAAMEANS EGSLTRPKKA IPPGCGDEVE EEDESILDTV IKYLPGPLQD MLKK // 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 LIGO1_HUMAN Reviewed; 620 AA. AC Q96FE5; D3DW80; Q6NUK3; Q6UXM3; Q6VVG0; Q6VVG1; Q6VVG2; Q8N3K5; Q96K52; DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2004, sequence version 2. DT 28-JAN-2026, entry version 195. DE RecName: Full=Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1; DE AltName: Full=Leucine-rich repeat and immunoglobulin domain-containing protein 1; DE AltName: Full=Leucine-rich repeat neuronal protein 1; DE AltName: Full=Leucine-rich repeat neuronal protein 6A; DE Flags: Precursor; GN Name=LINGO1; Synonyms=LERN1, LRRN6A; ORFNames=UNQ201/PRO227; 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), TISSUE SPECIFICITY, AND VARIANT RP PHE-183. RX PubMed=14686891; DOI=10.1111/j.1460-9568.2003.03003.x; RA Carim-Todd L., Escarceller M., Estivill X., Sumoy L.; RT "LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with RT enriched expression in limbic system and neocortex."; RL Eur. J. Neurosci. 18:3167-3182(2003). RN [2] 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). 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 [LARGE SCALE MRNA] OF 44-620. 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 [7] RP FUNCTION, AND INTERACTION WITH NGFR AND RTN4R. RX PubMed=14966521; DOI=10.1038/nn1188; RA Mi S., Lee X., Shao Z., Thill G., Ji B., Relton J., Levesque M., RA Allaire N., Perrin S., Sands B., Crowell T., Cate R.L., McCoy J.M., RA Pepinsky R.B.; RT "LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex."; RL Nat. Neurosci. 7:221-228(2004). RN [8] RP TISSUE SPECIFICITY, AND FUNCTION. RX PubMed=15895088; DOI=10.1038/nn1460; RA Mi S., Miller R.H., Lee X., Scott M.L., Shulag-Morskaya S., Shao Z., RA Chang J., Thill G., Levesque M., Zhang M., Hession C., Sah D., Trapp B., RA He Z., Jung V., McCoy J.M., Pepinsky R.B.; RT "LINGO-1 negatively regulates myelination by oligodendrocytes."; RL Nat. Neurosci. 8:745-751(2005). RN [9] RP INTERACTION WITH TNFRSF19, AND FUNCTION. RX PubMed=15694321; DOI=10.1016/j.neuron.2004.12.040; RA Park J.B., Yiu G., Kaneko S., Wang J., Chang J., He X.L., Garcia K.C., RA He Z.; RT "A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in RT mediating the inhibitory activity of myelin inhibitors."; RL Neuron 45:345-351(2005). RN [10] RP TISSUE SPECIFICITY. RX PubMed=17726113; DOI=10.1073/pnas.0700901104; RA Inoue H., Lin L., Lee X., Shao Z., Mendes S., Snodgrass-Belt P., RA Sweigard H., Engber T., Pepinsky B., Yang L., Beal M.F., Mi S., Isacson O.; RT "Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, RT structure, and function of dopaminergic neurons in Parkinson's disease RT models."; RL Proc. Natl. Acad. Sci. U.S.A. 104:14430-14435(2007). RN [11] RP INTERACTION WITH RTN4R. RX PubMed=19052207; DOI=10.1523/jneurosci.3828-08.2008; RA Budel S., Padukkavidana T., Liu B.P., Feng Z., Hu F., Johnson S., RA Lauren J., Park J.H., McGee A.W., Liao J., Stillman A., Kim J.E., RA Yang B.Z., Sodi S., Gelernter J., Zhao H., Hisama F., Arnsten A.F., RA Strittmatter S.M.; RT "Genetic variants of Nogo-66 receptor with possible association to RT schizophrenia block myelin inhibition of axon growth."; RL J. Neurosci. 28:13161-13172(2008). RN [12] RP INVOLVEMENT IN MRT64, AND VARIANTS MRT64 CYS-288 AND HIS-290. RX PubMed=28837161; DOI=10.1038/gim.2017.113; RA Ansar M., Riazuddin S., Sarwar M.T., Makrythanasis P., Paracha S.A., RA Iqbal Z., Khan J., Assir M.Z., Hussain M., Razzaq A., Polla D.L., Taj A.S., RA Holmgren A., Batool N., Misceo D., Iwaszkiewicz J., de Brouwer A.P.M., RA Guipponi M., Hanquinet S., Zoete V., Santoni F.A., Frengen E., Ahmed J., RA Riazuddin S., van Bokhoven H., Antonarakis S.E.; RT "Biallelic variants in LINGO1 are associated with autosomal recessive RT intellectual disability, microcephaly, speech and motor delay."; RL Genet. Med. 20:778-784(2018). RN [13] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 40-516, FUNCTION, SUBUNIT, RP INTERACTION WITH NGFR AND RTN4R, DISULFIDE BONDS, IDENTIFICATION BY MASS RP SPECTROMETRY, AND GLYCOSYLATION AT ASN-144; ASN-202; ASN-264; ASN-274; RP ASN-293; ASN-341 AND ASN-492. RX PubMed=17005555; DOI=10.1074/jbc.m607314200; RA Mosyak L., Wood A., Dwyer B., Buddha M., Johnson M., Aulabaugh A., RA Zhong X., Presman E., Benard S., Kelleher K., Wilhelm J., Stahl M.L., RA Kriz R., Gao Y., Cao Z., Ling H.P., Pangalos M.N., Walsh F.S., Somers W.S.; RT "The structure of the Lingo-1 ectodomain, a module implicated in central RT nervous system repair inhibition."; RL J. Biol. Chem. 281:36378-36390(2006). CC -!- FUNCTION: Functional component of the Nogo receptor signaling complex CC (RTN4R/NGFR) in RhoA activation responsible for some inhibition of CC axonal regeneration by myelin-associated factors (PubMed:14966521, CC PubMed:15694321). Is also an important negative regulator of CC oligodentrocyte differentiation and axonal myelination CC (PubMed:15895088). Acts in conjunction with RTN4 and RTN4R in CC regulating neuronal precursor cell motility during cortical development CC (By similarity). {ECO:0000250|UniProtKB:Q9D1T0, CC ECO:0000269|PubMed:14966521, ECO:0000269|PubMed:15694321, CC ECO:0000269|PubMed:15895088}. CC -!- SUBUNIT: Homotetramer (PubMed:17005555). Forms a ternary complex with CC RTN4R/NGFR and RTN4R/TNFRSF19 (PubMed:14966521, PubMed:15694321, CC PubMed:17005555). Interacts with NGRF and MYT1L (By similarity). CC Interacts with RTN4R (PubMed:19052207). {ECO:0000250|UniProtKB:Q9D1T0, CC ECO:0000269|PubMed:14966521, ECO:0000269|PubMed:15694321, CC ECO:0000269|PubMed:17005555, ECO:0000269|PubMed:19052207}. CC -!- INTERACTION: CC Q96FE5; P05067: APP; NbExp=3; IntAct=EBI-719955, EBI-77613; CC Q96FE5; P05067-4: APP; NbExp=2; IntAct=EBI-719955, EBI-302641; CC Q96FE5; P00533: EGFR; NbExp=2; IntAct=EBI-719955, EBI-297353; CC Q96FE5; P23142-4: FBLN1; NbExp=3; IntAct=EBI-719955, EBI-11956479; CC Q96FE5; O43559: FRS3; NbExp=3; IntAct=EBI-719955, EBI-725515; CC Q96FE5; Q08379: GOLGA2; NbExp=3; IntAct=EBI-719955, EBI-618309; CC Q96FE5; Q9H2F3: HSD3B7; NbExp=3; IntAct=EBI-719955, EBI-3918847; CC Q96FE5; Q6L8G9: KRTAP5-6; NbExp=3; IntAct=EBI-719955, EBI-10250562; CC Q96FE5; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-719955, EBI-3958099; CC Q96FE5; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-719955, EBI-1044640; CC Q96FE5; Q7L985: LINGO2; NbExp=4; IntAct=EBI-719955, EBI-21691123; CC Q96FE5; Q8N5G2: MACO1; NbExp=3; IntAct=EBI-719955, EBI-2683507; CC Q96FE5; P08138: NGFR; NbExp=2; IntAct=EBI-719955, EBI-1387782; CC Q96FE5; Q9P121-3: NTM; NbExp=3; IntAct=EBI-719955, EBI-12027160; CC Q96FE5; Q96R06: SPAG5; NbExp=3; IntAct=EBI-719955, EBI-413317; CC Q96FE5; P14373: TRIM27; NbExp=3; IntAct=EBI-719955, EBI-719493; CC Q96FE5; Q99M75: Rtn4r; Xeno; NbExp=2; IntAct=EBI-719955, EBI-7370412; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q9D1T0}; CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:Q9D1T0}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96FE5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96FE5-2; Sequence=VSP_032749; CC -!- TISSUE SPECIFICITY: Expressed exclusively in the central nervous CC system. Highest level in the in amygdala, hippocampus, thalamus and CC cerebral cortex. In the rest of the brain a basal expression seems to CC be always present. Up-regulated in substantia nigra neurons from CC Parkinson disease patients. {ECO:0000269|PubMed:14686891, CC ECO:0000269|PubMed:15895088, ECO:0000269|PubMed:17726113}. CC -!- DOMAIN: The intracellular domain of LINGO1 interacts with MYT1L. CC {ECO:0000250|UniProtKB:Q9D1T0}. CC -!- PTM: N-glycosylated. Contains predominantly high-mannose glycans. CC {ECO:0000269|PubMed:17005555}. CC -!- DISEASE: Intellectual developmental disorder, autosomal recessive 64 CC (MRT64) [MIM:618103]: A disorder characterized by significantly below CC average general intellectual functioning associated with impairments in CC adaptive behavior and manifested during the developmental period. MRT64 CC patients have moderate to severe intellectual disability, delayed motor CC development, aggressive behavior, and slurred or absent speech. CC {ECO:0000269|PubMed:28837161}. Note=The disease is caused by variants CC affecting the gene represented in this entry. 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; AY324320; AAQ97216.1; -; mRNA. DR EMBL; AY324322; AAQ97217.1; -; mRNA. DR EMBL; AY324323; AAQ97218.1; -; mRNA. DR EMBL; AY358284; AAQ88651.1; -; mRNA. DR EMBL; AK027500; BAB55157.1; -; mRNA. DR EMBL; AK291363; BAF84052.1; -; mRNA. DR EMBL; CH471136; EAW99195.1; -; Genomic_DNA. DR EMBL; CH471136; EAW99196.1; -; Genomic_DNA. DR EMBL; CH471136; EAW99197.1; -; Genomic_DNA. DR EMBL; CH471136; EAW99198.1; -; Genomic_DNA. DR EMBL; BC011057; AAH11057.2; -; mRNA. DR EMBL; BC068558; AAH68558.1; -; mRNA. DR EMBL; AL834260; CAD38935.1; -; mRNA. DR CCDS; CCDS45313.1; -. [Q96FE5-1] DR CCDS; CCDS73766.1; -. [Q96FE5-2] DR RefSeq; NP_001288115.1; NM_001301186.2. [Q96FE5-2] DR RefSeq; NP_001288116.1; NM_001301187.2. [Q96FE5-2] DR RefSeq; NP_001288118.1; NM_001301189.2. [Q96FE5-2] DR RefSeq; NP_001288120.1; NM_001301191.2. [Q96FE5-2] DR RefSeq; NP_001288121.1; NM_001301192.2. [Q96FE5-2] DR RefSeq; NP_001288123.1; NM_001301194.2. [Q96FE5-2] DR RefSeq; NP_001288124.1; NM_001301195.2. [Q96FE5-2] DR RefSeq; NP_001288126.1; NM_001301197.2. [Q96FE5-2] DR RefSeq; NP_001288127.1; NM_001301198.2. [Q96FE5-2] DR RefSeq; NP_001288128.1; NM_001301199.2. [Q96FE5-2] DR RefSeq; NP_001288129.1; NM_001301200.2. [Q96FE5-2] DR RefSeq; NP_116197.4; NM_032808.6. [Q96FE5-1] DR RefSeq; XP_011520420.1; XM_011522118.3. [Q96FE5-2] DR RefSeq; XP_016878171.1; XM_017022682.2. [Q96FE5-2] DR RefSeq; XP_024305859.1; XM_024450091.2. [Q96FE5-2] DR RefSeq; XP_054234980.1; XM_054379005.1. [Q96FE5-2] DR RefSeq; XP_054234981.1; XM_054379006.1. [Q96FE5-2] DR RefSeq; XP_054234982.1; XM_054379007.1. [Q96FE5-2] DR PDB; 2ID5; X-ray; 2.70 A; A/B/C/D=40-516. DR PDB; 4OQT; X-ray; 3.23 A; A=40-517. DR PDBsum; 2ID5; -. DR PDBsum; 4OQT; -. DR AlphaFoldDB; Q96FE5; -. DR SMR; Q96FE5; -. DR BioGRID; 124334; 55. DR CORUM; Q96FE5; -. DR DIP; DIP-60981N; -. DR FunCoup; Q96FE5; 427. DR IntAct; Q96FE5; 56. DR MINT; Q96FE5; -. DR STRING; 9606.ENSP00000347451; -. DR ChEMBL; CHEMBL3712965; -. DR GuidetoPHARMACOLOGY; 2882; -. DR TCDB; 8.A.43.1.15; the neat-domain containing methaemoglobin heme sequestration (n-mhs) family. DR GlyConnect; 1450; 1 N-Linked glycan (1 site). DR GlyCosmos; Q96FE5; 10 sites, No reported glycans. DR GlyGen; Q96FE5; 10 sites, 3 N-linked glycans (3 sites). DR iPTMnet; Q96FE5; -. DR PhosphoSitePlus; Q96FE5; -. DR BioMuta; LINGO1; -. DR DMDM; 74760819; -. DR jPOST; Q96FE5; -. DR MassIVE; Q96FE5; -. DR PaxDb; 9606-ENSP00000347451; -. DR PeptideAtlas; Q96FE5; -. DR ProteomicsDB; 76516; -. [Q96FE5-1] DR ProteomicsDB; 76517; -. [Q96FE5-2] DR ABCD; Q96FE5; 2 sequenced antibodies. DR Antibodypedia; 2624; 441 antibodies from 36 providers. DR DNASU; 84894; -. DR Ensembl; ENST00000355300.7; ENSP00000347451.6; ENSG00000169783.13. [Q96FE5-1] DR Ensembl; ENST00000561030.5; ENSP00000453853.1; ENSG00000169783.13. [Q96FE5-2] DR GeneID; 84894; -. DR KEGG; hsa:84894; -. DR MANE-Select; ENST00000355300.7; ENSP00000347451.6; NM_032808.7; NP_116197.4. DR UCSC; uc002bct.2; human. [Q96FE5-1] DR AGR; HGNC:21205; -. DR ClinPGx; PA162394087; -. DR CTD; 84894; -. DR DisGeNET; 84894; -. DR GeneCards; LINGO1; -. DR HGNC; HGNC:21205; LINGO1. DR HPA; ENSG00000169783; Tissue enriched (brain). DR MalaCards; LINGO1; -. DR MIM; 609791; gene. DR MIM; 618103; phenotype. DR OpenTargets; ENSG00000169783; -. DR VEuPathDB; HostDB:ENSG00000169783; -. DR eggNOG; KOG0619; Eukaryota. DR GeneTree; ENSGT00940000154996; -. DR HOGENOM; CLU_000288_18_24_1; -. DR InParanoid; Q96FE5; -. DR OMA; MVAREAT; -. DR OrthoDB; 10061535at2759; -. DR PAN-GO; Q96FE5; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q96FE5; -. DR PathwayCommons; Q96FE5; -. DR Reactome; R-HSA-193634; Axonal growth inhibition (RHOA activation). DR SignaLink; Q96FE5; -. DR SIGNOR; Q96FE5; -. DR Agora; ENSG00000169783; -. DR BioGRID-ORCS; 84894; 14 hits in 1141 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; LINGO1; human. DR EvolutionaryTrace; Q96FE5; -. DR GeneWiki; LINGO1; -. DR GenomeRNAi; 84894; -. DR Pharos; Q96FE5; Tbio. DR PRO; PR:Q96FE5; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q96FE5; protein. DR Bgee; ENSG00000169783; Expressed in cortical plate and 157 other cell types or tissues. DR ExpressionAtlas; Q96FE5; baseline and differential. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IBA:GO_Central. DR GO; GO:0038023; F:signaling receptor activity; IBA:GO_Central. DR GO; GO:0048666; P:neuron development; IBA:GO_Central. DR CDD; cd20969; IgI_Lingo-1; 1. DR FunFam; 2.60.40.10:FF:000076; Leucine-rich repeat and Ig domain-containing 4; 1. DR FunFam; 3.80.10.10:FF:000014; Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013098; Ig_I-set. DR InterPro; IPR003599; Ig_sub. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR050541; LRR_TM_domain-containing. DR InterPro; IPR000372; LRRNT. DR PANTHER; PTHR24369; ANTIGEN BSP, PUTATIVE-RELATED; 1. DR PANTHER; PTHR24369:SF178; LEUCINE-RICH REPEAT AND IMMUNOGLOBULIN-LIKE DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 1; 1. DR Pfam; PF07679; I-set; 1. DR Pfam; PF13855; LRR_8; 3. DR SMART; SM00409; IG; 1. DR SMART; SM00408; IGc2; 1. DR SMART; SM00369; LRR_TYP; 9. DR SMART; SM00013; LRRNT; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. DR SUPFAM; SSF52058; L domain-like; 1. DR PROSITE; PS50835; IG_LIKE; 1. DR PROSITE; PS51450; LRR; 10. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Disease variant; KW Disulfide bond; Glycoprotein; Immunoglobulin domain; KW Intellectual disability; Leucine-rich repeat; Membrane; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..41 FT /evidence="ECO:0000255" FT CHAIN 42..620 FT /note="Leucine-rich repeat and immunoglobulin-like domain- FT containing nogo receptor-interacting protein 1" FT /id="PRO_0000328642" FT TOPO_DOM 42..561 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 562..582 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 583..620 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 42..71 FT /note="LRRNT" FT REPEAT 72..93 FT /note="LRR 1" FT REPEAT 96..117 FT /note="LRR 2" FT REPEAT 120..141 FT /note="LRR 3" FT REPEAT 144..165 FT /note="LRR 4" FT REPEAT 168..189 FT /note="LRR 5" FT REPEAT 192..213 FT /note="LRR 6" FT REPEAT 216..237 FT /note="LRR 7" FT REPEAT 264..285 FT /note="LRR 8" FT REPEAT 288..309 FT /note="LRR 9" FT REPEAT 312..333 FT /note="LRR 10" FT REPEAT 336..357 FT /note="LRR 11" FT DOMAIN 369..423 FT /note="LRRCT" FT DOMAIN 411..513 FT /note="Ig-like C2-type" FT MOD_RES 602 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9D1T0" FT CARBOHYD 144 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 202 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 264 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 274 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 293 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 341 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 492 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17005555" FT CARBOHYD 505 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 526 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 542 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 42..48 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17005555" FT DISULFID 46..57 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17005555" FT DISULFID 373..396 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17005555" FT DISULFID 375..421 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17005555" FT DISULFID 446..497 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17005555" FT VAR_SEQ 1..6 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_032749" FT VARIANT 183 FT /note="S -> F (in dbSNP:rs9855)" FT /evidence="ECO:0000269|PubMed:14686891" FT /id="VAR_042436" FT VARIANT 288 FT /note="Y -> C (in MRT64; dbSNP:rs750612085)" FT /evidence="ECO:0000269|PubMed:28837161" FT /id="VAR_081164" FT VARIANT 290 FT /note="R -> H (in MRT64; dbSNP:rs757077698)" FT /evidence="ECO:0000269|PubMed:28837161" FT /id="VAR_081165" FT CONFLICT 46 FT /note="C -> Y (in Ref. 5; AAH68558)" FT /evidence="ECO:0000305" FT CONFLICT 61 FT /note="R -> C (in Ref. 2; AAQ88651)" FT /evidence="ECO:0000305" FT CONFLICT 148 FT /note="L -> Q (in Ref. 2; AAQ88651)" FT /evidence="ECO:0000305" FT CONFLICT 170 FT /note="K -> R (in Ref. 5; AAH68558)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="P -> R (in Ref. 5; AAH68558)" FT /evidence="ECO:0000305" FT CONFLICT 353 FT /note="S -> L (in Ref. 3; BAB55157)" FT /evidence="ECO:0000305" FT STRAND 47..49 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 50..53 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 54..56 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 74..77 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 88..93 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 112..117 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 123..125 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 147..149 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 160..165 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 171..174 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 195..200 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 208..211 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 219..224 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 243..247 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 257..262 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 266..273 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 280..283 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 291..293 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 315..317 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 324..326 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 328..330 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 339..341 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 352..354 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 358..360 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 375..377 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 378..381 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 382..385 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 395..399 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 400..402 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:2ID5" FT TURN 416..419 FT /evidence="ECO:0007829|PDB:4OQT" FT STRAND 422..427 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 432..437 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 442..444 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 448..452 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 455..459 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 472..476 FT /evidence="ECO:0007829|PDB:4OQT" FT STRAND 482..486 FT /evidence="ECO:0007829|PDB:2ID5" FT HELIX 489..491 FT /evidence="ECO:0007829|PDB:4OQT" FT STRAND 493..501 FT /evidence="ECO:0007829|PDB:2ID5" FT STRAND 504..515 FT /evidence="ECO:0007829|PDB:2ID5" SQ SEQUENCE 620 AA; 69876 MW; 1A96D311A20180C1 CRC64; MQVSKRMLAG GVRSMPSPLL ACWQPILLLV LGSVLSGSAT GCPPRCECSA QDRAVLCHRK RFVAVPEGIP TETRLLDLGK NRIKTLNQDE FASFPHLEEL ELNENIVSAV EPGAFNNLFN LRTLGLRSNR LKLIPLGVFT GLSNLTKLDI SENKIVILLD YMFQDLYNLK SLEVGDNDLV YISHRAFSGL NSLEQLTLEK CNLTSIPTEA LSHLHGLIVL RLRHLNINAI RDYSFKRLYR LKVLEISHWP YLDTMTPNCL YGLNLTSLSI THCNLTAVPY LAVRHLVYLR FLNLSYNPIS TIEGSMLHEL LRLQEIQLVG GQLAVVEPYA FRGLNYLRVL NVSGNQLTTL EESVFHSVGN LETLILDSNP LACDCRLLWV FRRRWRLNFN RQQPTCATPE FVQGKEFKDF PDVLLPNYFT CRRARIRDRK AQQVFVDEGH TVQFVCRADG DPPPAILWLS PRKHLVSAKS NGRLTVFPDG TLEVRYAQVQ DNGTYLCIAA NAGGNDSMPA HLHVRSYSPD WPHQPNKTFA FISNQPGEGE ANSTRATVPF PFDIKTLIIA TTMGFISFLG VVLFCLVLLF LWSRGKGNTK HNIEIEYVPR KSDAGISSAD APRKFNMKMI // ID MECP2_HUMAN Reviewed; 486 AA. AC P51608; O15233; Q6QHH9; Q7Z384; 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=Methyl-CpG-binding protein 2; DE Short=MeCp-2 protein; DE Short=MeCp2; GN Name=MECP2; 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 A). RX PubMed=9710633; DOI=10.1128/mcb.18.9.5492; RA Kudo S.; RT "Methyl-CpG-binding protein MeCP2 represses Sp1-activated transcription of RT the human leukosialin gene when the promoter is methylated."; RL Mol. Cell. Biol. 18:5492-5499(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RX PubMed=8976388; DOI=10.1159/000134438; RA Vilain A., Apiou F., Vogt N., Dutrillaux B., Malfoy B.; RT "Assignment of the gene for methyl-CpG-binding protein 2 (MECP2) to human RT chromosome band Xq28 by in situ hybridization."; RL Cytogenet. Cell Genet. 74:293-294(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RX PubMed=10369871; DOI=10.1093/hmg/8.7.1253; RA Coy J.F., Sedlacek Z., Baechner D., Delius H., Poustka A.; RT "A complex pattern of evolutionary conservation and alternative RT polyadenylation within the long 3'-untranslated region of the methyl-CpG- RT binding protein 2 gene (MeCP2) suggests a regulatory role in gene RT expression."; RL Hum. Mol. Genet. 8:1253-1262(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RX PubMed=10723722; DOI=10.1007/s003350010035; RA Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A., RA Platzer M., Stratling W.H., Kioschis P.; RT "Comparative sequence analysis of the MECP2-locus in human and mouse RT reveals new transcribed regions."; RL Mamm. Genome 11:182-190(2000). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND INVOLVEMENT IN RTT. RX PubMed=15034579; DOI=10.1038/ng1327; RA Mnatzakanian G.N., Lohi H., Munteanu I., Alfred S.E., Yamada T., RA MacLeod P.J.M., Jones J.R., Scherer S.W., Schanen N.C., Friez M.J., RA Vincent J.B., Minassian B.A.; RT "A previously unidentified MECP2 open reading frame defines a new protein RT isoform relevant to Rett syndrome."; RL Nat. Genet. 36:339-341(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RC TISSUE=Placenta; RA Straetling W.H.; RL Submitted (APR-1997) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). RC TISSUE=Colon endothelium; 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 [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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). 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 [MRNA] OF 10-486 (ISOFORM A). RC TISSUE=Skeletal muscle; RX PubMed=8672133; DOI=10.1007/s003359900157; RA D'Esposito M., Quaderi N.A., Ciccodicola A., Bruni P., Esposito T., RA D'Urso M., Brown S.D.M.; RT "Isolation, physical mapping, and Northern analysis of the X-linked human RT gene encoding methyl CpG-binding protein, MECP2."; RL Mamm. Genome 7:533-535(1996). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 10-486 (ISOFORM A). RA Reichwald K., Bauer D., Brenner V., Drescher B., Coy J.F., Kioschis P., RA Korn B., Nyakatura G., Platzer M., Poustka A., Sandoval N., Rosenthal A.; RT "Genetic organization of human methyl-CpG-binding protein 2."; RL Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases. RN [12] RP IDENTIFICATION (ISOFORM B). RX PubMed=15034150; DOI=10.1093/nar/gkh349; RA Kriaucionis S., Bird A.; RT "The major form of MeCP2 has a novel N-terminus generated by alternative RT splicing."; RL Nucleic Acids Res. 32:1818-1823(2004). RN [13] RP REVIEW ON VARIANTS. RX PubMed=12872250; DOI=10.1002/humu.10243; RA Miltenberger-Miltenyi G., Laccone F.; RT "Mutations and polymorphisms in the human methyl CpG-binding protein RT MECP2."; RL Hum. Mutat. 22:107-115(2003). RN [14] RP INTERACTION WITH CDKL5. RX PubMed=15917271; DOI=10.1093/hmg/ddi198; RA Mari F., Azimonti S., Bertani I., Bolognese F., Colombo E., Caselli R., RA Scala E., Longo I., Grosso S., Pescucci C., Ariani F., Hayek G., RA Balestri P., Bergo A., Badaracco G., Zappella M., Broccoli V., Renieri A., RA Kilstrup-Nielsen C., Landsberger N.; RT "CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible RT for the early-onset seizure variant of Rett syndrome."; RL Hum. Mol. Genet. 14:1935-1946(2005). RN [15] RP IDENTIFICATION BY 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 [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=T-cell; RX PubMed=19367720; DOI=10.1021/pr800500r; RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.; RT "Phosphorylation analysis of primary human T lymphocytes using sequential RT IMAC and titanium oxide enrichment."; RL J. Proteome Res. 7:5167-5176(2008). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80; SER-116 AND SER-426, 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 [18] 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 [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80, 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 [20] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-449, 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 [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80 AND SER-216, 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 [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80, 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 [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80 AND SER-229, 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 [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-426, 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 [25] RP STRUCTURE BY NMR OF 77-166. RX PubMed=10518942; DOI=10.1006/jmbi.1999.3023; RA Wakefield R.I., Smith B.O., Nan X., Free A., Soteriou A., Uhrin D., RA Bird A.P., Barlow P.N.; RT "The solution structure of the domain from MeCP2 that binds to methylated RT DNA."; RL J. Mol. Biol. 291:1055-1065(1999). RN [26] RP VARIANTS RTT TRP-106; CYS-133; SER-155; MET-158 AND CYS-306, AND VARIANT RP LYS-397. RX PubMed=10577905; DOI=10.1086/302690; RA Wan M., Lee S.S.J., Zhang X., Houwink-Manville I., Song H.-R., Amir R.E., RA Budden S., Naidu S., Pereira J.L.P., Lo I.F.M., Zoghbi H.Y., Schanen N.C., RA Francke U.; RT "Rett syndrome and beyond: recurrent spontaneous and familial MECP2 RT mutations at CpG hotspots."; RL Am. J. Hum. Genet. 65:1520-1529(1999). RN [27] RP VARIANTS RTT TRP-106; CYS-133; SER-155 AND MET-158. RX PubMed=10508514; DOI=10.1038/13810; RA Amir R.E., Van den Veyver I.B., Wan M., Tran C.Q., Francke U., Zoghbi H.Y.; RT "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- RT CpG-binding protein 2."; RL Nat. Genet. 23:185-188(1999). RN [28] RP INVOLVEMENT IN MRXS13. RX PubMed=10986043; DOI=10.1086/303078; RA Meloni I., Bruttini M., Longo I., Mari F., Rizzolio F., D'Adamo P., RA Denvriendt K., Fryns J.-P., Toniolo D., Renieri A.; RT "A mutation in the Rett syndrome gene, MECP2, causes X-linked mental RT retardation and progressive spasticity in males."; RL Am. J. Hum. Genet. 67:982-985(2000). RN [29] RP VARIANTS RTT VAL-100; GLN-106; TRP-106; CYS-133; ARG-152; SER-155; MET-158; RP ARG-305; CYS-306 AND HIS-306, AND VARIANTS CYS-86; MET-203; PRO-287; RP ALA-291; LYS-397; ILE-412 AND THR-444. RX PubMed=11055898; DOI=10.1086/316913; RA Buyse I.M., Fang P., Hoon K.T., Amir R.E., Zoghbi H.Y., Roa B.B.; RT "Diagnostic testing for Rett syndrome by DHPLC and direct sequencing RT analysis of the MECP2 gene: identification of several novel mutations and RT polymorphisms."; RL Am. J. Hum. Genet. 67:1428-1436(2000). RN [30] RP VARIANT MRXS13 VAL-140, AND VARIANT MET-203. RX PubMed=11007980; DOI=10.1016/s0014-5793(00)01994-3; RA Orrico A., Lam C., Galli L., Dotti M.T., Hayek G., Tong S.F., Poon P.M., RA Zappella M., Federico A., Sorrentino V.; RT "MECP2 mutation in male patients with non-specific X-linked mental RT retardation."; RL FEBS Lett. 481:285-288(2000). RN [31] RP VARIANTS RTT LEU-101; HIS-101; THR-101; TRP-106; CYS-133; CYS-134; ARG-152; RP MET-158; ARG-225; LEU-302; CYS-306 AND HIS-306, AND VARIANTS LEU-229 AND RP THR-439. RX PubMed=10767337; DOI=10.1093/hmg/9.7.1119; RA Cheadle J.P., Gill H., Fleming N., Maynard J., Kerr A., Leonard H., RA Krawczak M., Cooper D.N., Lynch S., Thomas N., Hughes H., Hulten M., RA Ravine D., Sampson J.R., Clarke A.; RT "Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: RT correlation of disease severity with mutation type and location."; RL Hum. Mol. Genet. 9:1119-1129(2000). RN [32] RP VARIANTS RTT GLN-106; MET-158; ARG-302; CYS-306 AND ALA-322. RX PubMed=10814719; DOI=10.1093/hmg/9.9.1377; RA Bienvenu T., Carrie A., de Roux N., Vinet M.-C., Jonveaux P., Couvert P., RA Villard L., Arzimanoglou A., Beldjord C., Fontes M., Tardieu M., Chelly J.; RT "MECP2 mutations account for most cases of typical forms of Rett RT syndrome."; RL Hum. Mol. Genet. 9:1377-1384(2000). RN [33] RP VARIANTS RTT MET-158; HIS-302 AND CYS-306, AND VARIANTS VAL-201; ALA-232; RP LEU-251 AND SER-376. RX PubMed=10944854; DOI=10.1007/s100380070032; RA Amano K., Nomura Y., Segawa M., Yamakawa K.; RT "Mutational analysis of the MECP2 gene in Japanese patients with Rett RT syndrome."; RL J. Hum. Genet. 45:231-236(2000). RN [34] RP VARIANTS RTT GLU-97; TRP-106; CYS-133; ILE-155; MET-158 AND CYS-306. RX PubMed=10745042; DOI=10.1136/jmg.37.4.250; RA Xiang F., Buervenich S., Nicolao P., Bailey M.E., Zhang Z., Anvret M.; RT "Mutation screening in Rett syndrome patients."; RL J. Med. Genet. 37:250-255(2000). RN [35] RP VARIANTS RTT TRP-106; PHE-124; CYS-133; CYS-134; ARG-152; MET-158 AND RP CYS-306. RX PubMed=10991688; DOI=10.1136/jmg.37.8.608; RA Obata K., Matsuishi T., Yamashita Y., Fukuda T., Kuwajima K., Horiuchi I., RA Nagamitsu S., Iwanaga R., Kimura A., Omori I., Endo S., Mori K., Kondo I.; RT "Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in RT patients with Rett syndrome."; RL J. Med. Genet. 37:608-610(2000). RN [36] RP VARIANTS RTT ARG-101; TRP-106; MET-158 AND CYS-306, AND VARIANT LYS-397. RX PubMed=10991689; DOI=10.1136/jmg.37.8.610; RA Hampson K., Woods C.G., Latif F., Webb T.; RT "Mutations in the MECP2 gene in a cohort of girls with Rett syndrome."; RL J. Med. Genet. 37:610-612(2000). RN [37] RP VARIANT RTT HIS-133. RX PubMed=11706982; DOI=10.1002/ana.1272; RA Armstrong J., Poo P., Pineda M., Aibar E., Gean E., Catala V., Monros E.; RT "Classic Rett syndrome in a boy as a result of somatic mosaicism for a RT MECP2 mutation."; RL Ann. Neurol. 50:692-692(2001). RN [38] RP VARIANTS RTT ASP-120; CYS-133; MET-158 AND CYS-306. RX PubMed=11376998; DOI=10.1016/s0387-7604(01)00197-8; RA Inui K., Akagi M., Ono J., Tsukamoto H., Shimono K., Mano T., Imai K., RA Yamada M., Muramatsu T., Sakai N., Okada S.; RT "Mutational analysis of MECP2 in Japanese patients with atypical Rett RT syndrome."; RL Brain Dev. 23:212-215(2001). RN [39] RP VARIANTS RTT TRP-106; CYS-134; ARG-152; MET-158; ALA-302; CYS-306 AND RP ALA-322, AND VARIANTS VAL-201 AND LYS-397. RX PubMed=11738883; DOI=10.1016/s0387-7604(01)00342-4; RA Giunti L., Pelagatti S., Lazzerini V., Guarducci S., Lapi E., Coviello S., RA Cecconi A., Ombroni L., Andreucci E., Sani I., Brusaferri A., Lasagni A., RA Ricotti G., Giometto B., Nicolao P., Gasparini P., Granatiero M., RA Giovannucci Uzielli M.L.; RT "Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome RT girls: tentative genotype/phenotype correlation."; RL Brain Dev. 23:S242-S245(2001). RN [40] RP VARIANTS MRXS13 GLY-137; VAL-140; TRP-167; GLU-284; LEU-399 AND GLN-453. RX PubMed=11309367; DOI=10.1093/hmg/10.9.941; RA Couvert P., Bienvenu T., Aquaviva C., Poirier K., Moraine C., Gendrot C., RA Verloes A., Andres C., Le Fevre A.C., Souville I., Steffann J., RA des Portes V., Ropers H.-H., Yntema H.G., Fryns J.-P., Briault S., RA Chelly J., Cherif B.; RT "MECP2 is highly mutated in X-linked mental retardation."; RL Hum. Mol. Genet. 10:941-946(2001). RN [41] RP VARIANTS RTT TRP-106; GLY-111; CYS-133; GLU-135; ARG-152; GLY-156; MET-158; RP ILE-210; ARG-302 AND CYS-306. RX PubMed=11241840; DOI=10.1002/humu.3; RA Laccone F., Huppke P., Hanefeld F., Meins M.; RT "Mutation spectrum in patients with Rett syndrome in the German population: RT evidence of hot spot regions."; RL Hum. Mutat. 17:183-190(2001). RN [42] RP VARIANT RTT ARG-101, AND INVOLVEMENT IN AS. RX PubMed=11283202; DOI=10.1136/jmg.38.4.224; RA Watson P., Black G., Ramsden S., Barrow M., Super M., Kerr B., RA Clayton-Smith J.; RT "Angelman syndrome phenotype associated with mutations in MECP2, a gene RT encoding a methyl CpG binding protein."; RL J. Med. Genet. 38:224-228(2001). RN [43] RP VARIANT ENS-MECP2 SER-428. RX PubMed=11238684; DOI=10.1136/jmg.38.3.171; RA Imessaoudene B., Bonnefont J.-P., Royer G., Cormier-Daire V., Lyonnet S., RA Lyon G., Munnich A., Amiel J.; RT "MECP2 mutation in non-fatal, non-progressive encephalopathy in a male."; RL J. Med. Genet. 38:171-174(2001). RN [44] RP VARIANTS RTT SER-101; TRP-106; CYS-133; CYS-134; ARG-152; ALA-158 AND RP MET-158. RX PubMed=11269512; DOI=10.1007/s001090000155; RA Vacca M., Filippini F., Budillon A., Rossi V., Mercadante G., Manzati E., RA Gualandi F., Bigoni S., Trabanelli C., Pini G., Calzolari E., Ferlini A., RA Meloni I., Hayek G., Zappella M., Renieri A., D'Urso M., D'Esposito M., RA MacDonald F., Kerr A., Dhanjal S., Hulten M.; RT "Mutation analysis of the MECP2 gene in British and Italian Rett syndrome RT females."; RL J. Mol. Med. 78:648-655(2001). RN [45] RP VARIANTS RTT TYR-97; TRP-106; HIS-133; CYS-133; ARG-152; MET-158; ARG-305; RP CYS-306 AND LEU-322, AND VARIANT MET-197. RX PubMed=11402105; DOI=10.1212/wnl.56.11.1486; RA Hoffbuhr K., Devaney J.M., LaFleur B., Sirianni N., Scacheri C., Giron J., RA Schuette J., Innis J., Marino M., Philippart M., Narayanan V., Umansky R., RA Kronn D., Hoffman E.P., Naidu S.; RT "MeCP2 mutations in children with and without the phenotype of Rett RT syndrome."; RL Neurology 56:1486-1495(2001). RN [46] RP VARIANT MRXS13 VAL-140. RX PubMed=11885030; DOI=10.1086/339553; RA Klauck S.M., Lindsay S., Beyer K.S., Splitt M., Burn J., Poustka A.; RT "A mutation hot spot for nonspecific X-linked mental retardation in the RT MECP2 gene causes the PPM-X syndrome."; RL Am. J. Hum. Genet. 70:1034-1037(2002). RN [47] RP VARIANTS PRO-359 AND LYS-397. RX PubMed=11896461; DOI=10.1038/sj.ejhg.5200761; RA Moncla A., Kpebe A., Missirian C., Mancini J., Villard L.; RT "Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped RT boys: implications for genetic counselling."; RL Eur. J. Hum. Genet. 10:86-89(2002). RN [48] RP VARIANTS SER-196; SER-228; LYS-394 AND SER-480. RX PubMed=12111644; DOI=10.1038/sj.ejhg.5200836; RA Yntema H.G., Kleefstra T., Oudakker A.R., Romein T., de Vries B.B.A., RA Nillesen W., Sistermans E.A., Brunner H.G., Hamel B.C.J., van Bokhoven H.; RT "Low frequency of MECP2 mutations in mentally retarded males."; RL Eur. J. Hum. Genet. 10:487-490(2002). RN [49] RP VARIANTS VAL-181; SER-376; PRO-388 DEL AND LEU-402. RX PubMed=12384770; DOI=10.1007/s00439-002-0786-3; RA Beyer K.S., Blasi F., Bacchelli E., Klauck S.M., Maestrini E., Poustka A.; RT "Mutation analysis of the coding sequence of the MECP2 gene in infantile RT autism."; RL Hum. Genet. 111:305-309(2002). RN [50] RP VARIANT MRXS13 VAL-140. RX PubMed=12325019; DOI=10.1002/humu.10130; RA Winnepenninckx B., Errijgers V., Hayez-Delatte F., Reyniers E., Kooy R.F.; RT "Identification of a family with nonspecific mental retardation (MRX79) RT with the A140V mutation in the MECP2 gene: is there a need for routine RT screening?"; RL Hum. Mutat. 20:249-252(2002). RN [51] RP VARIANT MRXS13 VAL-140, VARIANT RTT TRP-344, VARIANTS MET-197; SER-376; RP LEU-399 AND SER-428, AND DISCUSSION OF PATHOGENIC ROLE. RX PubMed=12161600; DOI=10.1136/jmg.39.8.586; RA Laccone F., Zoll B., Huppke P., Hanefeld F., Pepinski W., Trappe R.; RT "MECP2 gene nucleotide changes and their pathogenicity in males: proceed RT with caution."; RL J. Med. Genet. 39:586-588(2002). RN [52] RP VARIANT MRXS13 VAL-140. RX PubMed=11805248; DOI=10.1212/wnl.58.2.226; RA Dotti M.T., Orrico A., De Stefano N., Battisti C., Sicurelli F., Severi S., RA Lam C.-W., Galli L., Sorrentino V., Federico A.; RT "A Rett syndrome MECP2 mutation that causes mental retardation in men."; RL Neurology 58:226-230(2002). RN [53] RP VARIANTS RTT CYS-133; MET-158; CYS-306 AND SER-388, AND VARIANT SER-376. RX PubMed=12567420; DOI=10.1002/ajmg.a.10898; RA Conforti F.L., Mazzei R., Magariello A., Patitucci A.L., Gabriele A.L., RA Muglia M., Quattrone A., Fiumara A., Pavone L., Barone R., Nistico R., RA Mangone L.; RT "Mutation analysis of the MECP2 gene in patients with Rett syndrome."; RL Am. J. Med. Genet. A 117:184-187(2003). RN [54] RP VARIANT RTT VAL-100. RX PubMed=12966522; DOI=10.1002/ajmg.a.20320; RA Hammer S., Dorrani N., Hartiala J., Stein S., Schanen N.C.; RT "Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation."; RL Am. J. Med. Genet. A 122:223-226(2003). RN [55] RP VARIANTS RTT GLN-10; PRO-128; CYS-133; ARG-152; MET-158 AND CYS-306. RX PubMed=12966523; DOI=10.1002/ajmg.a.20321; RA Smeets E., Schollen E., Moog U., Matthijs G., Herbergs J., Smeets H., RA Curfs L., Schrander-Stumpel C., Fryns J.-P.; RT "Rett syndrome in adolescent and adult females: clinical and molecular RT genetic findings."; RL Am. J. Med. Genet. A 122:227-233(2003). RN [56] RP VARIANT MRXS13 LEU-225. RX PubMed=12615169; DOI=10.1016/s1090-3798(02)00134-4; RA Moog U., Smeets E.E.J., van Roozendaal K.E.P., Schoenmakers S., RA Herbergs J., Schoonbrood-Lenssen A.M.J., Schrander-Stumpel C.T.R.M.; RT "Neurodevelopmental disorders in males related to the gene causing Rett RT syndrome in females (MECP2)."; RL Eur. J. Paediatr. Neurol. 7:5-12(2003). RN [57] RP INVOLVEMENT IN AUTSX3. RX PubMed=12770674; DOI=10.1016/s0887-8994(02)00624-0; RA Carney R.M., Wolpert C.M., Ravan S.A., Shahbazian M., Ashley-Koch A., RA Cuccaro M.L., Vance J.M., Pericak-Vance M.A.; RT "Identification of MeCP2 mutations in a series of females with autistic RT disorder."; RL Pediatr. Neurol. 28:205-211(2003). RN [58] RP VARIANTS RTT ARG-100; VAL-100; TRP-106; CYS-133; ARG-152; ALA-158; MET-158; RP VAL-161; CYS-306 AND HIS-306. RX PubMed=15057977; DOI=10.1002/ajmg.a.20571; RA Schanen C., Houwink E.J.F., Dorrani N., Lane J., Everett R., Feng A., RA Cantor R.M., Percy A.; RT "Phenotypic manifestations of MECP2 mutations in classical and atypical RT Rett syndrome."; RL Am. J. Med. Genet. A 126:129-140(2004). RN [59] RP INVOLVEMENT IN MRXSL. RX PubMed=16080119; DOI=10.1086/444549; RA Van Esch H., Bauters M., Ignatius J., Jansen M., Raynaud M., Hollanders K., RA Lugtenberg D., Bienvenu T., Jensen L.R., Gecz J., Moraine C., Marynen P., RA Fryns J.-P., Froyen G.; RT "Duplication of the MECP2 region is a frequent cause of severe mental RT retardation and progressive neurological symptoms in males."; RL Am. J. Hum. Genet. 77:442-453(2005). RN [60] RP VARIANT MRXS13 SER-322. RX PubMed=16966553; DOI=10.1212/01.wnl.0000233990.87889.15; RA Ventura P., Galluzzi R., Bacca S.M., Giorda R., Massagli A.; RT "A novel familial MECP2 mutation in a young boy: clinical and molecular RT findings."; RL Neurology 67:867-868(2006). RN [61] RP CHARACTERIZATION OF VARIANT RTT CYS-133, AND CHARACTERIZATION OF VARIANT RP MRXS13 VAL-140. RX PubMed=17296936; DOI=10.1073/pnas.0608056104; RA Nan X., Hou J., Maclean A., Nasir J., Lafuente M.J., Shu X., RA Kriaucionis S., Bird A.; RT "Interaction between chromatin proteins MECP2 and ATRX is disrupted by RT mutations that cause inherited mental retardation."; RL Proc. Natl. Acad. Sci. U.S.A. 104:2709-2714(2007). RN [62] RP VARIANT RTT 270-ARG--SER-486 DEL. RX PubMed=23662938; DOI=10.1111/epi.12203; RA Kodera H., Kato M., Nord A.S., Walsh T., Lee M., Yamanaka G., Tohyama J., RA Nakamura K., Nakagawa E., Ikeda T., Ben-Zeev B., Lev D., Lerman-Sagie T., RA Straussberg R., Tanabe S., Ueda K., Amamoto M., Ohta S., Nonoda Y., RA Nishiyama K., Tsurusaki Y., Nakashima M., Miyake N., Hayasaka K., RA King M.C., Matsumoto N., Saitsu H.; RT "Targeted capture and sequencing for detection of mutations causing early RT onset epileptic encephalopathy."; RL Epilepsia 54:1262-1269(2013). RN [63] RP VARIANT RTT CYS-133. RX PubMed=25818041; DOI=10.1111/epi.12954; RA Mercimek-Mahmutoglu S., Patel J., Cordeiro D., Hewson S., Callen D., RA Donner E.J., Hahn C.D., Kannu P., Kobayashi J., Minassian B.A., Moharir M., RA Siriwardena K., Weiss S.K., Weksberg R., Snead O.C. III; RT "Diagnostic yield of genetic testing in epileptic encephalopathy in RT childhood."; RL Epilepsia 56:707-716(2015). RN [64] RP VARIANTS RTT 270-ARG--SER-486 DEL AND CYS-306. RX PubMed=26993267; DOI=10.1136/jmedgenet-2015-103263; RA Trump N., McTague A., Brittain H., Papandreou A., Meyer E., Ngoh A., RA Palmer R., Morrogh D., Boustred C., Hurst J.A., Jenkins L., Kurian M.A., RA Scott R.H.; RT "Improving diagnosis and broadening the phenotypes in early-onset seizure RT and severe developmental delay disorders through gene panel analysis."; RL J. Med. Genet. 53:310-317(2016). RN [65] RP VARIANT RTT TRP-344. RX PubMed=28709814; DOI=10.1016/j.braindev.2017.06.003; RA Liang J.S., Lin L.J., Yang M.T., Wang J.S., Lu J.F.; RT "The therapeutic implication of a novel SCN2A mutation associated early- RT onset epileptic encephalopathy with Rett-like features."; RL Brain Dev. 39:877-881(2017). RN [66] RP VARIANT RTT CYS-133, AND VARIANT ASN-305. RX PubMed=27864847; DOI=10.1002/humu.23149; RG Clinical Study Group; RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D., RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S., RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.; RT "Diagnostic targeted resequencing in 349 patients with drug-resistant RT pediatric epilepsies identifies causative mutations in 30 different RT genes."; RL Hum. Mutat. 38:216-225(2017). RN [67] RP VARIANTS RTT ARG-305 AND CYS-306, CHARACTERIZATION OF VARIANTS RTT ARG-305 RP AND CYS-306, SUBCELLULAR LOCATION, AND INTERACTION WITH TBL1XR1 AND TBL1X. RX PubMed=28348241; DOI=10.1073/pnas.1700731114; RA Kruusvee V., Lyst M.J., Taylor C., Tarnauskaite Z., Bird A.P., Cook A.G.; RT "Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett RT syndrome and related disorders."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E3243-E3250(2017). CC -!- FUNCTION: Chromosomal protein that binds to methylated DNA. It can bind CC specifically to a single methyl-CpG pair. It is not influenced by CC sequences flanking the methyl-CpGs. Mediates transcriptional repression CC through interaction with histone deacetylase and the corepressor SIN3A. CC Binds both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)- CC containing DNA, with a preference for 5-methylcytosine (5mC). CC {ECO:0000250|UniProtKB:Q9Z2D6}. CC -!- SUBUNIT: Interacts with FNBP3 (By similarity). Interacts with CDKL5 CC (PubMed:15917271). Interacts with ATRX; MECP2 recruits ATRX to CC pericentric heterochromatin in neuronal cells (By similarity). CC Interacts with NCOR2 (By similarity). Interacts with TBL1XR1; bridges CC interaction between MECP2 and NCOR1 (PubMed:28348241). Interacts with CC TBL1X; recruits TBL1X to the heterochromatin foci (PubMed:28348241). CC {ECO:0000250|UniProtKB:Q9Z2D6, ECO:0000269|PubMed:15917271, CC ECO:0000269|PubMed:28348241}. CC -!- INTERACTION: CC P51608; Q6PCB6: ABHD17C; NbExp=3; IntAct=EBI-1189067, EBI-22011868; CC P51608; P63010-2: AP2B1; NbExp=3; IntAct=EBI-1189067, EBI-11529439; CC P51608; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-1189067, EBI-14199987; CC P51608; Q9UII2: ATP5IF1; NbExp=3; IntAct=EBI-1189067, EBI-718459; CC P51608; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-1189067, EBI-2837444; CC P51608; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-1189067, EBI-350590; CC P51608; P35222: CTNNB1; NbExp=3; IntAct=EBI-1189067, EBI-491549; CC P51608; Q7L576: CYFIP1; NbExp=3; IntAct=EBI-1189067, EBI-1048143; CC P51608; Q9UHI6: DDX20; NbExp=3; IntAct=EBI-1189067, EBI-347658; CC P51608; O75398: DEAF1; NbExp=3; IntAct=EBI-1189067, EBI-718185; CC P51608; Q99504: EYA3; NbExp=3; IntAct=EBI-1189067, EBI-9089567; CC P51608; Q6PIV2: FOXR1; NbExp=3; IntAct=EBI-1189067, EBI-10253815; CC P51608; Q9H2X6: HIPK2; NbExp=2; IntAct=EBI-1189067, EBI-348345; CC P51608; P04792: HSPB1; NbExp=3; IntAct=EBI-1189067, EBI-352682; CC P51608; P42858: HTT; NbExp=18; IntAct=EBI-1189067, EBI-466029; CC P51608; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-1189067, EBI-21911304; CC P51608; Q92993-2: KAT5; NbExp=3; IntAct=EBI-1189067, EBI-20795332; CC P51608; Q9Y2M5: KLHL20; NbExp=4; IntAct=EBI-1189067, EBI-714379; CC P51608; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-1189067, EBI-10261141; CC P51608; P07948: LYN; NbExp=3; IntAct=EBI-1189067, EBI-79452; CC P51608; P61244: MAX; NbExp=2; IntAct=EBI-1189067, EBI-751711; CC P51608; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-1189067, EBI-4397720; CC P51608; O43196-2: MSH5; NbExp=3; IntAct=EBI-1189067, EBI-25844576; CC P51608; Q99457: NAP1L3; NbExp=3; IntAct=EBI-1189067, EBI-8645631; CC P51608; P07196: NEFL; NbExp=3; IntAct=EBI-1189067, EBI-475646; CC P51608; Q96CV9: OPTN; NbExp=3; IntAct=EBI-1189067, EBI-748974; CC P51608; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-1189067, EBI-1058491; CC P51608; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-1189067, EBI-25830200; CC P51608; O75925: PIAS1; NbExp=3; IntAct=EBI-1189067, EBI-629434; CC P51608; P60891: PRPS1; NbExp=3; IntAct=EBI-1189067, EBI-749195; CC P51608; P57729: RAB38; NbExp=3; IntAct=EBI-1189067, EBI-6552718; CC P51608; Q9NS23-4: RASSF1; NbExp=3; IntAct=EBI-1189067, EBI-438710; CC P51608; Q8WWW0-2: RASSF5; NbExp=3; IntAct=EBI-1189067, EBI-960502; CC P51608; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-1189067, EBI-25829984; CC P51608; Q96D59: RNF183; NbExp=3; IntAct=EBI-1189067, EBI-743938; CC P51608; Q96ST3: SIN3A; NbExp=2; IntAct=EBI-1189067, EBI-347218; CC P51608; P51531: SMARCA2; NbExp=4; IntAct=EBI-1189067, EBI-679562; CC P51608; Q12824: SMARCB1; NbExp=3; IntAct=EBI-1189067, EBI-358419; CC P51608; Q16637-3: SMN2; NbExp=3; IntAct=EBI-1189067, EBI-395447; CC P51608; Q7Z6I5: SPATA12; NbExp=3; IntAct=EBI-1189067, EBI-10696971; CC P51608; O75558: STX11; NbExp=3; IntAct=EBI-1189067, EBI-714135; CC P51608; P63165: SUMO1; NbExp=2; IntAct=EBI-1189067, EBI-80140; CC P51608; Q86WT6-2: TRIM69; NbExp=3; IntAct=EBI-1189067, EBI-11525489; CC P51608; Q86UV6-2: TRIM74; NbExp=3; IntAct=EBI-1189067, EBI-10259086; CC P51608; P10599: TXN; NbExp=3; IntAct=EBI-1189067, EBI-594644; CC P51608; O76024: WFS1; NbExp=3; IntAct=EBI-1189067, EBI-720609; CC P51608; Q9QZR5: Hipk2; Xeno; NbExp=3; IntAct=EBI-1189067, EBI-366905; CC P51608; Q60974: Ncor1; Xeno; NbExp=4; IntAct=EBI-1189067, EBI-349004; CC P51608; Q9WU42: Ncor2; Xeno; NbExp=4; IntAct=EBI-1189067, EBI-6673326; CC P51608; Q9QXE7: Tbl1x; Xeno; NbExp=3; IntAct=EBI-1189067, EBI-8821270; CC P51608; Q8BHJ5: Tbl1xr1; Xeno; NbExp=4; IntAct=EBI-1189067, EBI-1216384; CC P51608-1; O88508: Dnmt3a; Xeno; NbExp=10; IntAct=EBI-26687319, EBI-995154; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9Z2D6}. CC Note=Colocalized with methyl-CpG in the genome. Colocalized with TBL1X CC to the heterochromatin foci. {ECO:0000269|PubMed:28348241}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=A; Synonyms=Beta; CC IsoId=P51608-1; Sequence=Displayed; CC Name=B; Synonyms=Alpha; CC IsoId=P51608-2; Sequence=VSP_022948; CC -!- TISSUE SPECIFICITY: Present in all adult somatic tissues tested. CC -!- PTM: Phosphorylated on Ser-423 in brain upon synaptic activity, which CC attenuates its repressor activity and seems to regulate dendritic CC growth and spine maturation. {ECO:0000250}. CC -!- DISEASE: Angelman syndrome (AS) [MIM:105830]: A neurodevelopmental CC disorder characterized by severe motor and intellectual retardation, CC ataxia, frequent jerky limb movements and flapping of the arms and CC hands, hypotonia, seizures, absence of speech, frequent smiling and CC episodes of paroxysmal laughter, open-mouthed expression revealing the CC tongue. {ECO:0000269|PubMed:11283202}. Note=The disease may be caused CC by variants affecting the gene represented in this entry. CC -!- DISEASE: Intellectual developmental disorder, X-linked, syndromic 13 CC (MRXS13) [MIM:300055]: A disorder characterized by significantly below CC average general intellectual functioning associated with impairments in CC adaptive behavior and manifested during the developmental period. CC MRXS13 patients manifest intellectual disability associated with other CC variable features such as spasticity, episodes of manic depressive CC psychosis, increased tone and macroorchidism. CC {ECO:0000269|PubMed:10986043, ECO:0000269|PubMed:11007980, CC ECO:0000269|PubMed:11309367, ECO:0000269|PubMed:11805248, CC ECO:0000269|PubMed:11885030, ECO:0000269|PubMed:12161600, CC ECO:0000269|PubMed:12325019, ECO:0000269|PubMed:12615169, CC ECO:0000269|PubMed:16966553, ECO:0000269|PubMed:17296936}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Rett syndrome (RTT) [MIM:312750]: An X-linked dominant CC neurodevelopmental disorder, and one of the most common causes of CC intellectual disability in females. Patients appear to develop normally CC until 6 to 18 months of age, then gradually lose speech and purposeful CC hand movements, and develop microcephaly, seizures, autism, ataxia, CC intellectual disability and stereotypic hand movements. After initial CC regression, the condition stabilizes and patients usually survive into CC adulthood. {ECO:0000269|PubMed:10508514, ECO:0000269|PubMed:10577905, CC ECO:0000269|PubMed:10745042, ECO:0000269|PubMed:10767337, CC ECO:0000269|PubMed:10814719, ECO:0000269|PubMed:10944854, CC ECO:0000269|PubMed:10991688, ECO:0000269|PubMed:10991689, CC ECO:0000269|PubMed:11055898, ECO:0000269|PubMed:11241840, CC ECO:0000269|PubMed:11269512, ECO:0000269|PubMed:11283202, CC ECO:0000269|PubMed:11376998, ECO:0000269|PubMed:11402105, CC ECO:0000269|PubMed:11706982, ECO:0000269|PubMed:11738883, CC ECO:0000269|PubMed:12161600, ECO:0000269|PubMed:12567420, CC ECO:0000269|PubMed:12966522, ECO:0000269|PubMed:12966523, CC ECO:0000269|PubMed:15034579, ECO:0000269|PubMed:15057977, CC ECO:0000269|PubMed:17296936, ECO:0000269|PubMed:23662938, CC ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26993267, CC ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:28348241, CC ECO:0000269|PubMed:28709814}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Autism, X-linked 3 (AUTSX3) [MIM:300496]: A complex CC multifactorial, pervasive developmental disorder characterized by CC impairments in reciprocal social interaction and communication, CC restricted and stereotyped patterns of interests and activities, and CC the presence of developmental abnormalities by 3 years of age. Most CC individuals with autism also manifest moderate intellectual disability. CC {ECO:0000269|PubMed:12770674}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Encephalopathy, neonatal severe, due to MECP2 mutations (ENS- CC MECP2) [MIM:300673]: A neurodevelopmental disorder characterized by CC severe neonatal encephalopathy, developmental delay, intellectual CC disability, microcephaly, seizures. Additional features include CC respiratory insufficiency and central hypoventilation, gastroesophageal CC reflux, axial hypotonia, hyperreflexia and dyskinetic movements. CC {ECO:0000269|PubMed:11238684}. Note=The disease is caused by variants CC affecting the gene represented in this entry. The MECP2 gene is mutated CC in Rett syndrome, a severe neurodevelopmental disorder that almost CC always occurs in females. Although it was first thought that MECP2 CC mutations causing Rett syndrome were lethal in males, later reports CC identified a severe neonatal encephalopathy in surviving male sibs of CC patients with Rett syndrome. Additional reports have confirmed a severe CC phenotype in males with Rett syndrome-associated MECP2 mutations. CC -!- DISEASE: Intellectual developmental disorder, X-linked, syndromic, Lubs CC type (MRXSL) [MIM:300260]: A disorder characterized by significantly CC below average general intellectual functioning associated with CC impairments in adaptive behavior and manifested during the CC developmental period. MRXSL patients manifest intellectual disability CC associated with variable features. They include swallowing dysfunction CC and gastroesophageal reflux with secondary recurrent respiratory CC infections, hypotonia, mild myopathy and characteristic facies such as CC downslanting palpebral fissures, hypertelorism and a short nose with a CC low nasal bridge. {ECO:0000269|PubMed:16080119}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC Increased dosage of MECP2 due to gene duplication appears to be CC responsible for the intellectual disability phenotype. CC -!- MISCELLANEOUS: [Isoform B]: Ten times higher expression levels than CC isoform A in brain. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAD97991.1; Type=Erroneous initiation; Note=Truncated N-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; L37298; AAC32737.1; -; mRNA. DR EMBL; X99686; CAA68001.1; -; mRNA. DR EMBL; AJ132917; CAB46446.1; -; mRNA. DR EMBL; AF158180; AAF33023.1; -; mRNA. DR EMBL; Y12643; CAA73190.1; -; mRNA. DR EMBL; AY541280; AAS55455.1; -; mRNA. DR EMBL; BX538060; CAD97991.1; ALT_INIT; mRNA. DR EMBL; AF030876; AAC08757.1; -; Genomic_DNA. DR EMBL; BC011612; AAH11612.1; -; mRNA. DR EMBL; X89430; CAA61599.1; -; mRNA. DR EMBL; X94628; CAA64331.1; -; Genomic_DNA. DR CCDS; CCDS14741.1; -. [P51608-1] DR CCDS; CCDS48193.1; -. [P51608-2] DR RefSeq; NP_001104262.1; NM_001110792.2. [P51608-2] DR RefSeq; NP_001303266.1; NM_001316337.1. DR RefSeq; NP_004983.1; NM_004992.4. [P51608-1] DR RefSeq; XP_047298071.1; XM_047442115.1. [P51608-1] DR RefSeq; XP_047298072.1; XM_047442116.1. [P51608-1] DR RefSeq; XP_054183066.1; XM_054327091.1. [P51608-1] DR RefSeq; XP_054183067.1; XM_054327092.1. [P51608-1] DR PDB; 1QK9; NMR; -; A=77-166. DR PDB; 3C2I; X-ray; 2.50 A; A=77-167. DR PDB; 5BT2; X-ray; 2.20 A; A=77-167. DR PDB; 6C1Y; X-ray; 2.30 A; A/B=80-164. DR PDB; 6OGJ; X-ray; 1.80 A; A/B=77-166. DR PDB; 6OGK; X-ray; 1.65 A; A=77-167. DR PDB; 6YWW; X-ray; 2.10 A; A=77-161. DR PDB; 8AJR; NMR; -; A=89-181. DR PDB; 8ALQ; NMR; -; A=89-181. DR PDBsum; 1QK9; -. DR PDBsum; 3C2I; -. DR PDBsum; 5BT2; -. DR PDBsum; 6C1Y; -. DR PDBsum; 6OGJ; -. DR PDBsum; 6OGK; -. DR PDBsum; 6YWW; -. DR PDBsum; 8AJR; -. DR PDBsum; 8ALQ; -. DR AlphaFoldDB; P51608; -. DR BMRB; P51608; -. DR SMR; P51608; -. DR BioGRID; 110368; 1281. DR CORUM; P51608; -. DR DIP; DIP-39983N; -. DR FunCoup; P51608; 855. DR IntAct; P51608; 217. DR MINT; P51608; -. DR STRING; 9606.ENSP00000395535; -. DR BindingDB; P51608; -. DR ChEMBL; CHEMBL3638346; -. DR GlyCosmos; P51608; 2 sites, 1 glycan. DR GlyGen; P51608; 8 sites, 1 O-linked glycan (8 sites). DR iPTMnet; P51608; -. DR MetOSite; P51608; -. DR PhosphoSitePlus; P51608; -. DR BioMuta; MECP2; -. DR DMDM; 1708973; -. DR jPOST; P51608; -. DR MassIVE; P51608; -. DR PaxDb; 9606-ENSP00000395535; -. DR PeptideAtlas; P51608; -. DR ProteomicsDB; 56344; -. [P51608-1] DR ProteomicsDB; 56345; -. [P51608-2] DR Pumba; P51608; -. DR ABCD; P51608; 1 sequenced antibody. DR Antibodypedia; 394; 899 antibodies from 47 providers. DR DNASU; 4204; -. DR Ensembl; ENST00000303391.11; ENSP00000301948.6; ENSG00000169057.26. [P51608-1] DR Ensembl; ENST00000453960.7; ENSP00000395535.2; ENSG00000169057.26. [P51608-2] DR Ensembl; ENST00000630151.3; ENSP00000486089.2; ENSG00000169057.26. [P51608-1] DR GeneID; 4204; -. DR KEGG; hsa:4204; -. DR MANE-Select; ENST00000453960.7; ENSP00000395535.2; NM_001110792.2; NP_001104262.1. [P51608-2] DR UCSC; uc004fjv.3; human. [P51608-1] DR AGR; HGNC:6990; -. DR ClinPGx; PA30729; -. DR CTD; 4204; -. DR DisGeNET; 4204; -. DR GeneCards; MECP2; -. DR GeneReviews; MECP2; -. DR HGNC; HGNC:6990; MECP2. DR HPA; ENSG00000169057; Low tissue specificity. DR MalaCards; MECP2; -. DR MIM; 105830; phenotype. DR MIM; 300005; gene. DR MIM; 300055; phenotype. DR MIM; 300260; phenotype. DR MIM; 300496; phenotype. DR MIM; 300673; phenotype. DR MIM; 312750; phenotype. DR OpenTargets; ENSG00000169057; -. DR Orphanet; 3095; Atypical Rett syndrome. DR Orphanet; 209370; MECP2-related severe neonatal encephalopathy. DR Orphanet; 1762; Proximal Xq28 duplication syndrome. DR Orphanet; 778; Rett syndrome. DR Orphanet; 536; Systemic lupus erythematosus. DR Orphanet; 3077; X-linked intellectual disability-psychosis-macroorchidism syndrome. DR Orphanet; 777; X-linked non-syndromic intellectual disability. DR VEuPathDB; HostDB:ENSG00000169057; -. DR eggNOG; KOG4161; Eukaryota. DR GeneTree; ENSGT00530000063687; -. DR HOGENOM; CLU_045066_0_0_1; -. DR InParanoid; P51608; -. DR OMA; PADKCRN; -. DR OrthoDB; 10072024at2759; -. DR PAN-GO; P51608; 6 GO annotations based on evolutionary models. DR PhylomeDB; P51608; -. DR PathwayCommons; P51608; -. DR Reactome; R-HSA-8986944; Transcriptional Regulation by MECP2. DR Reactome; R-HSA-9022534; Loss of MECP2 binding ability to 5hmC-DNA. DR Reactome; R-HSA-9022535; Loss of phosphorylation of MECP2 at T308. DR Reactome; R-HSA-9022537; Loss of MECP2 binding ability to the NCoR/SMRT complex. DR Reactome; R-HSA-9022538; Loss of MECP2 binding ability to 5mC-DNA. DR Reactome; R-HSA-9022692; Regulation of MECP2 expression and activity. DR Reactome; R-HSA-9022699; MECP2 regulates neuronal receptors and channels. DR Reactome; R-HSA-9022702; MECP2 regulates transcription of neuronal ligands. DR Reactome; R-HSA-9022707; MECP2 regulates transcription factors. DR Reactome; R-HSA-9022927; MECP2 regulates transcription of genes involved in GABA signaling. DR Reactome; R-HSA-9725371; Nuclear events stimulated by ALK signaling in cancer. DR SignaLink; P51608; -. DR SIGNOR; P51608; -. DR Agora; ENSG00000169057; -. DR BioGRID-ORCS; 4204; 9 hits in 796 CRISPR screens. DR ChiTaRS; MECP2; human. DR EvolutionaryTrace; P51608; -. DR GeneWiki; MECP2; -. DR GenomeRNAi; 4204; -. DR Pharos; P51608; Tchem. DR PRO; PR:P51608; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; P51608; protein. DR Bgee; ENSG00000169057; Expressed in paraflocculus and 186 other cell types or tissues. DR ExpressionAtlas; P51608; baseline and differential. DR GO; GO:0005813; C:centrosome; IMP:CAFA. DR GO; GO:0005829; C:cytosol; IEA:Ensembl. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0000792; C:heterochromatin; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0003682; F:chromatin binding; IBA:GO_Central. DR GO; GO:0003677; F:DNA binding; TAS:ProtInc. DR GO; GO:0010385; F:double-stranded methylated DNA binding; IMP:MGI. DR GO; GO:0140566; F:histone reader activity; IEA:Ensembl. DR GO; GO:0008327; F:methyl-CpG binding; IBA:GO_Central. DR GO; GO:0060090; F:molecular adaptor activity; EXP:DisProt. DR GO; GO:0140693; F:molecular condensate scaffold activity; IMP:DisProt. DR GO; GO:0003729; F:mRNA binding; IEA:Ensembl. DR GO; GO:0003676; F:nucleic acid binding; EXP:DisProt. DR GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0035197; F:siRNA binding; IEA:Ensembl. DR GO; GO:0003714; F:transcription corepressor activity; IDA:ARUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0006576; P:biogenic amine metabolic process; IEA:Ensembl. DR GO; GO:0032048; P:cardiolipin metabolic process; IEA:Ensembl. DR GO; GO:0050432; P:catecholamine secretion; IEA:Ensembl. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0016358; P:dendrite development; IEA:Ensembl. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0071514; P:genomic imprinting; IMP:MGI. DR GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl. DR GO; GO:0008211; P:glucocorticoid metabolic process; IEA:Ensembl. DR GO; GO:0006541; P:glutamine metabolic process; IEA:Ensembl. DR GO; GO:0031507; P:heterochromatin formation; IEA:Ensembl. DR GO; GO:0006020; P:inositol metabolic process; IEA:Ensembl. DR GO; GO:0008104; P:intracellular protein localization; IEA:Ensembl. DR GO; GO:0007616; P:long-term memory; IEA:Ensembl. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:BHF-UCL. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:BHF-UCL. DR GO; GO:0044027; P:negative regulation of gene expression via chromosomal CpG island methylation; IDA:BHF-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051151; P:negative regulation of smooth muscle cell differentiation; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0001976; P:nervous system process involved in regulation of systemic arterial blood pressure; IEA:Ensembl. DR GO; GO:0042551; P:neuron maturation; IEA:Ensembl. DR GO; GO:0007219; P:Notch signaling pathway; IEA:Ensembl. DR GO; GO:0046470; P:phosphatidylcholine metabolic process; IEA:Ensembl. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IEA:Ensembl. DR GO; GO:0090063; P:positive regulation of microtubule nucleation; IMP:CAFA. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0019230; P:proprioception; IEA:Ensembl. DR GO; GO:0002087; P:regulation of respiratory gaseous exchange by nervous system process; IEA:Ensembl. DR GO; GO:0007585; P:respiratory gaseous exchange by respiratory system; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0051707; P:response to other organism; IEA:Ensembl. DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl. DR GO; GO:0035176; P:social behavior; IEA:Ensembl. DR GO; GO:0001964; P:startle response; IEA:Ensembl. DR GO; GO:0007416; P:synapse assembly; IEA:Ensembl. DR GO; GO:0099191; P:trans-synaptic signaling by BDNF; IEA:Ensembl. DR GO; GO:0021591; P:ventricular system development; IEA:Ensembl. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd01396; MeCP2_MBD; 1. DR DisProt; DP00539; -. DR FunFam; 3.30.890.10:FF:000004; Methyl-CpG-binding protein 2; 1. DR Gene3D; 3.30.890.10; Methyl-cpg-binding Protein 2, Chain A; 1. DR IDEAL; IID00717; -. DR InterPro; IPR016177; DNA-bd_dom_sf. DR InterPro; IPR017353; Me_CpG-bd_MeCP2. DR InterPro; IPR045138; MeCP2/MBD4. DR InterPro; IPR001739; Methyl_CpG_DNA-bd. DR PANTHER; PTHR15074; METHYL-CPG-BINDING PROTEIN; 1. DR PANTHER; PTHR15074:SF6; METHYL-CPG-BINDING PROTEIN 2; 1. DR Pfam; PF01429; MBD; 1. DR PIRSF; PIRSF038006; Methyl_CpG_bd_MeCP2; 1. DR SMART; SM00391; MBD; 1. DR SUPFAM; SSF54171; DNA-binding domain; 1. DR PROSITE; PS50982; MBD; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Autism; KW Autism spectrum disorder; Chromosomal rearrangement; Disease variant; KW DNA-binding; Intellectual disability; Methylation; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation. FT CHAIN 1..486 FT /note="Methyl-CpG-binding protein 2" FT /id="PRO_0000096345" FT DOMAIN 90..162 FT /note="MBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00338" FT DNA_BIND 185..197 FT /note="A.T hook 1" FT DNA_BIND 265..277 FT /note="A.T hook 2" FT REGION 1..119 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 147..275 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..309 FT /note="Interaction with NCOR2" FT /evidence="ECO:0000250|UniProtKB:Q9Z2D6" FT REGION 285..309 FT /note="Interaction with TBL1XR1" FT /evidence="ECO:0000250|UniProtKB:Q9Z2D6" FT REGION 324..486 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 34..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 52..64 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 68..81 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 352..361 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 378..393 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 435..447 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 13 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00566" FT MOD_RES 80 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 116 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 162 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q9Z2D6" FT MOD_RES 216 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 229 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 321 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q9Z2D6" FT MOD_RES 423 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z2D6" FT MOD_RES 426 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:24275569" FT MOD_RES 449 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT VAR_SEQ 1..9 FT /note="MVAGMLGLR -> MAAAAAAAPSGGGGGGEEERL (in isoform B)" FT /evidence="ECO:0000303|PubMed:15034579, FT ECO:0000303|PubMed:17974005" FT /id="VSP_022948" FT VARIANT 10 FT /note="E -> Q (in RTT; dbSNP:rs61754421)" FT /evidence="ECO:0000269|PubMed:12966523" FT /id="VAR_018180" FT VARIANT 86 FT /note="S -> C (in dbSNP:rs61754445)" FT /evidence="ECO:0000269|PubMed:11055898" FT /id="VAR_018181" FT VARIANT 97 FT /note="D -> E (in RTT; dbSNP:rs61754449)" FT /evidence="ECO:0000269|PubMed:10745042" FT /id="VAR_023552" FT VARIANT 97 FT /note="D -> Y (in RTT; dbSNP:rs61754448)" FT /evidence="ECO:0000269|PubMed:11402105" FT /id="VAR_018182" FT VARIANT 100 FT /note="L -> R (in RTT; dbSNP:rs61754451)" FT /evidence="ECO:0000269|PubMed:15057977" FT /id="VAR_023553" FT VARIANT 100 FT /note="L -> V (in RTT; dbSNP:rs28935168)" FT /evidence="ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:12966522, ECO:0000269|PubMed:15057977" FT /id="VAR_017462" FT VARIANT 101 FT /note="P -> H (in RTT; dbSNP:rs61754453)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018183" FT VARIANT 101 FT /note="P -> L (in RTT; dbSNP:rs61754453)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018184" FT VARIANT 101 FT /note="P -> R (in RTT; also in a patient with Angelman FT syndrome and some typical RTT features; dbSNP:rs61754453)" FT /evidence="ECO:0000269|PubMed:10991689, FT ECO:0000269|PubMed:11283202" FT /id="VAR_010276" FT VARIANT 101 FT /note="P -> S (in RTT; dbSNP:rs61754452)" FT /evidence="ECO:0000269|PubMed:11269512" FT /id="VAR_023554" FT VARIANT 101 FT /note="P -> T (in RTT; dbSNP:rs61754452)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018185" FT VARIANT 106 FT /note="R -> Q (in RTT; dbSNP:rs61754457)" FT /evidence="ECO:0000269|PubMed:10814719, FT ECO:0000269|PubMed:11055898" FT /id="VAR_018186" FT VARIANT 106 FT /note="R -> W (in RTT; dbSNP:rs28934907)" FT /evidence="ECO:0000269|PubMed:10508514, FT ECO:0000269|PubMed:10577905, ECO:0000269|PubMed:10745042, FT ECO:0000269|PubMed:10767337, ECO:0000269|PubMed:10991688, FT ECO:0000269|PubMed:10991689, ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:11241840, ECO:0000269|PubMed:11269512, FT ECO:0000269|PubMed:11402105, ECO:0000269|PubMed:11738883, FT ECO:0000269|PubMed:15057977" FT /id="VAR_010272" FT VARIANT 111 FT /note="R -> G (in RTT; dbSNP:rs61754459)" FT /evidence="ECO:0000269|PubMed:11241840" FT /id="VAR_018187" FT VARIANT 120 FT /note="Y -> D (in RTT; dbSNP:rs267608454)" FT /evidence="ECO:0000269|PubMed:11376998" FT /id="VAR_023555" FT VARIANT 124 FT /note="L -> F (in RTT; dbSNP:rs61755763)" FT /evidence="ECO:0000269|PubMed:10991688" FT /id="VAR_010277" FT VARIANT 128 FT /note="Q -> P (in RTT; dbSNP:rs61748383)" FT /evidence="ECO:0000269|PubMed:12966523" FT /id="VAR_018188" FT VARIANT 133 FT /note="R -> C (in RTT; impairs interaction with ATRX and FT abolishes ATRX recruitment to heterochromatin; FT dbSNP:rs28934904)" FT /evidence="ECO:0000269|PubMed:10508514, FT ECO:0000269|PubMed:10577905, ECO:0000269|PubMed:10745042, FT ECO:0000269|PubMed:10767337, ECO:0000269|PubMed:10991688, FT ECO:0000269|PubMed:11055898, ECO:0000269|PubMed:11241840, FT ECO:0000269|PubMed:11269512, ECO:0000269|PubMed:11376998, FT ECO:0000269|PubMed:11402105, ECO:0000269|PubMed:12567420, FT ECO:0000269|PubMed:12966523, ECO:0000269|PubMed:15057977, FT ECO:0000269|PubMed:17296936, ECO:0000269|PubMed:25818041, FT ECO:0000269|PubMed:27864847" FT /id="VAR_010273" FT VARIANT 133 FT /note="R -> H (in RTT; dbSNP:rs61748389)" FT /evidence="ECO:0000269|PubMed:11402105, FT ECO:0000269|PubMed:11706982" FT /id="VAR_018189" FT VARIANT 134 FT /note="S -> C (in RTT; dbSNP:rs61748390)" FT /evidence="ECO:0000269|PubMed:10767337, FT ECO:0000269|PubMed:10991688, ECO:0000269|PubMed:11269512, FT ECO:0000269|PubMed:11738883" FT /id="VAR_010278" FT VARIANT 135 FT /note="K -> E (in RTT; dbSNP:rs61748391)" FT /evidence="ECO:0000269|PubMed:11241840" FT /id="VAR_018190" FT VARIANT 137 FT /note="E -> G (in MRXS13; dbSNP:rs61748392)" FT /evidence="ECO:0000269|PubMed:11309367" FT /id="VAR_017581" FT VARIANT 140 FT /note="A -> V (in MRXS13; impairs interaction with ATRX and FT abolishes ATRX recruitment to heterochromatin; FT dbSNP:rs28934908)" FT /evidence="ECO:0000269|PubMed:11007980, FT ECO:0000269|PubMed:11309367, ECO:0000269|PubMed:11805248, FT ECO:0000269|PubMed:11885030, ECO:0000269|PubMed:12161600, FT ECO:0000269|PubMed:12325019, ECO:0000269|PubMed:17296936" FT /id="VAR_010279" FT VARIANT 152 FT /note="P -> R (in RTT; dbSNP:rs61748404)" FT /evidence="ECO:0000269|PubMed:10767337, FT ECO:0000269|PubMed:10991688, ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:11241840, ECO:0000269|PubMed:11269512, FT ECO:0000269|PubMed:11402105, ECO:0000269|PubMed:11738883, FT ECO:0000269|PubMed:12966523, ECO:0000269|PubMed:15057977" FT /id="VAR_010280" FT VARIANT 155 FT /note="F -> I (in RTT; dbSNP:rs61748406)" FT /evidence="ECO:0000269|PubMed:10745042" FT /id="VAR_023556" FT VARIANT 155 FT /note="F -> S (in RTT; dbSNP:rs28934905)" FT /evidence="ECO:0000269|PubMed:10508514, FT ECO:0000269|PubMed:10577905, ECO:0000269|PubMed:11055898" FT /id="VAR_010274" FT VARIANT 156 FT /note="D -> G (in RTT; dbSNP:rs61748407)" FT /evidence="ECO:0000269|PubMed:11241840" FT /id="VAR_018191" FT VARIANT 158 FT /note="T -> A (in RTT; dbSNP:rs61748411)" FT /evidence="ECO:0000269|PubMed:11269512, FT ECO:0000269|PubMed:15057977" FT /id="VAR_023557" FT VARIANT 158 FT /note="T -> M (in RTT; dbSNP:rs28934906)" FT /evidence="ECO:0000269|PubMed:10508514, FT ECO:0000269|PubMed:10577905, ECO:0000269|PubMed:10745042, FT ECO:0000269|PubMed:10767337, ECO:0000269|PubMed:10814719, FT ECO:0000269|PubMed:10944854, ECO:0000269|PubMed:10991688, FT ECO:0000269|PubMed:10991689, ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:11241840, ECO:0000269|PubMed:11269512, FT ECO:0000269|PubMed:11376998, ECO:0000269|PubMed:11402105, FT ECO:0000269|PubMed:11738883, ECO:0000269|PubMed:12567420, FT ECO:0000269|PubMed:12966523, ECO:0000269|PubMed:15057977" FT /id="VAR_010275" FT VARIANT 161 FT /note="G -> V (in RTT; dbSNP:rs61748417)" FT /evidence="ECO:0000269|PubMed:15057977" FT /id="VAR_023558" FT VARIANT 167 FT /note="R -> W (in MRXS13; dbSNP:rs61748420)" FT /evidence="ECO:0000269|PubMed:11309367" FT /id="VAR_018192" FT VARIANT 181 FT /note="A -> V (in dbSNP:rs61749705)" FT /evidence="ECO:0000269|PubMed:12384770" FT /id="VAR_018193" FT VARIANT 196 FT /note="T -> S (in dbSNP:rs61749713)" FT /evidence="ECO:0000269|PubMed:12111644" FT /id="VAR_018194" FT VARIANT 197 FT /note="T -> M (in dbSNP:rs61749714)" FT /evidence="ECO:0000269|PubMed:11402105, FT ECO:0000269|PubMed:12161600" FT /id="VAR_018195" FT VARIANT 201 FT /note="A -> V (in dbSNP:rs61748381)" FT /evidence="ECO:0000269|PubMed:10944854, FT ECO:0000269|PubMed:11738883" FT /id="VAR_010281" FT VARIANT 203 FT /note="T -> M (in dbSNP:rs61749720)" FT /evidence="ECO:0000269|PubMed:11007980, FT ECO:0000269|PubMed:11055898" FT /id="VAR_018196" FT VARIANT 210 FT /note="K -> I (in RTT; dbSNP:rs61749730)" FT /evidence="ECO:0000269|PubMed:11241840" FT /id="VAR_018197" FT VARIANT 225 FT /note="P -> L (in MRXS13; dbSNP:rs61749715)" FT /evidence="ECO:0000269|PubMed:12615169" FT /id="VAR_037664" FT VARIANT 225 FT /note="P -> R (in RTT; dbSNP:rs61749715)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018198" FT VARIANT 228 FT /note="T -> S (in dbSNP:rs61749738)" FT /evidence="ECO:0000269|PubMed:12111644" FT /id="VAR_018199" FT VARIANT 229 FT /note="S -> L (in dbSNP:rs61749739)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018200" FT VARIANT 232 FT /note="G -> A (in dbSNP:rs61748422)" FT /evidence="ECO:0000269|PubMed:10944854" FT /id="VAR_018201" FT VARIANT 251 FT /note="P -> L (in dbSNP:rs61750229)" FT /evidence="ECO:0000269|PubMed:10944854" FT /id="VAR_018202" FT VARIANT 270..486 FT /note="Missing (in RTT)" FT /evidence="ECO:0000269|PubMed:23662938, FT ECO:0000269|PubMed:26993267" FT /id="VAR_078720" FT VARIANT 284 FT /note="K -> E (in MRXS13; dbSNP:rs61750255)" FT /evidence="ECO:0000269|PubMed:11309367" FT /id="VAR_018203" FT VARIANT 287 FT /note="A -> P (in dbSNP:rs61750257)" FT /evidence="ECO:0000269|PubMed:11055898" FT /id="VAR_018204" FT VARIANT 291 FT /note="S -> A (in dbSNP:rs61751360)" FT /evidence="ECO:0000269|PubMed:11055898" FT /id="VAR_018205" FT VARIANT 302 FT /note="P -> A (in RTT; dbSNP:rs61751373)" FT /evidence="ECO:0000269|PubMed:11738883" FT /id="VAR_018206" FT VARIANT 302 FT /note="P -> H (in RTT; dbSNP:rs61749723)" FT /evidence="ECO:0000269|PubMed:10944854" FT /id="VAR_018207" FT VARIANT 302 FT /note="P -> L (in RTT; dbSNP:rs61749723)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018208" FT VARIANT 302 FT /note="P -> R (in RTT; dbSNP:rs61749723)" FT /evidence="ECO:0000269|PubMed:10814719, FT ECO:0000269|PubMed:11241840" FT /id="VAR_018209" FT VARIANT 305 FT /note="K -> N (found in a patient with drug-resistant FT epilepsy with intellectual disability, parkinsonism and FT other neurologic symptoms; likely pathogenic; FT dbSNP:rs1057519543)" FT /evidence="ECO:0000269|PubMed:27864847" FT /id="VAR_078221" FT VARIANT 305 FT /note="K -> R (in RTT; abolishes interaction with TBL1X; FT dbSNP:rs61751441)" FT /evidence="ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:11402105, ECO:0000269|PubMed:28348241" FT /id="VAR_018210" FT VARIANT 306 FT /note="R -> C (in RTT; abolishes interaction with TBL1X and FT TBL1XR1; dbSNP:rs28935468)" FT /evidence="ECO:0000269|PubMed:10577905, FT ECO:0000269|PubMed:10745042, ECO:0000269|PubMed:10767337, FT ECO:0000269|PubMed:10814719, ECO:0000269|PubMed:10944854, FT ECO:0000269|PubMed:10991688, ECO:0000269|PubMed:10991689, FT ECO:0000269|PubMed:11055898, ECO:0000269|PubMed:11241840, FT ECO:0000269|PubMed:11376998, ECO:0000269|PubMed:11402105, FT ECO:0000269|PubMed:11738883, ECO:0000269|PubMed:12567420, FT ECO:0000269|PubMed:12966523, ECO:0000269|PubMed:15057977, FT ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:28348241" FT /id="VAR_010282" FT VARIANT 306 FT /note="R -> H (in RTT; dbSNP:rs61751443)" FT /evidence="ECO:0000269|PubMed:10767337, FT ECO:0000269|PubMed:11055898, ECO:0000269|PubMed:15057977" FT /id="VAR_018211" FT VARIANT 322 FT /note="P -> A (in RTT; dbSNP:rs61751449)" FT /evidence="ECO:0000269|PubMed:10814719, FT ECO:0000269|PubMed:11738883" FT /id="VAR_018212" FT VARIANT 322 FT /note="P -> L (in RTT; dbSNP:rs61751450)" FT /evidence="ECO:0000269|PubMed:11402105" FT /id="VAR_018213" FT VARIANT 322 FT /note="P -> S (in MRXS13; dbSNP:rs61751449)" FT /evidence="ECO:0000269|PubMed:16966553" FT /id="VAR_037665" FT VARIANT 344 FT /note="R -> W (in RTT; dbSNP:rs61752361)" FT /evidence="ECO:0000269|PubMed:12161600, FT ECO:0000269|PubMed:28709814" FT /id="VAR_018214" FT VARIANT 359 FT /note="S -> P (in dbSNP:rs61752371)" FT /evidence="ECO:0000269|PubMed:11896461" FT /id="VAR_018215" FT VARIANT 376 FT /note="P -> S (in dbSNP:rs61752387)" FT /evidence="ECO:0000269|PubMed:10944854, FT ECO:0000269|PubMed:12161600, ECO:0000269|PubMed:12384770, FT ECO:0000269|PubMed:12567420" FT /id="VAR_018216" FT VARIANT 388 FT /note="P -> L (in dbSNP:rs61753006)" FT /id="VAR_023559" FT VARIANT 388 FT /note="P -> S (in RTT; benign; dbSNP:rs61753000)" FT /evidence="ECO:0000269|PubMed:12567420" FT /id="VAR_018218" FT VARIANT 388 FT /note="Missing (in dbSNP:rs2065921248)" FT /evidence="ECO:0000269|PubMed:12384770" FT /id="VAR_018217" FT VARIANT 394 FT /note="E -> K (in dbSNP:rs63094662)" FT /evidence="ECO:0000269|PubMed:12111644" FT /id="VAR_018219" FT VARIANT 397 FT /note="E -> K (in dbSNP:rs56268439)" FT /evidence="ECO:0000269|PubMed:10577905, FT ECO:0000269|PubMed:10991689, ECO:0000269|PubMed:11055898, FT ECO:0000269|PubMed:11738883, ECO:0000269|PubMed:11896461" FT /id="VAR_010283" FT VARIANT 399 FT /note="P -> L (in MRXS13; likely benign; dbSNP:rs62915962)" FT /evidence="ECO:0000269|PubMed:11309367, FT ECO:0000269|PubMed:12161600" FT /id="VAR_018220" FT VARIANT 402 FT /note="P -> L (in dbSNP:rs61753014)" FT /evidence="ECO:0000269|PubMed:12384770" FT /id="VAR_018221" FT VARIANT 412 FT /note="V -> I (in dbSNP:rs61753966)" FT /evidence="ECO:0000269|PubMed:11055898" FT /id="VAR_018222" FT VARIANT 428 FT /note="G -> S (in ENS-MECP2; uncertain significance; FT dbSNP:rs61753971)" FT /evidence="ECO:0000269|PubMed:11238684, FT ECO:0000269|PubMed:12161600" FT /id="VAR_017463" FT VARIANT 439 FT /note="A -> T (in dbSNP:rs61753973)" FT /evidence="ECO:0000269|PubMed:10767337" FT /id="VAR_018223" FT VARIANT 444 FT /note="A -> T (in dbSNP:rs61753975)" FT /evidence="ECO:0000269|PubMed:11055898" FT /id="VAR_018224" FT VARIANT 453 FT /note="R -> Q (in MRXS13; dbSNP:rs61753980)" FT /evidence="ECO:0000269|PubMed:11309367" FT /id="VAR_018225" FT VARIANT 480 FT /note="P -> S (in dbSNP:rs267608636)" FT /evidence="ECO:0000269|PubMed:12111644" FT /id="VAR_018226" FT CONFLICT 72..75 FT /note="PAVP -> RLC (in Ref. 10; CAA61599)" FT /evidence="ECO:0000305" FT CONFLICT 290 FT /note="E -> G (in Ref. 2; CAA68001)" FT /evidence="ECO:0000305" FT CONFLICT 466 FT /note="M -> V (in Ref. 7; CAD97991)" FT /evidence="ECO:0000305" FT TURN 88..91 FT /evidence="ECO:0007829|PDB:6OGJ" FT STRAND 95..97 FT /evidence="ECO:0007829|PDB:1QK9" FT STRAND 100..103 FT /evidence="ECO:0007829|PDB:1QK9" FT STRAND 105..110 FT /evidence="ECO:0007829|PDB:6OGK" FT TURN 115..118 FT /evidence="ECO:0007829|PDB:6OGK" FT STRAND 120..125 FT /evidence="ECO:0007829|PDB:6OGK" FT TURN 127..129 FT /evidence="ECO:0007829|PDB:1QK9" FT STRAND 130..134 FT /evidence="ECO:0007829|PDB:1QK9" FT HELIX 135..144 FT /evidence="ECO:0007829|PDB:6OGK" FT STRAND 148..150 FT /evidence="ECO:0007829|PDB:8ALQ" FT HELIX 152..154 FT /evidence="ECO:0007829|PDB:6OGK" FT HELIX 158..160 FT /evidence="ECO:0007829|PDB:8AJR" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8AJR" SQ SEQUENCE 486 AA; 52441 MW; EB6A33233AEDA566 CRC64; MVAGMLGLRE EKSEDQDLQG LKDKPLKFKK VKKDKKEEKE GKHEPVQPSA HHSAEPAEAG KAETSEGSGS APAVPEASAS PKQRRSIIRD RGPMYDDPTL PEGWTRKLKQ RKSGRSAGKY DVYLINPQGK AFRSKVELIA YFEKVGDTSL DPNDFDFTVT GRGSPSRREQ KPPKKPKSPK APGTGRGRGR PKGSGTTRPK AATSEGVQVK RVLEKSPGKL LVKMPFQTSP GGKAEGGGAT TSTQVMVIKR PGRKRKAEAD PQAIPKKRGR KPGSVVAAAA AEAKKKAVKE SSIRSVQETV LPIKKRKTRE TVSIEVKEVV KPLLVSTLGE KSGKGLKTCK SPGRKSKESS PKGRSSSASS PPKKEHHHHH HHSESPKAPV PLLPPLPPPP PEPESSEDPT SPPEPQDLSS SVCKEEKMPR GGSLESDGCP KEPAKTQPAV ATAATAAEKY KHRGEGERKD IVSSSMPRPN REEPVDSRTP VTERVS // ID NGBR_HUMAN Reviewed; 293 AA. AC Q96E22; B2RWQ4; O00251; DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 178. DE RecName: Full=Dehydrodolichyl diphosphate synthase complex subunit NUS1 {ECO:0000305}; DE EC=2.5.1.87 {ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490}; DE AltName: Full=Cis-prenyltransferase subunit NgBR {ECO:0000303|PubMed:28842490}; DE AltName: Full=Nogo-B receptor {ECO:0000303|PubMed:16835300}; DE Short=NgBR {ECO:0000303|PubMed:16835300, ECO:0000303|PubMed:28842490}; DE AltName: Full=Nuclear undecaprenyl pyrophosphate synthase 1 homolog {ECO:0000305}; GN Name=NUS1 {ECO:0000303|PubMed:28842490, ECO:0000312|HGNC:HGNC:21042}; GN Synonyms=C6orf68, NGBR; 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=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 [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]. RC TISSUE=Lymph, Muscle, 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 [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 171-293, AND VARIANTS ARG-216 AND LYS-219. RX PubMed=9294218; DOI=10.1073/pnas.94.19.10373; RA Still I.H., Vince P., Cowell J.K.; RT "Direct isolation of human transcribed sequences from yeast artificial RT chromosomes through the application of RNA fingerprinting."; RL Proc. Natl. Acad. Sci. U.S.A. 94:10373-10378(1997). RN [5] RP FUNCTION, AND LACK OF TRANSFERASE ACTIVITY. RX PubMed=16835300; DOI=10.1073/pnas.0602427103; RA Miao R.Q., Gao Y., Harrison K.D., Prendergast J., Acevedo L.M., Yu J., RA Hu F., Strittmatter S.M., Sessa W.C.; RT "Identification of a receptor necessary for Nogo-B stimulated chemotaxis RT and morphogenesis of endothelial cells."; RL Proc. Natl. Acad. Sci. U.S.A. 103:10997-11002(2006). RN [6] RP SUBCELLULAR LOCATION, AND INTERACTION WITH NPC2. RX PubMed=19723497; DOI=10.1016/j.cmet.2009.07.003; RA Harrison K.D., Miao R.Q., Fernandez-Hernando C., Suarez Y., Davalos A., RA Sessa W.C.; RT "Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates RT intracellular cholesterol trafficking."; RL Cell Metab. 10:208-218(2009). RN [7] RP FUNCTION IN DOLICHOL BIOSYNTHESIS, SUBCELLULAR LOCATION, GLYCOSYLATION AT RP ASN-144 AND ASN-271, AND INTERACTION WITH DHDDS. RX PubMed=21572394; DOI=10.1038/emboj.2011.147; RA Harrison K.D., Park E.J., Gao N., Kuo A., Rush J.S., Waechter C.J., RA Lehrman M.A., Sessa W.C.; RT "Nogo-B receptor is necessary for cellular dolichol biosynthesis and RT protein N-glycosylation."; RL EMBO J. 30:2490-2500(2011). RN [8] RP INVOLVEMENT IN CDG1AA, VARIANT CDG1AA HIS-290, CHARACTERIZATION OF VARIANT RP CDG1AA HIS-290, CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, AND PATHWAY. RX PubMed=25066056; DOI=10.1016/j.cmet.2014.06.016; RA Park E.J., Grabinska K.A., Guan Z., Stranecky V., Hartmannova H., RA Hodanova K., Baresova V., Sovova J., Jozsef L., Ondruskova N., RA Hansikova H., Honzik T., Zeman J., Hulkova H., Wen R., Kmoch S., RA Sessa W.C.; RT "Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a RT congenital disorder of glycosylation."; RL Cell Metab. 20:448-457(2014). RN [9] RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, RP MUTAGENESIS OF HIS-100; GLY-292 AND LYS-293, ACTIVITY REGULATION, RP CHARACTERIZATION OF VARIANT HIS-290, PATHWAY, AND COFACTOR. RX PubMed=28842490; DOI=10.1074/jbc.m117.806034; RA Grabinska K.A., Edani B.H., Park E.J., Kraehling J.R., Sessa W.C.; RT "A conserved C-terminal RXG motif in the NgBR subunit of cis- RT prenyltransferase is critical for prenyltransferase activity."; RL J. Biol. Chem. 292:17351-17361(2017). RN [10] {ECO:0007744|PDB:6Z1N} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS, RP FUNCTION, PATHWAY, SUBUNIT, AND CHARACTERIZATION OF VARIANT HIS-290. RX PubMed=33077723; DOI=10.1038/s41467-020-18970-z; RA Bar-El M.L., Vankova P., Yeheskel A., Simhaev L., Engel H., Man P., RA Haitin Y., Giladi M.; RT "Structural basis of heterotetrameric assembly and disease mutations in the RT human cis-prenyltransferase complex."; RL Nat. Commun. 11:5273-5273(2020). RN [11] RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS AND RP ISOPENTENYL DIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, DOMAIN, MUTAGENESIS OF GLY-196; LYS-197; ILE-200; LEU-226; RP LEU-230; GLY-252; PHE-253 AND PRO-255, AND VARIANT CYS-91. RX PubMed=32817466; DOI=10.1073/pnas.2008381117; RA Edani B.H., Grabinska K.A., Zhang R., Park E.J., Siciliano B., Surmacz L., RA Ha Y., Sessa W.C.; RT "Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex RT reveals insights in regulation of protein glycosylation."; RL Proc. Natl. Acad. Sci. U.S.A. 117:20794-20802(2020). RN [12] {ECO:0007744|PDB:7PAX, ECO:0007744|PDB:7PAY, ECO:0007744|PDB:7PB0, ECO:0007744|PDB:7PB1} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS, AND RP SUBUNIT. RX PubMed=35584224; DOI=10.1126/sciadv.abn1171; RA Giladi M., Lisnyansky Bar-El M., Vankova P., Ferofontov A., Melvin E., RA Alkaderi S., Kavan D., Redko B., Haimov E., Wiener R., Man P., Haitin Y.; RT "Structural basis for long-chain isoprenoid synthesis by cis- RT prenyltransferases."; RL Sci. Adv. 8:eabn1171-eabn1171(2022). RN [13] RP INVOLVEMENT IN MRD55. RX PubMed=29100083; DOI=10.1016/j.ajhg.2017.09.008; RG Deciphering Developmental Disorders Study; RA Hamdan F.F., Myers C.T., Cossette P., Lemay P., Spiegelman D., RA Laporte A.D., Nassif C., Diallo O., Monlong J., Cadieux-Dion M., RA Dobrzeniecka S., Meloche C., Retterer K., Cho M.T., Rosenfeld J.A., Bi W., RA Massicotte C., Miguet M., Brunga L., Regan B.M., Mo K., Tam C., RA Schneider A., Hollingsworth G., FitzPatrick D.R., Donaldson A., Canham N., RA Blair E., Kerr B., Fry A.E., Thomas R.H., Shelagh J., Hurst J.A., RA Brittain H., Blyth M., Lebel R.R., Gerkes E.H., Davis-Keppen L., Stein Q., RA Chung W.K., Dorison S.J., Benke P.J., Fassi E., Corsten-Janssen N., RA Kamsteeg E.J., Mau-Them F.T., Bruel A.L., Verloes A., Ounap K., RA Wojcik M.H., Albert D.V.F., Venkateswaran S., Ware T., Jones D., Liu Y.C., RA Mohammad S.S., Bizargity P., Bacino C.A., Leuzzi V., Martinelli S., RA Dallapiccola B., Tartaglia M., Blumkin L., Wierenga K.J., Purcarin G., RA O'Byrne J.J., Stockler S., Lehman A., Keren B., Nougues M.C., Mignot C., RA Auvin S., Nava C., Hiatt S.M., Bebin M., Shao Y., Scaglia F., Lalani S.R., RA Frye R.E., Jarjour I.T., Jacques S., Boucher R.M., Riou E., Srour M., RA Carmant L., Lortie A., Major P., Diadori P., Dubeau F., D'Anjou G., RA Bourque G., Berkovic S.F., Sadleir L.G., Campeau P.M., Kibar Z., RA Lafreniere R.G., Girard S.L., Mercimek-Mahmutoglu S., Boelman C., RA Rouleau G.A., Scheffer I.E., Mefford H.C., Andrade D.M., Rossignol E., RA Minassian B.A., Michaud J.L.; RT "High rate of recurrent de novo mutations in developmental and epileptic RT encephalopathies."; RL Am. J. Hum. Genet. 101:664-685(2017). RN [14] RP VARIANT 104-VAL--LYS-293 DEL. RX PubMed=33798445; DOI=10.1016/j.ajhg.2021.03.013; RA Courage C., Oliver K.L., Park E.J., Cameron J.M., Grabinska K.A., Muona M., RA Canafoglia L., Gambardella A., Said E., Afawi Z., Baykan B., Brandt C., RA di Bonaventura C., Chew H.B., Criscuolo C., Dibbens L.M., Castellotti B., RA Riguzzi P., Labate A., Filla A., Giallonardo A.T., Berecki G., RA Jackson C.B., Joensuu T., Damiano J.A., Kivity S., Korczyn A., Palotie A., RA Striano P., Uccellini D., Giuliano L., Andermann E., Scheffer I.E., RA Michelucci R., Bahlo M., Franceschetti S., Sessa W.C., Berkovic S.F., RA Lehesjoki A.E.; RT "Progressive myoclonus epilepsies-Residual unsolved cases have marked RT genetic heterogeneity including dolichol-dependent protein glycosylation RT pathway genes."; RL Am. J. Hum. Genet. 108:722-738(2021). CC -!- FUNCTION: With DHDDS, forms the dehydrodolichyl diphosphate synthase CC (DDS) complex, an essential component of the dolichol monophosphate CC (Dol-P) biosynthetic machinery (PubMed:21572394, PubMed:25066056, CC PubMed:28842490, PubMed:32817466, PubMed:33077723). Both subunits CC contribute to enzymatic activity, i.e. condensation of multiple copies CC of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to CC produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol CC phosphate which is utilized as a sugar carrier in protein glycosylation CC in the endoplasmic reticulum (ER) (PubMed:21572394, PubMed:25066056, CC PubMed:28842490, PubMed:32817466, PubMed:33077723). Synthesizes long- CC chain polyprenols, mostly of C95 and C100 chain length CC (PubMed:32817466). Regulates the glycosylation and stability of nascent CC NPC2, thereby promoting trafficking of LDL-derived cholesterol CC (PubMed:21572394). Acts as a specific receptor for the N-terminus of CC Nogo-B, a neural and cardiovascular regulator (PubMed:16835300). CC {ECO:0000269|PubMed:16835300, ECO:0000269|PubMed:21572394, CC ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490, CC ECO:0000269|PubMed:32817466, ECO:0000269|PubMed:33077723}. CC -!- CATALYTIC ACTIVITY: CC Reaction=n isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = a CC di-trans,poly-cis-polyprenyl diphosphate + n diphosphate; CC Xref=Rhea:RHEA:53008, Rhea:RHEA-COMP:19494, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:128769, ChEBI:CHEBI:136960, ChEBI:CHEBI:175763; CC EC=2.5.1.87; Evidence={ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:28842490}; CC -!- ACTIVITY REGULATION: Activated by phospholipids including cardiolipin, CC phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and CC phosphatidylserine. {ECO:0000269|PubMed:28842490, CC ECO:0000269|PubMed:32817466}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=11.1 uM for isopentenyl diphosphate {ECO:0000269|PubMed:28842490}; CC KM=0.68 uM for (2E,6E)-farnesyl diphosphate CC {ECO:0000269|PubMed:28842490}; CC Note=Values were measured with the heterodimer. kcat is 0.58 sec(-1) CC with (2E,6E)-farnesyl diphosphate and isopentenyl diphosphate as CC substrates. {ECO:0000269|PubMed:28842490}; CC pH dependence: CC Optimum pH is 8-9. Active from pH 5.5 to 9.3. CC {ECO:0000269|PubMed:28842490}; CC -!- PATHWAY: Protein modification; protein glycosylation. CC {ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:33077723}. CC -!- PATHWAY: Lipid metabolism. {ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490}. CC -!- SUBUNIT: The active dehydrodolichyl diphosphate synthase complex is a CC heterotetramer composed of a dimer of heterodimer of DHDDS and NUS1 CC (PubMed:19723497, PubMed:25066056, PubMed:28842490, PubMed:32817466, CC PubMed:33077723, PubMed:35584224). Interacts with NPC2 CC (PubMed:21572394). {ECO:0000269|PubMed:19723497, CC ECO:0000269|PubMed:21572394, ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466, CC ECO:0000269|PubMed:33077723, ECO:0000269|PubMed:35584224}. CC -!- INTERACTION: CC Q96E22; Q9H7T3: C10orf95; NbExp=3; IntAct=EBI-6949352, EBI-6949335; CC Q96E22; Q86SQ9: DHDDS; NbExp=6; IntAct=EBI-6949352, EBI-26942900; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:19723497, ECO:0000269|PubMed:21572394}; Multi-pass CC membrane protein {ECO:0000303|PubMed:21572394}. Note=Colocalizes with CC Nogo-B during VEGF and wound healing angiogenesis. CC {ECO:0000269|PubMed:19723497}. CC -!- DOMAIN: Contains the RXG motif, which is important for substrate CC binding and prenyltransferase activity. The catalytic site at NUS1- CC DHDDS interface accomodates both the allylic and the homoallylic IPP CC substrates to the S1 and S2 pockets respectively. The beta-phosphate CC groups of IPP substrates form hydrogen bonds with the RXG motif of NUS1 CC and four conserved residues of DHDDS ('Arg-85', 'Arg-205', 'Arg-211' CC and 'Ser-213'), while the allylic isopentenyl group is pointed toward CC the hydrophobic tunnel of the S1 pocket where the product elongation CC occurs. {ECO:0000269|PubMed:32817466}. CC -!- DISEASE: Congenital disorder of glycosylation 1AA (CDG1AA) CC [MIM:617082]: A form of congenital disorder of glycosylation, a CC multisystem disorder caused by a defect in glycoprotein biosynthesis CC and characterized by under-glycosylated serum glycoproteins. Congenital CC disorders of glycosylation result in a wide variety of clinical CC features, such as defects in the nervous system development, CC psychomotor retardation, dysmorphic features, hypotonia, coagulation CC disorders, and immunodeficiency. The broad spectrum of features CC reflects the critical role of N-glycoproteins during embryonic CC development, differentiation, and maintenance of cell functions. CDG1AA CC inheritance is autosomal recessive. {ECO:0000269|PubMed:25066056}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Intellectual developmental disorder, autosomal dominant 55, CC with seizures (MRD55) [MIM:617831]: A form of intellectual disability, CC a disorder characterized by significantly below average general CC intellectual functioning associated with impairments in adaptive CC behavior and manifested during the developmental period. MRD55 patients CC suffer from seizures appearing during the first years of life. CC {ECO:0000269|PubMed:29100083}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: NUS1 seems to exist in two topological orientations, a CC minor glycosylated species with its C-terminus oriented towards the CC lumen regulating NPC2 stability, and a major fraction oriented with its CC C-terminus directed towards the cytosol where it regulates cis-IPTase CC activity. {ECO:0000303|PubMed:21572394}. CC -!- SIMILARITY: Belongs to the UPP synthase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB72234.1; 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; Z98172; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590303; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48201.1; -; Genomic_DNA. DR EMBL; BC013026; AAH13026.1; -; mRNA. DR EMBL; BC063794; AAH63794.1; -; mRNA. DR EMBL; BC066910; AAH66910.1; -; mRNA. DR EMBL; BC110325; AAI10326.1; -; mRNA. DR EMBL; BC150654; AAI50655.1; -; mRNA. DR EMBL; BC150655; AAI50656.1; -; mRNA. DR EMBL; U82319; AAB72234.1; ALT_FRAME; mRNA. DR CCDS; CCDS5118.1; -. DR RefSeq; NP_612468.1; NM_138459.5. DR PDB; 6W2L; X-ray; 2.31 A; B=80-293. DR PDB; 6Z1N; X-ray; 2.30 A; B=73-293. DR PDB; 7PAX; X-ray; 2.00 A; B=73-293. DR PDB; 7PAY; X-ray; 2.40 A; B=73-293. DR PDB; 7PB0; X-ray; 2.30 A; B=73-293. DR PDB; 7PB1; X-ray; 2.59 A; B=73-293. DR PDBsum; 6W2L; -. DR PDBsum; 6Z1N; -. DR PDBsum; 7PAX; -. DR PDBsum; 7PAY; -. DR PDBsum; 7PB0; -. DR PDBsum; 7PB1; -. DR AlphaFoldDB; Q96E22; -. DR SMR; Q96E22; -. DR BioGRID; 125481; 80. DR ComplexPortal; CPX-6701; Dehydrodolichyl diphosphate synthase complex. DR CORUM; Q96E22; -. DR DIP; DIP-61225N; -. DR FunCoup; Q96E22; 1500. DR IntAct; Q96E22; 47. DR MINT; Q96E22; -. DR STRING; 9606.ENSP00000357480; -. DR GlyCosmos; Q96E22; 2 sites, No reported glycans. DR GlyGen; Q96E22; 2 sites. DR iPTMnet; Q96E22; -. DR PhosphoSitePlus; Q96E22; -. DR BioMuta; NUS1; -. DR DMDM; 74762651; -. DR jPOST; Q96E22; -. DR MassIVE; Q96E22; -. DR PaxDb; 9606-ENSP00000357480; -. DR PeptideAtlas; Q96E22; -. DR ProteomicsDB; 76366; -. DR Pumba; Q96E22; -. DR Antibodypedia; 32563; 111 antibodies from 22 providers. DR DNASU; 116150; -. DR Ensembl; ENST00000368494.4; ENSP00000357480.3; ENSG00000153989.9. DR GeneID; 116150; -. DR KEGG; hsa:116150; -. DR MANE-Select; ENST00000368494.4; ENSP00000357480.3; NM_138459.5; NP_612468.1. DR UCSC; uc003pxw.4; human. DR AGR; HGNC:21042; -. DR ClinPGx; PA162398248; -. DR CTD; 116150; -. DR DisGeNET; 116150; -. DR GeneCards; NUS1; -. DR HGNC; HGNC:21042; NUS1. DR HPA; ENSG00000153989; Low tissue specificity. DR MalaCards; NUS1; -. DR MIM; 610463; gene. DR MIM; 617082; phenotype. DR MIM; 617831; phenotype. DR OpenTargets; ENSG00000153989; -. DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy. DR VEuPathDB; HostDB:ENSG00000153989; -. DR eggNOG; KOG2818; Eukaryota. DR GeneTree; ENSGT00390000003223; -. DR HOGENOM; CLU_051870_2_1_1; -. DR InParanoid; Q96E22; -. DR OMA; AWSSCAG; -. DR OrthoDB; 19639at2759; -. DR PAN-GO; Q96E22; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96E22; -. DR BioCyc; MetaCyc:ENSG00000153989-MONOMER; -. DR BRENDA; 2.5.1.87; 2681. DR PathwayCommons; Q96E22; -. DR Reactome; R-HSA-446199; Synthesis of dolichyl-phosphate. DR Reactome; R-HSA-4755609; Defective DHDDS causes RP59. DR SABIO-RK; Q96E22; -. DR SignaLink; Q96E22; -. DR UniPathway; UPA00378; -. DR Agora; ENSG00000153989; -. DR BioGRID-ORCS; 116150; 791 hits in 1115 CRISPR screens. DR ChiTaRS; NUS1; human. DR GenomeRNAi; 116150; -. DR Pharos; Q96E22; Tbio. DR PRO; PR:Q96E22; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q96E22; protein. DR Bgee; ENSG00000153989; Expressed in endometrium and 186 other cell types or tissues. DR GO; GO:1904423; C:dehydrodolichyl diphosphate synthase complex; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:MGI. DR GO; GO:0045547; F:ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl. DR GO; GO:0006489; P:dolichyl diphosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0043048; P:dolichyl monophosphate biosynthetic process; IMP:MGI. DR GO; GO:1903589; P:positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis; IMP:BHF-UCL. DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; IMP:BHF-UCL. DR GO; GO:0032383; P:regulation of intracellular cholesterol transport; IGI:MGI. DR GO; GO:0038084; P:vascular endothelial growth factor signaling pathway; IMP:BHF-UCL. DR FunFam; 3.40.1180.10:FF:000008; NUS1, dehydrodolichyl diphosphate synthase subunit; 1. DR Gene3D; 3.40.1180.10; Decaprenyl diphosphate synthase-like; 1. DR InterPro; IPR038887; Nus1/NgBR. DR InterPro; IPR001441; UPP_synth-like. DR InterPro; IPR036424; UPP_synth-like_sf. DR PANTHER; PTHR21528; DEHYDRODOLICHYL DIPHOSPHATE SYNTHASE COMPLEX SUBUNIT NUS1; 1. DR PANTHER; PTHR21528:SF0; DEHYDRODOLICHYL DIPHOSPHATE SYNTHASE COMPLEX SUBUNIT NUS1; 1. DR Pfam; PF01255; Prenyltransf; 1. DR SUPFAM; SSF64005; Undecaprenyl diphosphate synthase; 1. PE 1: Evidence at protein level; KW 3D-structure; Angiogenesis; Congenital disorder of glycosylation; KW Developmental protein; Differentiation; Disease variant; KW Endoplasmic reticulum; Glycoprotein; Intellectual disability; KW Lipid metabolism; Magnesium; Membrane; Metal-binding; KW Proteomics identification; Receptor; Reference proteome; Transferase; KW Transmembrane; Transmembrane helix. FT CHAIN 1..293 FT /note="Dehydrodolichyl diphosphate synthase complex subunit FT NUS1" FT /id="PRO_0000273167" FT TRANSMEM 1..23 FT /note="Helical; Name=1" FT /evidence="ECO:0000303|PubMed:21572394" FT TRANSMEM 35..56 FT /note="Helical; Name=2" FT /evidence="ECO:0000303|PubMed:21572394" FT TRANSMEM 117..135 FT /note="Helical; Name=3" FT /evidence="ECO:0000303|PubMed:21572394" FT MOTIF 290..292 FT /note="RXG motif; crucial for prenyltransferase activity" FT /evidence="ECO:0000269|PubMed:32817466, FT ECO:0000305|PubMed:28842490" FT BINDING 291 FT /ligand="isopentenyl diphosphate" FT /ligand_id="ChEBI:CHEBI:128769" FT /evidence="ECO:0000269|PubMed:32817466" FT BINDING 292 FT /ligand="isopentenyl diphosphate" FT /ligand_id="ChEBI:CHEBI:128769" FT /evidence="ECO:0000269|PubMed:32817466" FT CARBOHYD 144 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21572394" FT CARBOHYD 271 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21572394" FT VARIANT 91 FT /note="G -> C (found in a patient with Parkinson's disease; FT likely pathogenic; 40 % reduction in prenyltransferase FT activity)" FT /evidence="ECO:0000269|PubMed:32817466" FT /id="VAR_083900" FT VARIANT 104..293 FT /note="Missing (found in a patient with progressive FT myoclonus epilepsy; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:33798445" FT /id="VAR_085036" FT VARIANT 175 FT /note="N -> Y (in dbSNP:rs28362518)" FT /id="VAR_030092" FT VARIANT 179 FT /note="D -> E (in dbSNP:rs28362519)" FT /id="VAR_030093" FT VARIANT 210 FT /note="Missing (in dbSNP:rs1052237)" FT /id="VAR_030094" FT VARIANT 216 FT /note="K -> R (in dbSNP:rs1052239)" FT /evidence="ECO:0000269|PubMed:9294218" FT /id="VAR_030095" FT VARIANT 219 FT /note="T -> K (in dbSNP:rs1132147)" FT /evidence="ECO:0000269|PubMed:9294218" FT /id="VAR_030096" FT VARIANT 290 FT /note="R -> H (in CDG1AA; loss of function in protein FT glycosylation; 5-fold reduction in catalytic activity and FT reduced affinity for FPP and IPP.; dbSNP:rs886037858)" FT /evidence="ECO:0000269|PubMed:25066056, FT ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:33077723" FT /id="VAR_071210" FT MUTAGEN 100 FT /note="H->A: 3.5-fold reduction in catalytic activity and FT no marked change in affinity for FPP and IPP." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 196 FT /note="G->A: Decreases binding to DHDDS." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 197 FT /note="K->A: Decreases binding to DHDDS." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 200 FT /note="I->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 226 FT /note="L->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 230 FT /note="L->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 252 FT /note="G->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 253 FT /note="F->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 255 FT /note="P->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 292 FT /note="G->A: Almost complete loss of catalytic activity." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 293 FT /note="K->KA: Almost complete loss of catalytic activity." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 293 FT /note="Missing: Almost complete loss of catalytic FT activity." FT /evidence="ECO:0000269|PubMed:28842490" FT HELIX 79..93 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 99..106 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 114..127 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 131..136 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 145..157 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 177..187 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 188..191 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 193..195 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 197..212 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 218..220 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 223..229 FT /evidence="ECO:0007829|PDB:7PAX" FT TURN 231..234 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 239..246 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 256..258 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 262..267 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 274..286 FT /evidence="ECO:0007829|PDB:7PAX" SQ SEQUENCE 293 AA; 33224 MW; E6A0C9D9B39D4BCA CRC64; MTGLYELVWR VLHALLCLHR TLTSWLRVRF GTWNWIWRRC CRAASAAVLA PLGFTLRKPP AVGRNRRHHR HPRGGSCLAA AHHRMRWRAD GRSLEKLPVH MGLVITEVEQ EPSFSDIASL VVWCMAVGIS YISVYDHQGI FKRNNSRLMD EILKQQQELL GLDCSKYSPE FANSNDKDDQ VLNCHLAVKV LSPEDGKADI VRAAQDFCQL VAQKQKRPTD LDVDTLASLL SSNGCPDPDL VLKFGPVDST LGFLPWHIRL TEIVSLPSHL NISYEDFFSA LRQYAACEQR LGK // 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 PTRD1_HUMAN Reviewed; 140 AA. AC Q6GMV3; DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot. DT 19-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 152. DE RecName: Full=Putative peptidyl-tRNA hydrolase PTRHD1 {ECO:0000305}; DE EC=3.1.1.29 {ECO:0000305}; DE AltName: Full=Peptidyl-tRNA hydrolase domain-containing protein 1; GN Name=PTRHD1; Synonyms=C2orf79; 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]. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Neuroblastoma; 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 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 [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 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 [6] RP FUNCTION. RX PubMed=27235175; DOI=10.1016/j.pep.2016.05.011; RA Burks G.L., McFeeters H., McFeeters R.L.; RT "Expression, purification, and buffer solubility optimization of the RT putative human peptidyl-tRNA hydrolase PTRHD1."; RL Protein Expr. Purif. 126:49-54(2016). RN [7] RP INVOLVEMENT IN NEDPBA. RX PubMed=30398675; DOI=10.1002/mds.27501; RA Kuipers D.J.S., Carr J., Bardien S., Thomas P., Sebate B., Breedveld G.J., RA van Minkelen R., Brouwer R.W.W., van Ijcken W.F.J., van Slegtenhorst M.A., RA Bonifati V., Quadri M.; RT "PTRHD1 Loss-of-function mutation in an african family with juvenile-onset RT Parkinsonism and intellectual disability."; RL Mov. Disord. 33:1814-1819(2018). RN [8] RP INVOLVEMENT IN NEDPBA. RX PubMed=34765690; DOI=10.1002/mdc3.13342; RA Al-Kasbi G., Al-Saegh A., Al-Qassabi A., Al-Jabry T., Zadjali F., RA Al-Yahyaee S., Al-Maawali A.; RT "Biallelic PTRHD1 Frameshift Variants Associated with Intellectual RT Disability, Spasticity, and Parkinsonism."; RL Mov. Disord. Clin. Pract. 8:1253-1257(2021). RN [9] RP VARIANT NEDPBA TYR-52, AND INVOLVEMENT IN NEDPBA. RX PubMed=27134041; DOI=10.1002/mds.26627; RA Jaberi E., Rohani M., Shahidi G.A., Nafissi S., Arefian E., Soleimani M., RA Moghadam A., Arzenani M.K., Keramatian F., Klotzle B., Fan J.B., Turk C., RA Steemers F., Elahi E.; RT "Mutation in ADORA1 identified as likely cause of early-onset parkinsonism RT and cognitive dysfunction."; RL Mov. Disord. 31:1004-1011(2016). RN [10] RP VARIANT NEDPBA TYR-53, AND INVOLVEMENT IN NEDPBA. RX PubMed=27753167; DOI=10.1002/mds.26824; RA Khodadadi H., Azcona L.J., Aghamollaii V., Omrani M.D., Garshasbi M., RA Taghavi S., Tafakhori A., Shahidi G.A., Jamshidi J., Darvish H., RA Paisan-Ruiz C.; RT "PTRHD1 (C2orf79) mutations lead to autosomal-recessive intellectual RT disability and parkinsonism."; RL Mov. Disord. 32:287-291(2017). RN [11] RP VARIANT NEDPBA TRP-122, AND INVOLVEMENT IN NEDPBA. RX PubMed=34816696; DOI=10.34172/aim.2021.110; RA Cheraghi S., Moghbelinejad S., Najmabadi H., Kahrizi K., Najafipour R.; RT "The PTRHD1 Mutation in Intellectual Disability."; RL Arch. Iran. Med. 24:747-751(2021). RN [12] RP VARIANT NEDPBA GLN-122, AND INVOLVEMENT IN NEDPBA. RX PubMed=38286424; DOI=10.1055/a-2256-0722; RA Gebert J., Brunet T., Wagner M., Rath J., Aull-Watschinger S., Pataraia E., RA Krenn M.; RT "A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with RT Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism."; RL Neuropediatrics 0:0-0(2024). CC -!- FUNCTION: As a putative peptidyl-tRNA hydrolase, it might be involved CC in releasing tRNAs from the ribosome during protein synthesis CC (Probable). Some evidence, however, suggests that it lacks peptidyl- CC tRNA hydrolase activity (PubMed:27235175). CC {ECO:0000269|PubMed:27235175, ECO:0000305}. CC -!- CATALYTIC ACTIVITY: CC Reaction=an N-acyl-L-alpha-aminoacyl-tRNA + H2O = an N-acyl-L-amino CC acid + a tRNA + H(+); Xref=Rhea:RHEA:54448, Rhea:RHEA-COMP:10123, CC Rhea:RHEA-COMP:13883, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:59874, ChEBI:CHEBI:78442, ChEBI:CHEBI:138191; CC EC=3.1.1.29; Evidence={ECO:0000305}; CC -!- INTERACTION: CC Q6GMV3; Q13156: RPA4; NbExp=3; IntAct=EBI-12807218, EBI-2856301; CC Q6GMV3; Q969E8: TSR2; NbExp=3; IntAct=EBI-12807218, EBI-746981; CC -!- DISEASE: Neurodevelopmental disorder with early-onset parkinsonism and CC behavioral abnormalities (NEDPBA) [MIM:620747]: An autosomal recessive CC disorder manifesting in late infancy or early childhood. It is CC characterized by developmental delay, intellectual disability, learning CC difficulties, behavioral abnormalities, and parkinsonism and spasticity CC usually developing in the third or fourth decades. CC {ECO:0000269|PubMed:27134041, ECO:0000269|PubMed:27753167, CC ECO:0000269|PubMed:30398675, ECO:0000269|PubMed:34765690, CC ECO:0000269|PubMed:34816696, ECO:0000269|PubMed:38286424}. Note=The CC disease may be caused by variants affecting the gene represented in CC this entry. CC -!- SIMILARITY: Belongs to the PTH2 family. PTRHD1 subfamily. CC {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; CH471053; EAX00745.1; -; Genomic_DNA. DR EMBL; BC073803; AAH73803.1; -; mRNA. DR CCDS; CCDS33156.1; -. DR RefSeq; NP_001013685.1; NM_001013663.2. DR AlphaFoldDB; Q6GMV3; -. DR SMR; Q6GMV3; -. DR BioGRID; 133896; 40. DR FunCoup; Q6GMV3; 580. DR IntAct; Q6GMV3; 13. DR STRING; 9606.ENSP00000330389; -. DR GlyGen; Q6GMV3; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q6GMV3; -. DR PhosphoSitePlus; Q6GMV3; -. DR SwissPalm; Q6GMV3; -. DR BioMuta; PTRHD1; -. DR DMDM; 74736452; -. DR jPOST; Q6GMV3; -. DR MassIVE; Q6GMV3; -. DR PaxDb; 9606-ENSP00000330389; -. DR PeptideAtlas; Q6GMV3; -. DR ProteomicsDB; 66305; -. DR Pumba; Q6GMV3; -. DR TopDownProteomics; Q6GMV3; -. DR Antibodypedia; 13171; 10 antibodies from 8 providers. DR DNASU; 391356; -. DR Ensembl; ENST00000328379.6; ENSP00000330389.4; ENSG00000184924.7. DR GeneID; 391356; -. DR KEGG; hsa:391356; -. DR MANE-Select; ENST00000328379.6; ENSP00000330389.4; NM_001013663.2; NP_001013685.1. DR UCSC; uc002rfm.4; human. DR AGR; HGNC:33782; -. DR ClinPGx; PA162379611; -. DR CTD; 391356; -. DR DisGeNET; 391356; -. DR GeneCards; PTRHD1; -. DR HGNC; HGNC:33782; PTRHD1. DR HPA; ENSG00000184924; Low tissue specificity. DR MalaCards; PTRHD1; -. DR MIM; 617342; gene. DR MIM; 620747; phenotype. DR OpenTargets; ENSG00000184924; -. DR VEuPathDB; HostDB:ENSG00000184924; -. DR eggNOG; KOG3305; Eukaryota. DR GeneTree; ENSGT00500000044959; -. DR HOGENOM; CLU_119261_0_1_1; -. DR InParanoid; Q6GMV3; -. DR OMA; AIIAQCC; -. DR OrthoDB; 201213at2759; -. DR PAN-GO; Q6GMV3; 0 GO annotations based on evolutionary models. DR PhylomeDB; Q6GMV3; -. DR BRENDA; 3.1.1.29; 2681. DR PathwayCommons; Q6GMV3; -. DR SignaLink; Q6GMV3; -. DR Agora; ENSG00000184924; -. DR BioGRID-ORCS; 391356; 11 hits in 1155 CRISPR screens. DR GenomeRNAi; 391356; -. DR Pharos; Q6GMV3; Tdark. DR PRO; PR:Q6GMV3; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q6GMV3; protein. DR Bgee; ENSG00000184924; Expressed in ileal mucosa and 186 other cell types or tissues. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0004045; F:peptidyl-tRNA hydrolase activity; IEA:UniProtKB-EC. DR Gene3D; 3.40.1490.10; Bit1; 1. DR InterPro; IPR023476; Pep_tRNA_hydro_II_dom_sf. DR InterPro; IPR002833; PTH2. DR InterPro; IPR042237; PTRHD1. DR PANTHER; PTHR46194; PEPTIDYL-TRNA HYDROLASE PTRHD1-RELATED; 1. DR PANTHER; PTHR46194:SF1; PEPTIDYL-TRNA HYDROLASE PTRHD1-RELATED; 1. DR Pfam; PF01981; PTH2; 1. DR SUPFAM; SSF102462; Peptidyl-tRNA hydrolase II; 1. PE 1: Evidence at protein level; KW Hydrolase; Intellectual disability; Parkinsonism; KW Proteomics identification; Reference proteome. FT CHAIN 1..140 FT /note="Putative peptidyl-tRNA hydrolase PTRHD1" FT /id="PRO_0000321818" FT VARIANT 52 FT /note="C -> Y (in NEDPBA; uncertain significance; FT dbSNP:rs781442277)" FT /evidence="ECO:0000269|PubMed:27134041" FT /id="VAR_078547" FT VARIANT 53 FT /note="H -> Y (in NEDPBA; uncertain significance; FT dbSNP:rs1057519631)" FT /evidence="ECO:0000269|PubMed:27753167" FT /id="VAR_078548" FT VARIANT 122 FT /note="R -> Q (in NEDPBA; uncertain significance; FT dbSNP:rs1238843879)" FT /evidence="ECO:0000269|PubMed:38286424" FT /id="VAR_089408" FT VARIANT 122 FT /note="R -> W (in NEDPBA; uncertain significance; FT dbSNP:rs753386543)" FT /evidence="ECO:0000269|PubMed:34816696" FT /id="VAR_089409" SQ SEQUENCE 140 AA; 15805 MW; 3AD1C82F3A9CF80B CRC64; MHRGVGPAFR VVRKMAASGA EPQVLVQYLV LRKDLSQAPF SWPAGALVAQ ACHAATAALH THRDHPHTAA YLQELGRMRK VVLEAPDETT LKELAETLQQ KNIDHMLWLE QPENIATCIA LRPYPKEEVG QYLKKFRLFK // ID RB39B_HUMAN Reviewed; 213 AA. AC Q96DA2; Q5JT79; Q8NEX3; DT 10-JAN-2003, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 189. DE RecName: Full=Ras-related protein Rab-39B; DE EC=3.6.5.2 {ECO:0000250|UniProtKB:P62820}; GN Name=RAB39B {ECO:0000312|HGNC:HGNC:16499}; 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]. RC TISSUE=Fetal brain; RX PubMed=12438742; DOI=10.1159/000064047; RA Cheng H., Ma Y., Ni X., Jiang M., Guo L., Ying K., Xie Y., Mao Y.; RT "Isolation and characterization of a human novel RAB (RAB39B) gene."; RL Cytogenet. Genome Res. 97:72-75(2002). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pancreas; 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 [5] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN XLID72. RX PubMed=20159109; DOI=10.1016/j.ajhg.2010.01.011; RA Giannandrea M., Bianchi V., Mignogna M.L., Sirri A., Carrabino S., RA D'Elia E., Vecellio M., Russo S., Cogliati F., Larizza L., Ropers H.H., RA Tzschach A., Kalscheuer V., Oehl-Jaschkowitz B., Skinner C., Schwartz C.E., RA Gecz J., Van Esch H., Raynaud M., Chelly J., de Brouwer A.P., Toniolo D., RA D'Adamo P.; RT "Mutations in the small GTPase gene RAB39B are responsible for X-linked RT mental retardation associated with autism, epilepsy, and macrocephaly."; RL Am. J. Hum. Genet. 86:185-195(2010). RN [6] RP SUBCELLULAR LOCATION. RX PubMed=24349490; DOI=10.1371/journal.pone.0083324; RA Seto S., Sugaya K., Tsujimura K., Nagata T., Horii T., Koide Y.; RT "Rab39a interacts with phosphatidylinositol 3-kinase and negatively RT regulates autophagy induced by lipopolysaccharide stimulation in RT macrophages."; RL PLoS ONE 8:E83324-E83324(2013). RN [7] RP INTERACTION WITH PICK1. RX PubMed=25784538; DOI=10.1038/ncomms7504; RA Mignogna M.L., Giannandrea M., Gurgone A., Fanelli F., Raimondi F., RA Mapelli L., Bassani S., Fang H., Van Anken E., Alessio M., Passafaro M., RA Gatti S., Esteban J.A., Huganir R., D'Adamo P.; RT "The intellectual disability protein RAB39B selectively regulates GluA2 RT trafficking to determine synaptic AMPAR composition."; RL Nat. Commun. 6:6504-6504(2015). RN [8] RP INVOLVEMENT IN WSMN, VARIANT WSMN LYS-168, AND CHARACTERIZATION OF VARIANT RP WSMN LYS-168. RX PubMed=25434005; DOI=10.1016/j.ajhg.2014.10.015; RA Wilson G.R., Sim J.C., McLean C., Giannandrea M., Galea C.A., Riseley J.R., RA Stephenson S.E., Fitzpatrick E., Haas S.A., Pope K., Hogan K.J., RA Gregg R.G., Bromhead C.J., Wargowski D.S., Lawrence C.H., James P.A., RA Churchyard A., Gao Y., Phelan D.G., Gillies G., Salce N., Stanford L., RA Marsh A.P., Mignogna M.L., Hayflick S.J., Leventer R.J., Delatycki M.B., RA Mellick G.D., Kalscheuer V.M., D'Adamo P., Bahlo M., Amor D.J., RA Lockhart P.J.; RT "Mutations in RAB39B cause X-linked intellectual disability and early-onset RT Parkinson disease with alpha-synuclein pathology."; RL Am. J. Hum. Genet. 95:729-735(2014). RN [9] RP FUNCTION, MUTAGENESIS OF SER-22 AND GLN-68, AND ACTIVITY REGULATION. RX PubMed=27103069; DOI=10.15252/embj.201593350; RA Sellier C., Campanari M.L., Julie Corbier C., Gaucherot A., RA Kolb-Cheynel I., Oulad-Abdelghani M., Ruffenach F., Page A., Ciura S., RA Kabashi E., Charlet-Berguerand N.; RT "Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to RT induce motor neuron dysfunction and cell death."; RL EMBO J. 35:1276-1297(2016). RN [10] RP DISCUSSION ON INVOLVEMENT IN WSMN. RX PubMed=27459931; DOI=10.1016/j.neurobiolaging.2016.03.021; RA Hodges K., Brewer S.S., Labbe C., Soto-Ortolaza A.I., Walton R.L., RA Strongosky A.J., Uitti R.J., van Gerpen J.A., Ertekin-Taner N., RA Kantarci K., Lowe V.J., Parisi J.E., Savica R., Graff-Radford J., RA Jones D.T., Knopman D.S., Petersen R.C., Murray M.E., Graff-Radford N.R., RA Ferman T.J., Dickson D.W., Wszolek Z.K., Boeve B.F., Ross O.A., RA Lorenzo-Betancor O.; RT "RAB39B gene mutations are not a common cause of Parkinson's disease or RT dementia with Lewy bodies."; RL Neurobiol. Aging 45:107-108(2016). RN [11] RP DISCUSSION ON INVOLVEMENT IN WSMN. RX PubMed=26739247; DOI=10.1016/j.parkreldis.2015.12.014; RA Loechte T., Brueggemann N., Vollstedt E.J., Krause P., Domingo A., RA Rosales R., Lee L.V., Hopfner F., Westenberger A., Kuehn A., Klein C., RA Lohmann K.; RT "RAB39B mutations are a rare finding in Parkinson disease patients."; RL Parkinsonism Relat. Disord. 23:116-117(2016). RN [12] RP FUNCTION, INTERACTION WITH 9ORF72; VPS39 AND VPS41, AND SUBCELLULAR RP LOCATION. RX PubMed=37821429; DOI=10.1038/s41467-023-42003-0; RA Zhang S., Tong M., Zheng D., Huang H., Li L., Ungermann C., Pan Y., Luo H., RA Lei M., Tang Z., Fu W., Chen S., Liu X., Zhong Q.; RT "C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane RT tethering and fusion in mammalian autophagy."; RL Nat. Commun. 14:6360-6360(2023). RN [13] {ECO:0007744|PDB:6S5F} RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-207 IN COMPLEX WITH MG(2+) AND RP GTP ANALOG, COFACTOR, AND DOMAIN. RA Diaz-Saez L., Jung S., Huber K., von Delft F., Arrowsmith C.H., Edwards A., RA Bountra C.; RT "Structure of the human RAB39B in complex with GMPPNP."; RL Submitted (JUL-2019) to the PDB data bank. RN [14] RP VARIANT WSMN ARG-192, AND SUBCELLULAR LOCATION. RX PubMed=26399558; DOI=10.1186/s13024-015-0045-4; RA Mata I.F., Jang Y., Kim C.H., Hanna D.S., Dorschner M.O., Samii A., RA Agarwal P., Roberts J.W., Klepitskaya O., Shprecher D.R., Chung K.A., RA Factor S.A., Espay A.J., Revilla F.J., Higgins D.S., Litvan I., RA Leverenz J.B., Yearout D., Inca-Martinez M., Martinez E., Thompson T.R., RA Cholerton B.A., Hu S.C., Edwards K.L., Kim K.S., Zabetian C.P.; RT "The RAB39B p.G192R mutation causes X-linked dominant Parkinson's RT disease."; RL Mol. Neurodegener. 10:50-50(2015). RN [15] RP VARIANT WSMN 186-TRP--CYS-213 DEL. RX PubMed=27066548; DOI=10.1212/nxg.0000000000000009; RG French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC); RA Lesage S., Bras J., Cormier-Dequaire F., Condroyer C., Nicolas A., RA Darwent L., Guerreiro R., Majounie E., Federoff M., Heutink P., Wood N.W., RA Gasser T., Hardy J., Tison F., Singleton A., Brice A.; RT "Loss-of-function mutations in RAB39B are associated with typical early- RT onset Parkinson disease."; RL Neurol. Genet. 1:E9-E9(2015). CC -!- FUNCTION: The small GTPases Rab are key regulators of intracellular CC membrane trafficking, from the formation of transport vesicles to their CC fusion with membranes. Rabs cycle between an inactive GDP-bound form CC and an active GTP-bound form that is able to recruit to membranes CC different sets of downstream effectors directly responsible for vesicle CC formation, movement, tethering and fusion (PubMed:27103069). RAB39B is CC involved in autophagy and may function in autophagosome formation CC (PubMed:27103069, PubMed:37821429). Binds downstream effector PICK1 to CC ensure selectively GRIA2 exit from the endoplasmic reticulum to the CC Golgi and to regulate AMPAR composition at the post-synapses and thus CC synaptic transmission (By similarity). May regulate the homeostasis of CC SNCA/alpha-synuclein (By similarity). {ECO:0000250|UniProtKB:Q8BHC1, CC ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:37821429}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.2; CC Evidence={ECO:0000250|UniProtKB:P62820}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670; CC Evidence={ECO:0000250|UniProtKB:P62820}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|Ref.13}; CC -!- ACTIVITY REGULATION: Regulated by guanine nucleotide exchange factors CC (GEFs) including C9orf72-SMCR8 complex, which promote the exchange of CC bound GDP for free GTP (PubMed:27103069). Regulated by GTPase CC activating proteins (GAPs) which increase the GTP hydrolysis activity CC (Probable). Inhibited by GDP dissociation inhibitors (GDIs) (Probable). CC {ECO:0000269|PubMed:27103069, ECO:0000305}. CC -!- SUBUNIT: Interacts (GDP-bound) with C9orf72; C9orf72 in complex with CC SMCR8 acts as a GEF for RAB39B (PubMed:37821429). Interacts (in GTP- CC bound form) with PICK1 (via PDZ domain); a PICK1 homodimer may allow CC simultaneous association of RAB39B and GRIA2 to PICK1 which is involved CC in GRIA2 trafficking (PubMed:25784538). Interacts with isoform c of CC RASSF1; the interaction is strong (By similarity). Interacts with CC isoform a of RASSF1; the interaction is weak (By similarity). Interacts CC with the DLG4/PSD-95 (By similarity). Interacts (GTP-bound) with HOPS CC complex components VPS39 and VPS41 (PubMed:37821429). CC {ECO:0000250|UniProtKB:Q8BHC1, ECO:0000269|PubMed:25784538, CC ECO:0000269|PubMed:37821429}. CC -!- INTERACTION: CC Q96DA2; Q08379: GOLGA2; NbExp=4; IntAct=EBI-9089467, EBI-618309; CC Q96DA2; Q96T51: RUFY1; NbExp=4; IntAct=EBI-9089467, EBI-3941207; CC Q96DA2; O14972: VPS26C; NbExp=3; IntAct=EBI-9089467, EBI-7207091; CC Q96DA2; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-9089467, EBI-524753; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Lipid-anchor CC {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Cytoplasmic vesicle CC membrane {ECO:0000269|PubMed:26399558}; Lipid-anchor {ECO:0000305}; CC Cytoplasmic side {ECO:0000305}. Golgi apparatus CC {ECO:0000269|PubMed:20159109, ECO:0000269|PubMed:24349490}. Cytoplasmic CC vesicle, autophagosome membrane {ECO:0000269|PubMed:37821429}. CC Autolysosome membrane {ECO:0000269|PubMed:37821429}. Note=Partial CC colocalization with markers that cycle from the cell surface to the CC trans-Golgi network. Colocalized with STX17 in autolysosomes in CC autophagy-induced conditions, although less compared with RAB39A CC (PubMed:37821429). {ECO:0000250|UniProtKB:Q8BHC1, CC ECO:0000269|PubMed:37821429}. CC -!- TISSUE SPECIFICITY: Highly expressed in the brain. CC {ECO:0000269|PubMed:20159109}. CC -!- DOMAIN: Switch I, switch II and the interswitch regions are CC characteristic of Rab GTPases and mediate the interactions with Rab CC downstream effectors. The switch regions undergo conformational changes CC upon nucleotide binding which drive interaction with specific sets of CC effector proteins, with most effectors only binding to GTP-bound Rab. CC {ECO:0000269|Ref.13}. CC -!- DISEASE: Intellectual developmental disorder, X-linked 72 (XLID72) CC [MIM:300271]: A disorder characterized by significantly below average CC general intellectual functioning associated with impairments in CC adaptive behavior and manifested during the developmental period. CC Intellectual deficiency is the only primary symptom of non-syndromic X- CC linked forms, while syndromic forms present with associated physical, CC neurological and/or psychiatric manifestations. XLID72 patients can CC manifest autism spectrum disorder, seizures and macrocephaly as CC additional features. {ECO:0000269|PubMed:20159109}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Waisman syndrome (WSMN) [MIM:311510]: A neurologic disorder CC characterized by delayed psychomotor development, intellectual CC disability, and early-onset Parkinson disease. CC {ECO:0000269|PubMed:25434005, ECO:0000269|PubMed:26399558, CC ECO:0000269|PubMed:27066548}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Its association with CC Parkinson disease is however unclear (PubMed:26739247, CC PubMed:27459931). According to a number of studies, variations CC affecting this gene are not a frequent cause of Parkinson disease, CC suggesting that RAB39B does not play a major role in Parkinson disease CC etiology (PubMed:26739247, PubMed:27459931). CC {ECO:0000269|PubMed:26739247, ECO:0000269|PubMed:27459931}. CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family. CC {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; AY052478; AAL12244.1; -; mRNA. DR EMBL; AL834460; CAD39120.1; -; mRNA. DR EMBL; AL356738; CAI41468.1; -; Genomic_DNA. DR EMBL; BC009714; AAH09714.1; -; mRNA. DR CCDS; CCDS14766.1; -. DR RefSeq; NP_741995.1; NM_171998.4. DR PDB; 6S5F; X-ray; 1.70 A; A=1-207. DR PDBsum; 6S5F; -. DR AlphaFoldDB; Q96DA2; -. DR SMR; Q96DA2; -. DR BioGRID; 125507; 57. DR FunCoup; Q96DA2; 1325. DR IntAct; Q96DA2; 57. DR MINT; Q96DA2; -. DR STRING; 9606.ENSP00000358466; -. DR iPTMnet; Q96DA2; -. DR PhosphoSitePlus; Q96DA2; -. DR BioMuta; RAB39B; -. DR DMDM; 27734447; -. DR jPOST; Q96DA2; -. DR MassIVE; Q96DA2; -. DR PaxDb; 9606-ENSP00000358466; -. DR PeptideAtlas; Q96DA2; -. DR ProteomicsDB; 76264; -. DR Pumba; Q96DA2; -. DR Antibodypedia; 350; 188 antibodies from 28 providers. DR DNASU; 116442; -. DR Ensembl; ENST00000369454.4; ENSP00000358466.3; ENSG00000155961.5. DR GeneID; 116442; -. DR KEGG; hsa:116442; -. DR MANE-Select; ENST00000369454.4; ENSP00000358466.3; NM_171998.4; NP_741995.1. DR UCSC; uc004fne.5; human. DR AGR; HGNC:16499; -. DR ClinPGx; PA34131; -. DR CTD; 116442; -. DR DisGeNET; 116442; -. DR GeneCards; RAB39B; -. DR GeneReviews; RAB39B; -. DR HGNC; HGNC:16499; RAB39B. DR HPA; ENSG00000155961; Tissue enhanced (brain, retina). DR MalaCards; RAB39B; -. DR MIM; 300271; phenotype. DR MIM; 300774; gene. DR MIM; 311510; phenotype. DR OpenTargets; ENSG00000155961; -. DR Orphanet; 2379; Early-onset parkinsonism-intellectual disability syndrome. DR Orphanet; 777; X-linked non-syndromic intellectual disability. DR VEuPathDB; HostDB:ENSG00000155961; -. DR eggNOG; KOG0091; Eukaryota. DR GeneTree; ENSGT00940000158132; -. DR HOGENOM; CLU_041217_23_1_1; -. DR InParanoid; Q96DA2; -. DR OMA; XSITRAY; -. DR OrthoDB; 9989112at2759; -. DR PAN-GO; Q96DA2; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q96DA2; -. DR PathwayCommons; Q96DA2; -. DR Reactome; R-HSA-8873719; RAB geranylgeranylation. DR Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs. DR SignaLink; Q96DA2; -. DR SIGNOR; Q96DA2; -. DR Agora; ENSG00000155961; -. DR BioGRID-ORCS; 116442; 12 hits in 769 CRISPR screens. DR GeneWiki; RAB39B; -. DR GenomeRNAi; 116442; -. DR Pharos; Q96DA2; Tbio. DR PRO; PR:Q96DA2; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q96DA2; protein. DR Bgee; ENSG00000155961; Expressed in endothelial cell and 123 other cell types or tissues. DR GO; GO:0120281; C:autolysosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031982; C:vesicle; IDA:UniProtKB. DR GO; GO:0003925; F:G protein activity; IEA:UniProtKB-EC. DR GO; GO:0005525; F:GTP binding; IBA:GO_Central. DR GO; GO:0003924; F:GTPase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0031489; F:myosin V binding; IPI:UniProtKB. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0032482; P:Rab protein signal transduction; IEA:InterPro. DR GO; GO:0010506; P:regulation of autophagy; IMP:UniProtKB. DR GO; GO:0050808; P:synapse organization; ISS:UniProtKB. DR GO; GO:0016192; P:vesicle-mediated transport; ISS:UniProtKB. DR CDD; cd04111; Rab39; 1. DR FunFam; 3.40.50.300:FF:000358; RAB39B, member RAS oncogene family; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR041818; Rab39. DR InterPro; IPR050209; Rab_GTPases_membrane_traffic. DR InterPro; IPR005225; Small_GTP-bd. DR InterPro; IPR001806; Small_GTPase. DR NCBIfam; TIGR00231; small_GTP; 1. DR PANTHER; PTHR47979; DRAB11-RELATED; 1. DR Pfam; PF00071; Ras; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00175; RAB; 1. DR SMART; SM00176; RAN; 1. DR SMART; SM00173; RAS; 1. DR SMART; SM00174; RHO; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51419; RAB; 1. PE 1: Evidence at protein level; KW 3D-structure; Autism spectrum disorder; Autophagy; Cell membrane; KW Cytoplasmic vesicle; Disease variant; Golgi apparatus; GTP-binding; KW Hydrolase; Intellectual disability; Lipoprotein; Lysosome; Magnesium; KW Membrane; Metal-binding; Methylation; Nucleotide-binding; KW Parkinson disease; Phosphoprotein; Prenylation; Protein transport; KW Proteomics identification; Reference proteome; Transport. FT CHAIN 1..213 FT /note="Ras-related protein Rab-39B" FT /id="PRO_0000121255" FT REGION 35..43 FT /note="Switch-I" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00753" FT REGION 67..83 FT /note="Switch-II" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00753" FT BINDING 17 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 20 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 21 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 22 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 22 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 23 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 37 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 40 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 40 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 64 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250|UniProtKB:P62820, FT ECO:0000269|Ref.13" FT BINDING 67 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 123 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 124 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 126 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 154 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT BINDING 155 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|Ref.13, ECO:0007744|PDB:6S5F" FT MOD_RES 201 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8BHC1" FT MOD_RES 213 FT /note="Cysteine methyl ester" FT /evidence="ECO:0000250|UniProtKB:P20336" FT LIPID 211 FT /note="S-geranylgeranyl cysteine" FT /evidence="ECO:0000250|UniProtKB:P20336" FT LIPID 213 FT /note="S-geranylgeranyl cysteine" FT /evidence="ECO:0000250|UniProtKB:P20336" FT VARIANT 168 FT /note="T -> K (in WSMN; loss of function mutation; FT expression of the mutation in neuroblastoma cells results FT in low levels of the mutant protein; dbSNP:rs587777874)" FT /evidence="ECO:0000269|PubMed:25434005" FT /id="VAR_073264" FT VARIANT 186..213 FT /note="Missing (in WSMN)" FT /evidence="ECO:0000269|PubMed:27066548" FT /id="VAR_078514" FT VARIANT 192 FT /note="G -> R (in WSMN; impaired localization to FT cytoplasmic vesicles; dbSNP:rs864309527)" FT /evidence="ECO:0000269|PubMed:26399558" FT /id="VAR_078515" FT MUTAGEN 22 FT /note="S->N: Dominant negative mutant." FT /evidence="ECO:0000269|PubMed:27103069" FT MUTAGEN 68 FT /note="Q->L: Constitutively active mutant locked in the FT active GTP-bound form." FT /evidence="ECO:0000269|PubMed:27103069" FT CONFLICT 57 FT /note="R -> T (in Ref. 1; AAL12244)" FT /evidence="ECO:0000305" FT STRAND 6..14 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 21..30 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 42..53 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 56..65 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 72..76 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 83..90 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 94..98 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 100..107 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 112..114 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 117..123 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 128..130 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 135..144 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 149..153 FT /evidence="ECO:0007829|PDB:6S5F" FT TURN 154..157 FT /evidence="ECO:0007829|PDB:6S5F" FT HELIX 160..176 FT /evidence="ECO:0007829|PDB:6S5F" FT STRAND 188..191 FT /evidence="ECO:0007829|PDB:6S5F" SQ SEQUENCE 213 AA; 24622 MW; 2B2C5B35C61FA88E CRC64; MEAIWLYQFR LIVIGDSTVG KSCLIRRFTE GRFAQVSDPT VGVDFFSRLV EIEPGKRIKL QIWDTAGQER FRSITRAYYR NSVGGLLLFD ITNRRSFQNV HEWLEETKVH VQPYQIVFVL VGHKCDLDTQ RQVTRHEAEK LAAAYGMKYI ETSARDAINV EKAFTDLTRD IYELVKRGEI TIQEGWEGVK SGFVPNVVHS SEEVVKSERR CLC // ID RENR_HUMAN Reviewed; 350 AA. AC O75787; B7Z9I3; Q5QTQ7; Q6T7F5; Q8NBP3; Q8NG15; Q96FV6; Q96LB5; Q9H2P8; AC Q9UG89; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 10-MAY-2005, sequence version 2. DT 28-JAN-2026, entry version 203. DE RecName: Full=Renin receptor {ECO:0000305}; DE AltName: Full=ATPase H(+)-transporting lysosomal accessory protein 2; DE AltName: Full=ATPase H(+)-transporting lysosomal-interacting protein 2; DE AltName: Full=ER-localized type I transmembrane adapter; DE AltName: Full=Embryonic liver differentiation factor 10; DE AltName: Full=N14F; DE AltName: Full=Renin/prorenin receptor; DE AltName: Full=Vacuolar ATP synthase membrane sector-associated protein M8-9; DE Short=ATP6M8-9; DE Short=V-ATPase M8.9 subunit; DE Contains: DE RecName: Full=Renin receptor N-terminal fragment {ECO:0000303|PubMed:29127204}; DE Contains: DE RecName: Full=Renin receptor C-terminal fragment {ECO:0000303|PubMed:29127204}; DE Flags: Precursor; GN Name=ATP6AP2 {ECO:0000312|HGNC:HGNC:18305}; GN Synonyms=ATP6IP2, CAPER, ELDF10; ORFNames=HT028, MSTP009, PSEC0072; 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 REN, RP PHOSPHORYLATION, TISSUE SPECIFICITY, AND FUNCTION. RC TISSUE=Mesangial cell; RX PubMed=12045255; DOI=10.1172/jci14276; RA Nguyen G., Delarue F., Burckle C., Bouzhir L., Giller T., Sraer J.-D.; RT "Pivotal role of the renin/prorenin receptor in angiotensin II production RT and cellular responses to renin."; RL J. Clin. Invest. 109:1417-1427(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Cervix carcinoma; RA Wang J., Kirby C., Herbst R.; RT "Cell cycle-dependent subcellular localization of the protein tyrosine RT phosphatase PTPCAAX1 and its implication in cell cycle regulation."; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Aorta; RA Hui R.T., Liu Y.Q., Liu B., Zhao B., Meng X.M., Sheng H., Xu Y.Y., RA Wang X.Y., Ye J., Song L., Gao Y., Wei Y.J., Zhang C.L., Zhang J., RA Chai M.Q., Chen J.Z., Sun Y.H., Zhou X.L., Jiang Y.X., Zhao X.W., Liu S., RA Cao H.Q., Zhao Y., Liu D.Q., Ding J.F., Liu L.S., Gao R.L., Wu Q.Y., RA Qiang B.Q., Yuan J.G., Liew C.C., Zhao M.S.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Hypothalamus; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain cortex; 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 MRNA] (ISOFORM 1). RC TISSUE=Teratocarcinoma; RX PubMed=16303743; DOI=10.1093/dnares/12.2.117; RA Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., RA Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., RA Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y., RA Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., RA Isogai T.; RT "Signal sequence and keyword trap in silico for selection of full-length RT human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA RT libraries."; RL DNA Res. 12:117-126(2005). RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 13-350 (ISOFORM 1). RC TISSUE=Liver; RA Zhang S., Yan H., Yang F.; RT "The cloning of a novel gene related with erythroid differentiation."; RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 21-350 (ISOFORM 1). 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 [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 188-350 (ISOFORM 1). RX PubMed=9556572; DOI=10.1074/jbc.273.18.10939; RA Ludwig J., Kerscher S., Brandt U., Pfeiffer K., Getlawi F., Apps D.K., RA Schaegger H.; RT "Identification and characterization of a novel 9.2-kDa membrane sector- RT associated protein of vacuolar proton-ATPase from chromaffin granules."; RL J. Biol. Chem. 273:10939-10947(1998). RN [12] RP INVOLVEMENT IN MRXSH, TISSUE SPECIFICITY, AND ALTERNATIVE SPLICING. RX PubMed=15746149; DOI=10.1093/hmg/ddi094; RA Ramser J., Abidi F.E., Burckle C.A., Lenski C., Toriello H., Wen G., RA Lubs H.A., Engert S., Stevenson R.E., Meindl A., Schwartz C.E., Nguyen G.; RT "A unique exonic splice enhancer mutation in a family with X-linked mental RT retardation and epilepsy points to a novel role of the renin receptor."; RL Hum. Mol. Genet. 14:1019-1027(2005). RN [13] 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 [14] RP INVOLVEMENT IN XPDS. RX PubMed=23595882; DOI=10.1093/hmg/ddt180; RA Korvatska O., Strand N.S., Berndt J.D., Strovas T., Chen D.H., RA Leverenz J.B., Kiianitsa K., Mata I.F., Karakoc E., Greenup J.L., RA Bonkowski E., Chuang J., Moon R.T., Eichler E.E., Nickerson D.A., RA Zabetian C.P., Kraemer B.C., Bird T.D., Raskind W.H.; RT "Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity RT (XPDS)."; RL Hum. Mol. Genet. 22:3259-3268(2013). 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 FUNCTION, INTERACTION WITH ATP6AP1 AND VMA21, SUBCELLULAR LOCATION, RP INVOLVEMENT IN CDG2R, MOTIF, CHARACTERIZATION OF VARIANTS CDG2R HIS-71 AND RP SER-98, AND MUTAGENESIS OF LYS-346 AND ARG-348. RX PubMed=29127204; DOI=10.1084/jem.20170453; RA Rujano M.A., Cannata Serio M., Panasyuk G., Peanne R., Reunert J., RA Rymen D., Hauser V., Park J.H., Freisinger P., Souche E., Guida M.C., RA Maier E.M., Wada Y., Jaeger S., Krogan N.J., Kretz O., Nobre S., Garcia P., RA Quelhas D., Bird T.D., Raskind W.H., Schwake M., Duvet S., Foulquier F., RA Matthijs G., Marquardt T., Simons M.; RT "Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with RT autophagic defects."; RL J. Exp. Med. 214:3707-3729(2017). RN [17] RP FUNCTION, AND INTERACTION WITH TMEM9 AND ATP6V0D1. RX PubMed=30374053; DOI=10.1038/s41556-018-0219-8; RA Jung Y.S., Jun S., Kim M.J., Lee S.H., Suh H.N., Lien E.M., Jung H.Y., RA Lee S., Zhang J., Yang J.I., Ji H., Wu J.Y., Wang W., Miller R.K., Chen J., RA McCrea P.D., Kopetz S., Park J.I.; RT "TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated RT Wnt/beta-catenin signalling."; RL Nat. Cell Biol. 20:1421-1433(2018). RN [18] RP INVOLVEMENT IN MRXSH. RX PubMed=30985297; DOI=10.1172/jci79990; RA Hirose T., Cabrera-Socorro A., Chitayat D., Lemonnier T., Feraud O., RA Cifuentes-Diaz C., Gervasi N., Mombereau C., Ghosh T., Stoica L., RA Bacha J.D.A., Yamada H., Lauterbach M.A., Guillon M., Kaneko K., RA Norris J.W., Siriwardena K., Blaser S., Teillon J., Mendoza-Londono R., RA Russeau M., Hadoux J., Ito S., Corvol P., Matheus M.G., Holden K.R., RA Takei K., Emiliani V., Bennaceur-Griscelli A., Schwartz C.E., Nguyen G., RA Groszer M.; RT "ATP6AP2 variant impairs CNS development and neuronal survival to cause RT fulminant neurodegeneration."; RL J. Clin. Invest. 129:2145-2162(2019). RN [19] RP FUNCTION. RX PubMed=32276428; DOI=10.3390/v12040414; RA Su W., Huang S., Zhu H., Zhang B., Wu X.; RT "Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and RT Affects EV-A71 Infection."; RL Viruses 12:0-0(2020). RN [20] {ECO:0007744|PDB:3LBS, ECO:0007744|PDB:3LC8} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 333-350. RX PubMed=21420935; DOI=10.1016/j.bbrc.2011.03.074; RA Zhang Y., Gao X., Michael Garavito R.; RT "Structural analysis of the intracellular domain of (pro)renin receptor RT fused to maltose-binding protein."; RL Biochem. Biophys. Res. Commun. 407:674-679(2011). RN [21] {ECO:0007744|PDB:6WLW, ECO:0007744|PDB:6WM2, ECO:0007744|PDB:6WM3, ECO:0007744|PDB:6WM4} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) IN COMPLEX WITH THE RP V-ATPASE. RX PubMed=33065002; DOI=10.1016/j.molcel.2020.09.029; RA Wang L., Wu D., Robinson C.V., Wu H., Fu T.M.; RT "Structures of a Complete Human V-ATPase Reveal Mechanisms of Its RT Assembly."; RL Mol. Cell 80:501-511.e3(2020). CC -!- FUNCTION: Multifunctional protein which functions as a renin, prorenin CC cellular receptor and is involved in the assembly of the lysosomal CC proton-transporting V-type ATPase (V-ATPase) and the acidification of CC the endo-lysosomal system (PubMed:12045255, PubMed:29127204, CC PubMed:30374053, PubMed:32276428). May mediate renin-dependent cellular CC responses by activating ERK1 and ERK2 (PubMed:12045255). By increasing CC the catalytic efficiency of renin in AGT/angiotensinogen conversion to CC angiotensin I, may also play a role in the renin-angiotensin system CC (RAS) (PubMed:12045255). Through its function in V-type ATPase (v- CC ATPase) assembly and acidification of the lysosome it regulates protein CC degradation and may control different signaling pathways important for CC proper brain development, synapse morphology and synaptic transmission CC (By similarity). {ECO:0000250|UniProtKB:Q9CYN9, CC ECO:0000269|PubMed:12045255, ECO:0000269|PubMed:29127204, CC ECO:0000269|PubMed:30374053, ECO:0000269|PubMed:32276428}. CC -!- SUBUNIT: Interacts with renin (PubMed:12045255). Accessory component of CC the multisubunit proton-transporting vacuolar (V)-ATPase protein pump CC (PubMed:33065002). Interacts (via N-terminus) with ATP6AP1 (via N- CC terminus) (PubMed:29127204, PubMed:33065002). Interacts with ATP6V0D1; CC ATP6V0D1 is a V-ATPase complex subunit and the interaction promotes V- CC ATPase complex assembly (PubMed:30374053, PubMed:33065002). Interacts CC with TMEM9; TMEM9 is a V-ATPase assembly regulator and the interaction CC induces the interaction with ATP6V0D1 (PubMed:30374053). Interacts with CC VMA21 (via N-terminus); VMA21 is a V-ATPase accessory component CC (PubMed:29127204). {ECO:0000269|PubMed:12045255, CC ECO:0000269|PubMed:29127204, ECO:0000269|PubMed:30374053, CC ECO:0000269|PubMed:33065002}. CC -!- INTERACTION: CC O75787; P21854: CD72; NbExp=3; IntAct=EBI-2512037, EBI-307924; CC O75787; Q16617: NKG7; NbExp=3; IntAct=EBI-2512037, EBI-3919611; CC O75787; P42857: NSG1; NbExp=3; IntAct=EBI-2512037, EBI-6380741; CC O75787; Q01453: PMP22; NbExp=3; IntAct=EBI-2512037, EBI-2845982; CC O75787; P53801: PTTG1IP; NbExp=3; IntAct=EBI-2512037, EBI-3906138; CC O75787; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-2512037, EBI-8652744; CC O75787; Q9NPL8: TIMMDC1; NbExp=3; IntAct=EBI-2512037, EBI-6268651; CC O75787; Q969S6: TMEM203; NbExp=3; IntAct=EBI-2512037, EBI-12274070; CC O75787; Q5BJF2: TMEM97; NbExp=3; IntAct=EBI-2512037, EBI-12111910; CC O75787; O00526: UPK2; NbExp=4; IntAct=EBI-2512037, EBI-10179682; CC O75787; O95183: VAMP5; NbExp=3; IntAct=EBI-2512037, EBI-10191195; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:29127204}; Single-pass type I membrane protein CC {ECO:0000305}. Lysosome membrane {ECO:0000269|PubMed:29127204}; Single- CC pass type I membrane protein {ECO:0000305}. Cytoplasmic vesicle, CC autophagosome membrane {ECO:0000250|UniProtKB:Q9CYN9}; Single-pass type CC I membrane protein {ECO:0000305}. Cell projection, dendritic spine CC membrane {ECO:0000250|UniProtKB:Q9CYN9}; Single-pass type I membrane CC protein {ECO:0000305}. Cell projection, axon CC {ECO:0000250|UniProtKB:Q9CYN9}. Endosome membrane CC {ECO:0000250|UniProtKB:Q9CYN9}; Single-pass type I membrane protein CC {ECO:0000305}. Cytoplasmic vesicle, clathrin-coated vesicle membrane CC {ECO:0000250|UniProtKB:Q6AXS4}; Single-pass type I membrane protein CC {ECO:0000305}. Cytoplasmic vesicle, secretory vesicle, synaptic vesicle CC membrane {ECO:0000250|UniProtKB:Q6AXS4}; Single-pass type I membrane CC protein {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O75787-1; Sequence=Displayed; CC Name=2; CC IsoId=O75787-2; Sequence=VSP_056910; CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, placenta, liver, kidney CC and pancreas. Barely detectable in lung and skeletal muscles. In the CC kidney cortex it is restricted to the mesangium of glomeruli. In the CC coronary and kidney artery it is expressed in the subendothelium, CC associated to smooth muscles where it colocalizes with REN. Expressed CC in vascular structures and by syncytiotrophoblast cells in the mature CC fetal placenta. {ECO:0000269|PubMed:12045255, CC ECO:0000269|PubMed:15746149}. CC -!- PTM: Phosphorylated. {ECO:0000269|PubMed:12045255}. CC -!- PTM: Proteolytically cleaved by a furin-like convertase in the trans- CC Golgi network to generate N- and C-terminal fragments. CC {ECO:0000269|PubMed:29127204}. CC -!- DISEASE: Intellectual developmental disorder, X-linked, syndromic, CC Hedera type (MRXSH) [MIM:300423]: A disorder characterized by CC significantly below average general intellectual functioning associated CC with impairments in adaptive behavior and manifested during the CC developmental period. MRXSH patients manifest mild to moderate CC intellectual disability associated with epilepsy, delays in motor CC milestones and speech acquisition in infancy. CC {ECO:0000269|PubMed:15746149, ECO:0000269|PubMed:30985297}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinsonism with spasticity, X-linked (XPDS) [MIM:300911]: A CC syndrome characterized by parkinsonian features, such as cogwheel CC rigidity, resting tremor and bradykinesia, and variably penetrant CC spasticity. {ECO:0000269|PubMed:23595882}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- DISEASE: Congenital disorder of glycosylation 2R (CDG2R) [MIM:301045]: CC A form of congenital disorder of glycosylation, a genetically CC heterogeneous group of multisystem disorders caused by a defect in CC glycoprotein biosynthesis and characterized by under-glycosylated serum CC glycoproteins. Congenital disorders of glycosylation result in a wide CC variety of clinical features, such as defects in the nervous system CC development, psychomotor retardation, dysmorphic features, hypotonia, CC coagulation disorders, and immunodeficiency. The broad spectrum of CC features reflects the critical role of N-glycoproteins during embryonic CC development, differentiation, and maintenance of cell functions. CDG2R CC is an X-linked recessive disorder characterized by infantile onset of CC liver failure, recurrent infections due to hypogammaglobulinemia, and CC cutis laxa. Some patients may also have mild intellectual impairment CC and dysmorphic features. {ECO:0000269|PubMed:29127204}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Note=Defects in ATP6AP2 may be involved in a glycosylation CC disorder with autophagic defects characterized by serum protein CC hypoglycosylation, immunodeficiency, liver disease, psychomotor CC impairment, and cutis laxa. {ECO:0000269|PubMed:25944712}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH10395.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAQ13511.1; Type=Frameshift; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; CC Sequence=CAA76984.1; Type=Erroneous initiation; Note=Truncated N-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; AF291814; AAM47531.1; -; mRNA. DR EMBL; AY038990; AAK83467.1; -; mRNA. DR EMBL; AF109363; AAQ13511.1; ALT_FRAME; mRNA. DR EMBL; AF248966; AAG44564.1; -; mRNA. DR EMBL; AK315948; BAH14319.1; -; mRNA. DR EMBL; AK075382; BAC11582.1; -; mRNA. DR EMBL; AC092473; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC010395; AAH10395.1; ALT_INIT; mRNA. DR EMBL; BC084541; AAH84541.1; -; mRNA. DR EMBL; AY429341; AAR06910.1; -; mRNA. DR EMBL; AL049929; CAB43210.1; -; mRNA. DR EMBL; Y17975; CAA76984.1; ALT_INIT; mRNA. DR CCDS; CCDS14252.1; -. [O75787-1] DR PIR; T08667; T08667. DR RefSeq; NP_005756.2; NM_005765.2. [O75787-1] DR PDB; 3LBS; X-ray; 2.15 A; A/B=333-350. DR PDB; 3LC8; X-ray; 2.00 A; A/B=333-350. DR PDB; 6WLW; EM; 3.00 A; V=1-350. DR PDB; 6WM2; EM; 3.10 A; V=1-350. DR PDB; 6WM3; EM; 3.40 A; V=1-350. DR PDB; 6WM4; EM; 3.60 A; V=1-350. DR PDB; 7U4T; EM; 3.60 A; V=1-350. DR PDB; 9CF8; EM; 3.46 A; V=1-350. DR PDB; 9CFC; EM; 3.47 A; V=1-350. DR PDB; 9DET; EM; 3.00 A; p=1-350. DR PDBsum; 3LBS; -. DR PDBsum; 3LC8; -. DR PDBsum; 6WLW; -. DR PDBsum; 6WM2; -. DR PDBsum; 6WM3; -. DR PDBsum; 6WM4; -. DR PDBsum; 7U4T; -. DR PDBsum; 9CF8; -. DR PDBsum; 9CFC; -. DR PDBsum; 9DET; -. DR AlphaFoldDB; O75787; -. DR EMDB; EMD-21844; -. DR EMDB; EMD-21847; -. DR EMDB; EMD-21848; -. DR EMDB; EMD-21849; -. DR EMDB; EMD-26334; -. DR EMDB; EMD-45533; -. DR EMDB; EMD-45536; -. DR SMR; O75787; -. DR BioGRID; 115461; 367. DR ComplexPortal; CPX-2470; Vacuolar proton translocating ATPase complex, ATP6V0A1 variant. DR ComplexPortal; CPX-6904; Vacuolar proton translocating ATPase complex, ATP6V0A2 variant. DR ComplexPortal; CPX-6905; Vacuolar proton translocating ATPase complex, ATP6V0A3 variant. DR ComplexPortal; CPX-6912; Vacuolar proton translocating ATPase complex, ATP6V0A4 variant. DR CORUM; O75787; -. DR FunCoup; O75787; 1050. DR IntAct; O75787; 242. DR MINT; O75787; -. DR STRING; 9606.ENSP00000490083; -. DR TCDB; 8.A.80.1.1; the (pro)renin receptor (prr) family. DR iPTMnet; O75787; -. DR PhosphoSitePlus; O75787; -. DR BioMuta; ATP6AP2; -. DR jPOST; O75787; -. DR MassIVE; O75787; -. DR PaxDb; 9606-ENSP00000367697; -. DR PeptideAtlas; O75787; -. DR ProteomicsDB; 50195; -. [O75787-1] DR ProteomicsDB; 7033; -. DR Pumba; O75787; -. DR TopDownProteomics; O75787-1; -. [O75787-1] DR Antibodypedia; 556; 361 antibodies from 37 providers. DR DNASU; 10159; -. DR Ensembl; ENST00000636409.1; ENSP00000489819.1; ENSG00000182220.16. [O75787-2] DR Ensembl; ENST00000636580.2; ENSP00000490083.1; ENSG00000182220.16. [O75787-1] DR GeneID; 10159; -. DR KEGG; hsa:10159; -. DR MANE-Select; ENST00000636580.2; ENSP00000490083.1; NM_005765.3; NP_005756.2. DR UCSC; uc004det.4; human. [O75787-1] DR AGR; HGNC:18305; -. DR ClinPGx; PA25148; -. DR CTD; 10159; -. DR DisGeNET; 10159; -. DR GeneCards; ATP6AP2; -. DR HGNC; HGNC:18305; ATP6AP2. DR HPA; ENSG00000182220; Tissue enriched (parathyroid). DR MalaCards; ATP6AP2; -. DR MIM; 300423; phenotype. DR MIM; 300556; gene. DR MIM; 300911; phenotype. DR MIM; 301045; phenotype. DR OpenTargets; ENSG00000182220; -. DR Orphanet; 93952; X-linked intellectual disability, Hedera type. DR Orphanet; 363654; X-linked parkinsonism-spasticity syndrome. DR VEuPathDB; HostDB:ENSG00000182220; -. DR eggNOG; KOG4737; Eukaryota. DR GeneTree; ENSGT00390000008856; -. DR HOGENOM; CLU_065819_0_0_1; -. DR InParanoid; O75787; -. DR OMA; QYAVIFN; -. DR OrthoDB; 7866065at2759; -. DR PAN-GO; O75787; 2 GO annotations based on evolutionary models. DR PhylomeDB; O75787; -. DR BioCyc; MetaCyc:MONOMER66-34369; -. DR PathwayCommons; O75787; -. DR Reactome; R-HSA-2022377; Metabolism of Angiotensinogen to Angiotensins. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; O75787; -. DR SIGNOR; O75787; -. DR Agora; ENSG00000182220; -. DR BioGRID-ORCS; 10159; 326 hits in 822 CRISPR screens. DR ChiTaRS; ATP6AP2; human. DR EvolutionaryTrace; O75787; -. DR GeneWiki; ATP6AP2; -. DR GenomeRNAi; 10159; -. DR Pharos; O75787; Tbio. DR PRO; PR:O75787; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; O75787; protein. DR Bgee; ENSG00000182220; Expressed in visceral pleura and 213 other cell types or tissues. DR ExpressionAtlas; O75787; baseline and differential. DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell. DR GO; GO:0030665; C:clathrin-coated vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0032591; C:dendritic spine membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; ISS:UniProtKB. DR GO; GO:0009897; C:external side of plasma membrane; IDA:HGNC-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0101003; C:ficolin-1-rich granule membrane; TAS:Reactome. DR GO; GO:0000139; C:Golgi membrane; NAS:ComplexPortal. DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:ComplexPortal. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0033176; C:proton-transporting V-type ATPase complex; NAS:ComplexPortal. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070821; C:tertiary granule membrane; TAS:Reactome. DR GO; GO:0016471; C:vacuolar proton-transporting V-type ATPase complex; IMP:UniProtKB. DR GO; GO:0000220; C:vacuolar proton-transporting V-type ATPase, V0 domain; ISS:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IEA:InterPro. DR GO; GO:0002003; P:angiotensin maturation; IDA:HGNC-UCL. DR GO; GO:0021626; P:central nervous system maturation; IMP:UniProtKB. DR GO; GO:0048388; P:endosomal lumen acidification; NAS:ComplexPortal. DR GO; GO:0048069; P:eye pigmentation; IMP:UniProtKB. DR GO; GO:0061795; P:Golgi lumen acidification; NAS:ComplexPortal. DR GO; GO:0060323; P:head morphogenesis; IMP:UniProtKB. DR GO; GO:0051452; P:intracellular pH reduction; NAS:ComplexPortal. DR GO; GO:0007042; P:lysosomal lumen acidification; IMP:UniProtKB. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; IDA:HGNC-UCL. DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IMP:UniProtKB. DR GO; GO:1902600; P:proton transmembrane transport; NAS:ComplexPortal. DR GO; GO:0043408; P:regulation of MAPK cascade; IDA:HGNC-UCL. DR GO; GO:0021903; P:rostrocaudal neural tube patterning; IMP:UniProtKB. DR GO; GO:0097401; P:synaptic vesicle lumen acidification; IEA:Ensembl. DR GO; GO:0007035; P:vacuolar acidification; NAS:ComplexPortal. DR InterPro; IPR056780; Renin_r_C. DR InterPro; IPR012493; Renin_rcpt. DR InterPro; IPR057318; RENR_N. DR PANTHER; PTHR13351; RENIN RECEPTOR; 1. DR PANTHER; PTHR13351:SF5; RENIN RECEPTOR; 1. DR Pfam; PF07850; Renin_r; 1. DR Pfam; PF25294; RENR_N; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW Cleavage on pair of basic residues; Congenital disorder of glycosylation; KW Cytoplasmic vesicle; Disease variant; Endoplasmic reticulum; Endosome; KW Epilepsy; Intellectual disability; Lysosome; Membrane; Neurodegeneration; KW Parkinsonism; Phosphoprotein; Postsynaptic cell membrane; KW Proteomics identification; Receptor; Reference proteome; Signal; Synapse; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..16 FT /evidence="ECO:0000255" FT CHAIN 17..350 FT /note="Renin receptor" FT /id="PRO_0000022203" FT CHAIN 17..275 FT /note="Renin receptor N-terminal fragment" FT /evidence="ECO:0000305" FT /id="PRO_0000447864" FT CHAIN 278..350 FT /note="Renin receptor C-terminal fragment" FT /evidence="ECO:0000305" FT /id="PRO_0000447865" FT TOPO_DOM 17..302 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 303..323 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 324..350 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT MOTIF 346..350 FT /note="Mediates retrograde transport to the ER" FT /evidence="ECO:0000269|PubMed:29127204" FT SITE 275..276 FT /note="Cleavage; by furin-like protease" FT /evidence="ECO:0000305|PubMed:29127204" FT SITE 277..278 FT /note="Cleavage; by furin-like protease" FT /evidence="ECO:0000305|PubMed:29127204" FT VAR_SEQ 101..132 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056910" FT VARIANT 71 FT /note="R -> H (in CDG2R; increases degradation rate via the FT ER-associated degradation pathway; loss of interaction with FT ATP6AP1; dbSNP:rs1057523485)" FT /evidence="ECO:0000269|PubMed:29127204" FT /id="VAR_082052" FT VARIANT 90 FT /note="P -> A (in dbSNP:rs9014)" FT /id="VAR_051313" FT VARIANT 98 FT /note="L -> S (in CDG2R; impairs export from the ER and FT cleavage; increases N-glycosylation post-translational FT modification which targets the misfolded protein to FT degradation via the ER-associated degradation pathway; FT results in loss of interaction with ATP6AP1; FT dbSNP:rs1926621737)" FT /evidence="ECO:0000269|PubMed:29127204" FT /id="VAR_082053" FT VARIANT 290 FT /note="A -> P (in dbSNP:rs35798522)" FT /id="VAR_051314" FT MUTAGEN 346 FT /note="K->Q: Increases cleavage and stability enhancing FT localization to the Golgi; when associated with Q-348." FT /evidence="ECO:0000269|PubMed:29127204" FT MUTAGEN 348 FT /note="R->Q: Increases cleavage and stability and enhancing FT localization to the Golgi; when associated with Q-346." FT /evidence="ECO:0000269|PubMed:29127204" FT CONFLICT 138 FT /note="G -> W (in Ref. 2; AAK83467)" FT /evidence="ECO:0000305" FT CONFLICT 153..154 FT /note="QL -> HV (in Ref. 2; AAK83467)" FT /evidence="ECO:0000305" FT CONFLICT 258 FT /note="N -> K (in Ref. 6; BAC11582)" FT /evidence="ECO:0000305" FT CONFLICT 285 FT /note="Q -> R (in Ref. 4 and 10)" FT /evidence="ECO:0000305" FT CONFLICT 287 FT /note="Missing (in Ref. 8; AAH10395)" FT /evidence="ECO:0000305" FT HELIX 303..329 FT /evidence="ECO:0007829|PDB:6WLW" FT TURN 334..337 FT /evidence="ECO:0007829|PDB:3LC8" FT HELIX 338..340 FT /evidence="ECO:0007829|PDB:3LBS" SQ SEQUENCE 350 AA; 39008 MW; 84084A4ACE9C5DE8 CRC64; MAVFVVLLAL VAGVLGNEFS ILKSPGSVVF RNGNWPIPGE RIPDVAALSM GFSVKEDLSW PGLAVGNLFH RPRATVMVMV KGVNKLALPP GSVISYPLEN AVPFSLDSVA NSIHSLFSEE TPVVLQLAPS EERVYMVGKA NSVFEDLSVT LRQLRNRLFQ ENSVLSSLPL NSLSRNNEVD LLFLSELQVL HDISSLLSRH KHLAKDHSPD LYSLELAGLD EIGKRYGEDS EQFRDASKIL VDALQKFADD MYSLYGGNAV VELVTVKSFD TSLIRKTRTI LEAKQAKNPA SPYNLAYKYN FEYSVVFNMV LWIMIALALA VIITSYNIWN MDPGYDSIIY RMTNQKIRMD // ID SAP_HUMAN Reviewed; 524 AA. AC P07602; P07292; P15793; P78538; P78541; P78546; P78547; P78558; Q53Y86; AC Q6IBQ6; Q92739; Q92740; Q92741; Q92742; DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 2. DT 28-JAN-2026, entry version 268. DE RecName: Full=Prosaposin; DE AltName: Full=Proactivator polypeptide; DE Contains: DE RecName: Full=Saposin-A; DE AltName: Full=Protein A; DE Contains: DE RecName: Full=Saposin-B-Val; DE Contains: DE RecName: Full=Saposin-B; DE AltName: Full=Cerebroside sulfate activator; DE Short=CSAct; DE AltName: Full=Dispersin; DE AltName: Full=Sphingolipid activator protein 1; DE Short=SAP-1; DE AltName: Full=Sulfatide/GM1 activator; DE Contains: DE RecName: Full=Saposin-C; DE AltName: Full=A1 activator; DE AltName: Full=Co-beta-glucosidase; DE AltName: Full=Glucosylceramidase activator; DE AltName: Full=Sphingolipid activator protein 2; DE Short=SAP-2; DE Contains: DE RecName: Full=Saposin-D; DE AltName: Full=Component C; DE AltName: Full=Protein C; DE Flags: Precursor; GN Name=PSAP; Synonyms=GLBA, SAP1; 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]. RC TISSUE=Liver; RX PubMed=2515150; DOI=10.1016/0888-7543(89)90014-1; RA Rorman E.G., Grabowski G.A.; RT "Molecular cloning of a human co-beta-glucosidase cDNA: evidence that four RT sphingolipid hydrolase activator proteins are encoded by single genes in RT humans and rats."; RL Genomics 5:486-492(1989). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2498298; DOI=10.1093/oxfordjournals.jbchem.a122629; RA Nakano T., Sandhoff K., Stuemper J., Christomanou H., Suzuki K.; RT "Structure of full-length cDNA coding for sulfatide activator, a Co-beta- RT glucosidase and two other homologous proteins: two alternate forms of the RT sulfatide activator."; RL J. Biochem. 105:152-154(1989). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SAP-MU-0). RC TISSUE=Brain, Eye, 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 [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-524. RX PubMed=2842863; DOI=10.1126/science.2842863; RA O'Brien J.S., Kretz K.A., Dewji N., Wenger D.A., Esch F., Fluharty A.L.; RT "Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same RT genetic locus."; RL Science 241:1098-1101(1988). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 14-524. RX PubMed=1612590; DOI=10.1016/0888-7543(92)90247-p; RA Rorman E.G., Scheinker V., Grabowski G.A.; RT "Structure and evolution of the human prosaposin chromosomal gene."; RL Genomics 13:312-318(1992). RN [10] RP PROTEIN SEQUENCE OF 17-24 AND 165-172. RX PubMed=8323276; DOI=10.1006/abbi.1993.1328; RA Hiraiwa M., O'Brien J.S., Kishimoto Y., Galdzicka M., Fluharty A.L., RA Ginns E.I., Martin B.M.; RT "Isolation, characterization, and proteolysis of human prosaposin, the RT precursor of saposins (sphingolipid activator proteins)."; RL Arch. Biochem. Biophys. 304:110-116(1993). RN [11] RP PROTEIN SEQUENCE OF 17-26. RC TISSUE=Milk; RX PubMed=1958198; DOI=10.1016/s0006-291x(05)81415-9; RA Kondoh K., Hineno T., Sano A., Kakimoto Y.; RT "Isolation and characterization of prosaposin from human milk."; RL Biochem. Biophys. Res. Commun. 181:286-292(1991). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 59-125 AND 304-513. RC TISSUE=Brain; RX PubMed=2013321; DOI=10.1016/0014-5793(91)80308-p; RA Holtschmidt H., Sandhoff K., Fuerst W., Kwon H.Y., Schnabel D., Suzuki K.; RT "The organization of the gene for the human cerebroside sulfate activator RT protein."; RL FEBS Lett. 280:267-270(1991). RN [13] RP PROTEIN SEQUENCE OF 60-142. RX PubMed=2717620; DOI=10.1073/pnas.86.9.3389; RA Morimoto S., Martin B.M., Yamamoto Y., Kretz K.A., O'Brien J.S., RA Kishimoto Y.; RT "Saposin A: second cerebrosidase activator protein."; RL Proc. Natl. Acad. Sci. U.S.A. 86:3389-3393(1989). RN [14] RP PROTEIN SEQUENCE OF 62-84 AND 410-431. RX PubMed=8370464; DOI=10.1016/0014-5793(93)80908-d; RA Tyynela J., Palmer D.N., Baumann M., Haltia M.; RT "Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis."; RL FEBS Lett. 330:8-12(1993). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 164-524. RX PubMed=2825202; DOI=10.1073/pnas.84.23.8652; RA Dewji N.N., Wenger D.A., O'Brien J.S.; RT "Nucleotide sequence of cloned cDNA for human sphingolipid activator RT protein 1 precursor."; RL Proc. Natl. Acad. Sci. U.S.A. 84:8652-8656(1987). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 195-263. RX PubMed=2868718; DOI=10.1016/s0006-291x(86)80518-6; RA Dewji N.N., Wenger D.A., Fujibayashi S., Donoviel M., Esch F., Hill F., RA O'Brien J.S.; RT "Molecular cloning of the sphingolipid activator protein-1 (SAP-1), the RT sulfatide sulfatase activator."; RL Biochem. Biophys. Res. Commun. 134:989-994(1986). RN [17] RP PROTEIN SEQUENCE OF 195-274. RX PubMed=3242555; DOI=10.1515/bchm3.1988.369.2.1361; RA Kleinschmidt T., Christomanou H., Braunitzer G.; RT "Complete amino-acid sequence of the naturally occurring A2 activator RT protein for enzymic sphingomyelin degradation: identity to the sulfatide RT activator protein (SAP-1)."; RL Biol. Chem. Hoppe-Seyler 369:1361-1365(1988). RN [18] RP PROTEIN SEQUENCE OF 195-274. RC TISSUE=Kidney; RX PubMed=2209618; DOI=10.1111/j.1432-1033.1990.tb19280.x; RA Furst W., Schubert J., Machleidt W., Meyer H.E., Sandhoff K.; RT "The complete amino-acid sequences of human ganglioside GM2 activator RT protein and cerebroside sulfate activator protein."; RL Eur. J. Biochem. 192:709-714(1990). RN [19] RP PROTEIN SEQUENCE OF 311-390. RX PubMed=3442600; DOI=10.1515/bchm3.1987.368.2.1571; RA Kleinschmidt T., Christomanou H., Braunitzer G.; RT "Complete amino-acid sequence and carbohydrate content of the naturally RT occurring glucosylceramide activator protein (A1 activator) absent from a RT new human Gaucher disease variant."; RL Biol. Chem. Hoppe-Seyler 368:1571-1578(1987). RN [20] RP PROTEIN SEQUENCE OF 405-484. RX PubMed=2845979; DOI=10.1016/s0006-291x(88)80855-6; RA Morimoto S., Martin B.M., Kishimoto Y., O'Brien J.S.; RT "Saposin D: a sphingomyelinase activator."; RL Biochem. Biophys. Res. Commun. 156:403-410(1988). RN [21] RP PROTEIN SEQUENCE OF 407-484. RX PubMed=3048308; DOI=10.1515/bchm3.1988.369.1.317; RA Furst W., Machleidt W., Sandhoff K.; RT "The precursor of sulfatide activator protein is processed to three RT different proteins."; RL Biol. Chem. Hoppe-Seyler 369:317-328(1988). RN [22] RP PARTIAL PROTEIN SEQUENCE (SAPOSIN-B), AND STRUCTURE OF CARBOHYDRATES. RC TISSUE=Urine; RX PubMed=10562467; DOI=10.1006/mgme.1999.2900; RA Fluharty A.L., Lombardo C., Louis A., Stevens R.L., Whitelegge J.P., RA Waring A.J., To T., Fluharty C.B., Faull K.F.; RT "Preparation of the cerebroside sulfate activator (CSAct or saposin B) from RT human urine."; RL Mol. Genet. Metab. 68:391-403(1999). RN [23] RP DISULFIDE BONDS IN SAPOSINS-B AND C, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=7730378; DOI=10.1074/jbc.270.17.9953; RA Vaccaro A.M., Salvioli R., Barca A., Tatti M., Ciaffoni F., Maras B., RA Siciliano R., Zappacosta F., Amoresano A., Pucci P.; RT "Structural analysis of saposin C and B. Complete localization of disulfide RT bridges."; RL J. Biol. Chem. 270:9953-9960(1995). RN [24] RP FUNCTION. RX PubMed=10383054; RX DOI=10.1002/(sici)1098-1136(199906)26:4<353::aid-glia9>3.3.co;2-7; RA Hiraiwa M., Campana W.M., Mizisin A.P., Mohiuddin L., O'Brien J.S.; RT "Prosaposin: a myelinotrophic protein that promotes expression of myelin RT constituents and is secreted after nerve injury."; RL Glia 26:353-360(1999). RN [25] RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Urine; RX PubMed=10510427; RX DOI=10.1002/(sici)1096-9888(199910)34:10<1040::aid-jms863>3.0.co;2-x; RA Faull K.F., Whitelegge J.P., Higginson J., To T., Johnson J., RA Krutchinsky A.N., Standing K.G., Waring A.J., Stevens R.L., Fluharty C.B., RA Fluharty A.L.; RT "Cerebroside sulfate activator protein (Saposin B): chromatographic and RT electrospray mass spectrometric properties."; RL J. Mass Spectrom. 34:1040-1054(1999). RN [26] RP GLYCOSYLATION AT ASN-215, AND STRUCTURE OF CARBOHYDRATE ON ASN-215. RX PubMed=11180632; RX DOI=10.1002/1096-9888(200012)35:12<1416::aid-jms75>3.0.co;2-k; RA Faull K.F., Johnson J., Kim M.J., To T., Whitelegge J.P., Stevens R.L., RA Fluharty C.B., Fluharty A.L.; RT "Structure of the asparagine-linked sugar chains of porcine kidney and RT human urine cerebroside sulfate activator protein."; RL J. Mass Spectrom. 35:1416-1424(2000). RN [27] RP DISULFIDE BONDS IN SAPOSIN-D. RX PubMed=10406958; DOI=10.1046/j.1432-1327.1999.00521.x; RA Tatti M., Salvioli R., Ciaffoni F., Pucci P., Andolfo A., Amoresano A., RA Vaccaro A.M.; RT "Structural and membrane-binding properties of saposin D."; RL Eur. J. Biochem. 263:486-494(1999). RN [28] RP SUBCELLULAR LOCATION, AND INTERACTION WITH SORT1. RX PubMed=14657016; DOI=10.1093/emboj/cdg629; RA Lefrancois S., Zeng J., Hassan A.J., Canuel M., Morales C.R.; RT "The lysosomal trafficking of sphingolipid activator proteins (SAPs) is RT mediated by sortilin."; RL EMBO J. 22:6430-6437(2003). RN [29] RP DISULFIDE BONDS IN SAPOSIN-B. RX PubMed=12510003; DOI=10.1016/s1046-5928(02)00597-1; RA Ahn V.E., Faull K.F., Whitelegge J.P., Higginson J., Fluharty A.L., RA Prive G.G.; RT "Expression, purification, crystallization, and preliminary X-ray analysis RT of recombinant human saposin B."; RL Protein Expr. Purif. 27:186-193(2003). RN [30] RP GLYCOSYLATION AT ASN-80; ASN-101; ASN-215; ASN-332 AND ASN-426. RX PubMed=19167329; DOI=10.1016/j.cell.2008.11.047; RA Ruiz-Canada C., Kelleher D.J., Gilmore R.; RT "Cotranslational and posttranslational N-glycosylation of polypeptides by RT distinct mammalian OST isoforms."; RL Cell 136:272-283(2009). RN [31] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-80; ASN-101; ASN-332 AND RP ASN-426. 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 [32] 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 [33] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=21835174; DOI=10.1016/j.yexcr.2011.07.017; RA Yuan L., Morales C.R.; RT "Prosaposin sorting is mediated by oligomerization."; RL Exp. Cell Res. 317:2456-2467(2011). RN [34] RP INTERACTION WITH SORT1, AND SUBCELLULAR LOCATION. RX PubMed=22431521; DOI=10.1128/mcb.06726-11; RA Mamo A., Jules F., Dumaresq-Doiron K., Costantino S., Lefrancois S.; RT "The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal RT sorting."; RL Mol. Cell. Biol. 32:1855-1866(2012). RN [35] 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 [36] RP INTERACTION WITH GRN. 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 [37] RP CLEAVAGE OF SIGNAL PEPTIDE [LARGE SCALE ANALYSIS] AFTER ALA-16, AND 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 [38] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 195-273, AND MUTAGENESIS OF RP ILE-240. RX PubMed=12518053; DOI=10.1073/pnas.0136947100; RA Ahn V.E., Faull K.F., Whitelegge J.P., Fluharty A.L., Prive G.G.; RT "Crystal structure of saposin B reveals a dimeric shell for lipid RT binding."; RL Proc. Natl. Acad. Sci. U.S.A. 100:38-43(2003). RN [39] RP REVIEW ON MLDSAPB VARIANTS. RX PubMed=7866401; DOI=10.1002/humu.1380040402; RA Gieselmann V., Zlotogora J., Harris A., Wenger D.A., Morris C.P.; RT "Molecular genetics of metachromatic leukodystrophy."; RL Hum. Mutat. 4:233-242(1994). RN [40] RP VARIANT MLDSAPB ILE-217. RX PubMed=2302219; DOI=10.1016/0006-291x(90)90912-7; RA Rafi M.A., Zhang X.-L., Degala G., Wenger D.A.; RT "Detection of a point mutation in sphingolipid activator protein-1 mRNA in RT patients with a variant form of metachromatic leukodystrophy."; RL Biochem. Biophys. Res. Commun. 166:1017-1023(1990). RN [41] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT MLDSAPB ILE-217. RX PubMed=2320574; DOI=10.1073/pnas.87.7.2541; RA Kretz K.A., Carson G.S., Morimoto S., Kishimoto Y., Fluharty A.L., RA O'Brien J.S.; RT "Characterization of a mutation in a family with saposin B deficiency: a RT glycosylation site defect."; RL Proc. Natl. Acad. Sci. U.S.A. 87:2541-2544(1990). RN [42] RP VARIANT MLDSAPB SER-241, NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE RP SPLICING. RX PubMed=2019586; DOI=10.1016/s0021-9258(20)89483-6; RA Holtschmidt H., Sandhoff K., Kwon H.Y., Harzer K., Nakano T., Suzuki K.; RT "Sulfatide activator protein. Alternative splicing that generates three RT mRNAs and a newly found mutation responsible for a clinical disease."; RL J. Biol. Chem. 266:7556-7560(1991). RN [43] RP INVOLVEMENT IN PSAPD. RX PubMed=1371116; DOI=10.1016/s0021-9258(19)50733-5; RA Schnabel D., Schroder M., Furst W., Klein A., Hurwitz R., Zenk T., RA Weber J., Harzer K., Paton B.C., Poulos A., Suzuki K., Sandhoff K.; RT "Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is RT caused by a mutation in the initiation codon of their common gene."; RL J. Biol. Chem. 267:3312-3315(1992). RN [44] RP VARIANT GDSAPC PHE-388. RX PubMed=2060627; DOI=10.1016/0014-5793(91)80760-z; RA Schnabel D., Schroeder M., Sandhoff K.; RT "Mutation in the sphingolipid activator protein 2 in a patient with a RT variant of Gaucher disease."; RL FEBS Lett. 284:57-59(1991). RN [45] RP VARIANT MLDSAPB LYS-215. RX PubMed=10196694; DOI=10.1038/sj.ejhg.5200266; RA Regis S., Filocamo M., Corsolini F., Caroli F., Keulemans J.L.M., RA van Diggelen O.P., Gatti R.; RT "An Asn > Lys substitution in saposin B involving a conserved amino acidic RT residue and leading to the loss of the single N-glycosylation site in a RT patient with metachromatic leukodystrophy and normal arylsulphatase A RT activity."; RL Eur. J. Hum. Genet. 7:125-130(1999). RN [46] RP VARIANT MLDSAPB HIS-215, AND CHARACTERIZATION OF VARIANT MLDSAPB HIS-215. RX PubMed=10682309; DOI=10.1023/a:1005603014401; RA Wrobe D., Henseler M., Huettler S., Pascual Pascual S.I., Chabas A., RA Sandhoff K.; RT "A non-glycosylated and functionally deficient mutant (N215H) of the RT sphingolipid activator protein B (SAP-B) in a novel case of metachromatic RT leukodystrophy (MLD)."; RL J. Inherit. Metab. Dis. 23:63-76(2000). RN [47] RP INVOLVEMENT IN PSAPD. RX PubMed=11309366; DOI=10.1093/hmg/10.9.927; RA Hulkova H., Cervenkova M., Ledvinova J., Tochackova M., Hrebicek M., RA Poupetova H., Befekadu A., Berna L., Paton B.C., Harzer K., Boor A., RA Smid F., Elleder M.; RT "A novel mutation in the coding region of the prosaposin gene leads to a RT complete deficiency of prosaposin and saposins, and is associated with a RT complex sphingolipidosis dominated by lactosylceramide accumulation."; RL Hum. Mol. Genet. 10:927-940(2001). RN [48] RP VARIANT KRBSAPA VAL-70 DEL. RX PubMed=15773042; DOI=10.1016/j.ymgme.2004.10.004; RA Spiegel R., Bach G., Sury V., Mengistu G., Meidan B., Shalev S., Shneor Y., RA Mandel H., Zeigler M.; RT "A mutation in the saposin A coding region of the prosaposin gene in an RT infant presenting as Krabbe disease: first report of saposin A deficiency RT in humans."; RL Mol. Genet. Metab. 84:160-166(2005). RN [49] RP VARIANT GDSAPC PRO-349. RX PubMed=17919309; DOI=10.1111/j.1399-0004.2007.00899.x; RA Tylki-Szymanska A., Czartoryska B., Vanier M.T., Poorthuis B.J., RA Groener J.A., Lugowska A., Millat G., Vaccaro A.M., Jurkiewicz E.; RT "Non-neuronopathic Gaucher disease due to saposin C deficiency."; RL Clin. Genet. 72:538-542(2007). RN [50] RP INVOLVEMENT IN PARK24, VARIANTS PARK24 TYR-412 AND PRO-453, AND RP CHARACTERIZATION OF VARIANTS PARK24 TYR-412 AND PRO-453. RX PubMed=32201884; DOI=10.1093/brain/awaa064; RA Oji Y., Hatano T., Ueno S.I., Funayama M., Ishikawa K.I., Okuzumi A., RA Noda S., Sato S., Satake W., Toda T., Li Y., Hino-Takai T., Kakuta S., RA Tsunemi T., Yoshino H., Nishioka K., Hattori T., Mizutani Y., Mutoh T., RA Yokochi F., Ichinose Y., Koh K., Shindo K., Takiyama Y., Hamaguchi T., RA Yamada M., Farrer M.J., Uchiyama Y., Akamatsu W., Wu Y.R., Matsuda J., RA Hattori N.; RT "Variants in saposin D domain of prosaposin gene linked to Parkinson's RT disease."; RL Brain 143:1190-1205(2020). CC -!- FUNCTION: Saposin-A and saposin-C stimulate the hydrolysis of CC glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and CC galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin- CC C apparently acts by combining with the enzyme and acidic lipid to form CC an activated complex, rather than by solubilizing the substrate. CC -!- FUNCTION: Saposin-B stimulates the hydrolysis of galacto-cerebroside CC sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta- CC galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha- CC galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex CC with the substrates of the sphingolipid hydrolases. CC -!- FUNCTION: Saposin-D is a specific sphingomyelin phosphodiesterase CC activator (EC 3.1.4.12). CC -!- FUNCTION: [Prosaposin]: Behaves as a myelinotrophic and neurotrophic CC factor, these effects are mediated by its G-protein-coupled receptors, CC GPR37 and GPR37L1, undergoing ligand-mediated internalization followed CC by ERK phosphorylation signaling. {ECO:0000250|UniProtKB:Q61207, CC ECO:0000269|PubMed:10383054}. CC -!- FUNCTION: Saposins are specific low-molecular mass non-enzymic CC proteins, they participate in the lysosomal degradation of CC sphingolipids, which takes place by the sequential action of specific CC hydrolases. CC -!- SUBUNIT: Saposin-B is a homodimer. Prosaposin exists as a roughly half- CC half mixture of monomers and disulfide-linked dimers (PubMed:10406958, CC PubMed:12510003, PubMed:21835174, PubMed:7730378). Monomeric prosaposin CC interacts (via C-terminus) with sortilin/SORT1, the interaction is CC required for targeting to lysosomes (PubMed:14657016, PubMed:22431521). CC Interacts with GRN; facilitates lysosomal delivery of progranulin from CC the extracellular space and the biosynthetic pathway (PubMed:26370502). CC {ECO:0000269|PubMed:10406958, ECO:0000269|PubMed:12510003, CC ECO:0000269|PubMed:14657016, ECO:0000269|PubMed:21835174, CC ECO:0000269|PubMed:22431521, ECO:0000269|PubMed:26370502, CC ECO:0000269|PubMed:7730378}. CC -!- INTERACTION: CC P07602; P05067: APP; NbExp=3; IntAct=EBI-716699, EBI-77613; CC P07602; Q92624: APPBP2; NbExp=3; IntAct=EBI-716699, EBI-743771; CC P07602; P31944: CASP14; NbExp=3; IntAct=EBI-716699, EBI-2510738; CC P07602; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-716699, EBI-9087876; CC P07602; P28799: GRN; NbExp=6; IntAct=EBI-716699, EBI-747754; CC P07602; P07948: LYN; NbExp=3; IntAct=EBI-716699, EBI-79452; CC P07602; P50542-3: PEX5; NbExp=3; IntAct=EBI-716699, EBI-12181987; CC P07602; O96006: ZBED1; NbExp=4; IntAct=EBI-716699, EBI-740037; CC P07602-1; P07602-1: PSAP; NbExp=5; IntAct=EBI-10635648, EBI-10635648; CC P07602-1; P55072: VCP; NbExp=3; IntAct=EBI-10635648, EBI-355164; CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:14657016, CC ECO:0000269|PubMed:21835174, ECO:0000269|PubMed:22431521}. CC -!- SUBCELLULAR LOCATION: [Prosaposin]: Secreted CC {ECO:0000250|UniProtKB:Q61207}. Note=Secreted as a fully glycosylated CC 70 kDa protein composed of complex glycans. CC {ECO:0000250|UniProtKB:Q61207}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=Sap-mu-0; CC IsoId=P07602-1; Sequence=Displayed; CC Name=Sap-mu-6; CC IsoId=P07602-2; Sequence=VSP_006014; CC Name=Sap-mu-9; CC IsoId=P07602-3; Sequence=VSP_006015; CC -!- PTM: The lysosomal precursor is proteolytically processed to 4 small CC peptides, which are similar to each other and are sphingolipid CC hydrolase activator proteins. CC -!- PTM: N-linked glycans show a high degree of microheterogeneity. CC {ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329}. CC -!- PTM: The one residue extended Saposin-B-Val is only found in 5% of the CC chains. CC -!- DISEASE: Combined saposin deficiency (PSAPD) [MIM:611721]: An autosomal CC recessive storage disorder characterized by hepatosplenomegaly and CC severe neurologic disease, due to absence of all saposins. PSAPD has a CC fatal outcome in infancy. {ECO:0000269|PubMed:11309366, CC ECO:0000269|PubMed:1371116}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Metachromatic leukodystrophy due to saposin B deficiency CC (MLDSAPB) [MIM:249900]: A form of metachromatic leukodystrophy CC biochemically characterized by tissue accumulation of cerebroside-3- CC sulfate, saposin B deficiency, and normal arylsulfatase A activity. CC Clinical manifestations include periventricular white matter CC abnormalities, demyelination, and peripheral neuropathy. Additional CC neurological features include dysarthria, ataxic gait, psychomotor CC regression, seizures, cognitive decline and spastic quadriparesis. CC {ECO:0000269|PubMed:10196694, ECO:0000269|PubMed:10682309, CC ECO:0000269|PubMed:2019586, ECO:0000269|PubMed:2302219, CC ECO:0000269|PubMed:2320574}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease, atypical, due to saposin C deficiency CC (GDSAPC) [MIM:610539]: A disease characterized by marked CC glucosylceramide accumulation in the spleen without having a deficiency CC of glucosylceramide-beta glucosidase characteristic of classic Gaucher CC disease. Gaucher disease is a lysosomal storage disorder characterized CC by skeletal deterioration, hepatosplenomegaly, and organ dysfunction. CC There are several subtypes based on the presence and severity of CC neurological involvement. {ECO:0000269|PubMed:17919309, CC ECO:0000269|PubMed:2060627}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Krabbe disease, atypical, due to saposin A deficiency CC (KRBSAPA) [MIM:611722]: An autosomal recessive disorder of CC galactosylceramide metabolism. Clinical features include neurologic CC regression around age 3 months, loss of spontaneous movements, CC hyporeflexia, generalized brain atrophy, and diffuse white matter CC dysmyelination. {ECO:0000269|PubMed:15773042}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PSAP saposin-D region are found in a variant CC of Tay-Sachs disease (GM2-gangliosidosis). CC -!- DISEASE: Parkinson disease 24, autosomal dominant (PARK24) CC [MIM:619491]: An autosomal dominant form of Parkinson disease, a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. PARK24 shows incomplete penetrance. CC {ECO:0000269|PubMed:32201884}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Saposin-B co-purifies with 1 molecule of CC phosphatidylethanolamine. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42980/PSAP"; 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; J03077; AAA52560.1; -; mRNA. DR EMBL; D00422; BAA00321.1; -; mRNA. DR EMBL; BT006849; AAP35495.1; -; mRNA. DR EMBL; CR456746; CAG33027.1; -; mRNA. DR EMBL; AC073370; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL731541; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471083; EAW54437.1; -; Genomic_DNA. DR EMBL; BC001503; AAH01503.1; -; mRNA. DR EMBL; BC004275; AAH04275.1; -; mRNA. DR EMBL; BC007612; AAH07612.1; -; mRNA. DR EMBL; M86181; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; X57107; CAA40391.1; -; Genomic_DNA. DR EMBL; X57108; CAA40392.1; -; Genomic_DNA. DR EMBL; M12710; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; J03015; AAB59494.1; -; mRNA. DR EMBL; M32221; AAA60303.1; -; mRNA. DR EMBL; M60257; AAA36595.1; -; mRNA. DR EMBL; M60258; AAA36596.1; -; mRNA. DR EMBL; M60255; AAA36594.1; -; mRNA. DR CCDS; CCDS7311.1; -. [P07602-1] DR PIR; JX0061; SAHUP. DR RefSeq; NP_001035930.1; NM_001042465.3. [P07602-3] DR RefSeq; NP_001035931.1; NM_001042466.3. [P07602-2] DR RefSeq; NP_002769.1; NM_002778.4. [P07602-1] DR PDB; 1M12; NMR; -; A=311-390. DR PDB; 1N69; X-ray; 2.20 A; A/B/C=195-273. DR PDB; 1SN6; NMR; -; A=311-390. DR PDB; 2DOB; X-ray; 2.00 A; A=60-140. DR PDB; 2GTG; X-ray; 2.40 A; A=311-391. DR PDB; 2QYP; X-ray; 2.45 A; A/B=311-392. DR PDB; 2R0R; X-ray; 2.50 A; A/B=407-484. DR PDB; 2R1Q; X-ray; 2.50 A; A=407-484. DR PDB; 2RB3; X-ray; 2.10 A; A/B/C/D=407-484. DR PDB; 2Z9A; X-ray; 2.50 A; A/B=311-389. DR PDB; 3BQP; X-ray; 1.30 A; A/B=405-484. DR PDB; 3BQQ; X-ray; 2.00 A; A/B/C/D=405-484. DR PDB; 4DDJ; X-ray; 1.90 A; A=60-140. DR PDB; 4UEX; X-ray; 1.80 A; A/B=60-142. DR PDB; 4V2O; X-ray; 2.13 A; A/B/C=195-273. DR PDB; 6SLR; X-ray; 2.38 A; A/B/C=195-272. DR PDB; 8EQU; EM; 2.80 A; C/F=60-140. DR PDB; 9AVS; X-ray; 3.53 A; C=195-273. DR PDB; 9AXG; X-ray; 2.68 A; A/B=195-273. DR PDB; 9I63; X-ray; 1.65 A; A/B=405-486. DR PDBsum; 1M12; -. DR PDBsum; 1N69; -. DR PDBsum; 1SN6; -. DR PDBsum; 2DOB; -. DR PDBsum; 2GTG; -. DR PDBsum; 2QYP; -. DR PDBsum; 2R0R; -. DR PDBsum; 2R1Q; -. DR PDBsum; 2RB3; -. DR PDBsum; 2Z9A; -. DR PDBsum; 3BQP; -. DR PDBsum; 3BQQ; -. DR PDBsum; 4DDJ; -. DR PDBsum; 4UEX; -. DR PDBsum; 4V2O; -. DR PDBsum; 6SLR; -. DR PDBsum; 8EQU; -. DR PDBsum; 9AVS; -. DR PDBsum; 9AXG; -. DR PDBsum; 9I63; -. DR AlphaFoldDB; P07602; -. DR EMDB; EMD-28546; -. DR SASBDB; P07602; -. DR SMR; P07602; -. DR BioGRID; 111639; 131. DR CORUM; P07602; -. DR DIP; DIP-29803N; -. DR FunCoup; P07602; 964. DR IntAct; P07602; 134. DR MINT; P07602; -. DR STRING; 9606.ENSP00000378394; -. DR BindingDB; P07602; -. DR ChEMBL; CHEMBL3580523; -. DR DrugBank; DB01966; Di-Stearoyl-3-Sn-Phosphatidylethanolamine. DR TCDB; 1.C.35.2.1; the amoebapore (amoebapore) family. DR GlyConnect; 1645; 140 N-Linked glycans (6 sites), 2 O-Linked glycans (3 sites). DR GlyCosmos; P07602; 14 sites, 167 glycans. DR GlyGen; P07602; 23 sites, 291 N-linked glycans (7 sites), 1 N-linked;o-linked glycan (2 sites), 4 O-linked glycans (16 sites). DR iPTMnet; P07602; -. DR MetOSite; P07602; -. DR PhosphoSitePlus; P07602; -. DR BioMuta; PSAP; -. DR DMDM; 134218; -. DR jPOST; P07602; -. DR MassIVE; P07602; -. DR PaxDb; 9606-ENSP00000378394; -. DR PeptideAtlas; P07602; -. DR PRIDE; P07602; -. DR ProteomicsDB; 52019; -. [P07602-1] DR ProteomicsDB; 52020; -. [P07602-2] DR ProteomicsDB; 52021; -. [P07602-3] DR Pumba; P07602; -. DR TopDownProteomics; P07602-1; -. [P07602-1] DR Antibodypedia; 1388; 513 antibodies from 37 providers. DR DNASU; 5660; -. DR Ensembl; ENST00000394936.8; ENSP00000378394.3; ENSG00000197746.16. [P07602-1] DR GeneID; 5660; -. DR KEGG; hsa:5660; -. DR MANE-Select; ENST00000394936.8; ENSP00000378394.3; NM_002778.4; NP_002769.1. DR UCSC; uc001jsm.4; human. [P07602-1] DR AGR; HGNC:9498; -. DR ClinPGx; PA33845; -. DR CTD; 5660; -. DR DisGeNET; 5660; -. DR GeneCards; PSAP; -. DR HGNC; HGNC:9498; PSAP. DR HPA; ENSG00000197746; Low tissue specificity. DR MalaCards; PSAP; -. DR MIM; 176801; gene. DR MIM; 249900; phenotype. DR MIM; 610539; phenotype. DR MIM; 611721; phenotype. DR MIM; 611722; phenotype. DR MIM; 619491; phenotype. DR OpenTargets; ENSG00000197746; -. DR Orphanet; 309252; Atypical Gaucher disease due to saposin C deficiency. DR Orphanet; 139406; Encephalopathy due to prosaposin deficiency. DR Orphanet; 206436; Infantile Krabbe disease. DR Orphanet; 309271; Metachromatic leukodystrophy, adult form. DR Orphanet; 309263; Metachromatic leukodystrophy, juvenile form. DR Orphanet; 309256; Metachromatic leukodystrophy, late infantile form. DR VEuPathDB; HostDB:ENSG00000197746; -. DR eggNOG; KOG1340; Eukaryota. DR GeneTree; ENSGT00940000156695; -. DR HOGENOM; CLU_033757_0_0_1; -. DR InParanoid; P07602; -. DR OrthoDB; 69496at2759; -. DR PAN-GO; P07602; 6 GO annotations based on evolutionary models. DR PhylomeDB; P07602; -. DR PathwayCommons; P07602; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SignaLink; P07602; -. DR SIGNOR; P07602; -. DR Agora; ENSG00000197746; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5660; 21 hits in 1170 CRISPR screens. DR ChiTaRS; PSAP; human. DR EvolutionaryTrace; P07602; -. DR GeneWiki; Prosaposin; -. DR GenomeRNAi; 5660; -. DR Pharos; P07602; Tbio. DR PRO; PR:P07602; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P07602; protein. DR Bgee; ENSG00000197746; Expressed in monocyte and 211 other cell types or tissues. DR ExpressionAtlas; P07602; baseline and differential. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; IDA:CAFA. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0008047; F:enzyme activator activity; TAS:ProtInc. DR GO; GO:1905573; F:ganglioside GM1 binding; IDA:CAFA. DR GO; GO:1905574; F:ganglioside GM2 binding; IDA:CAFA. DR GO; GO:1905575; F:ganglioside GM3 binding; IDA:CAFA. DR GO; GO:1905577; F:ganglioside GP1c binding; IDA:CAFA. DR GO; GO:1905576; F:ganglioside GT1b binding; IDA:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005543; F:phospholipid binding; IDA:CAFA. DR GO; GO:0002020; F:protease binding; IPI:MGI. DR GO; GO:0042803; F:protein homodimerization activity; IDA:CAFA. DR GO; GO:0097110; F:scaffold protein binding; IPI:ARUK-UCL. DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0060742; P:epithelial cell differentiation involved in prostate gland development; IBA:GO_Central. DR GO; GO:1905572; P:ganglioside GM1 transport to membrane; IDA:CAFA. DR GO; GO:0010467; P:gene expression; IDA:MGI. DR GO; GO:0007041; P:lysosomal transport; IDA:UniProtKB. DR GO; GO:0060736; P:prostate gland growth; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IBA:GO_Central. DR GO; GO:0006665; P:sphingolipid metabolic process; IEA:UniProtKB-KW. DR FunFam; 1.10.225.10:FF:000002; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000004; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000005; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000006; prosaposin isoform X2; 1. DR Gene3D; 1.10.225.10; Saposin-like; 4. DR InterPro; IPR003119; SAP_A. DR InterPro; IPR007856; SapB_1. DR InterPro; IPR008138; SapB_2. DR InterPro; IPR008373; Saposin. DR InterPro; IPR011001; Saposin-like. DR InterPro; IPR021165; Saposin_chordata. DR InterPro; IPR008139; SaposinB_dom. DR InterPro; IPR051428; Sphingo_Act-Surfact_Prot. DR PANTHER; PTHR11480:SF36; PROSAPOSIN; 1. DR PANTHER; PTHR11480; SAPOSIN-RELATED; 1. DR Pfam; PF02199; SapA; 2. DR Pfam; PF05184; SapB_1; 3. DR Pfam; PF03489; SapB_2; 4. DR PIRSF; PIRSF002431; Saposin; 1. DR PRINTS; PR01797; SAPOSIN. DR SMART; SM00162; SAPA; 2. DR SMART; SM00741; SapB; 4. DR SUPFAM; SSF47862; Saposin; 4. DR PROSITE; PS51110; SAP_A; 2. DR PROSITE; PS50015; SAP_B; 4. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Direct protein sequencing; KW Disease variant; Disulfide bond; Gangliosidosis; Gaucher disease; KW Glycoprotein; Leukodystrophy; Lipid metabolism; Lysosome; KW Metachromatic leukodystrophy; Neurodegeneration; Parkinson disease; KW Parkinsonism; Proteomics identification; Reference proteome; Repeat; KW Secreted; Signal; Sphingolipid metabolism. FT SIGNAL 1..16 FT /evidence="ECO:0000269|PubMed:1958198, FT ECO:0000269|PubMed:8323276, ECO:0007744|PubMed:25944712" FT CHAIN 17..524 FT /note="Prosaposin" FT /evidence="ECO:0000269|PubMed:8323276" FT /id="PRO_0000424774" FT PROPEP 17..59 FT /evidence="ECO:0000305" FT /id="PRO_0000031616" FT CHAIN 60..142 FT /note="Saposin-A" FT /evidence="ECO:0000269|PubMed:2717620" FT /id="PRO_0000031617" FT PROPEP 143..194 FT /evidence="ECO:0000305" FT /id="PRO_0000031618" FT CHAIN 195..274 FT /note="Saposin-B-Val" FT /evidence="ECO:0000269|PubMed:2209618, FT ECO:0000269|PubMed:3242555" FT /id="PRO_0000031619" FT CHAIN 195..273 FT /note="Saposin-B" FT /evidence="ECO:0000269|PubMed:2209618" FT /id="PRO_0000031620" FT PROPEP 275..310 FT /evidence="ECO:0000305" FT /id="PRO_0000031621" FT CHAIN 311..390 FT /note="Saposin-C" FT /evidence="ECO:0000269|PubMed:3442600" FT /id="PRO_0000031622" FT PROPEP 393..404 FT /evidence="ECO:0000305" FT /id="PRO_0000031623" FT CHAIN 405..486 FT /note="Saposin-D" FT /evidence="ECO:0000269|PubMed:2845979" FT /id="PRO_0000031624" FT PROPEP 487..524 FT /evidence="ECO:0000305" FT /id="PRO_0000031625" FT DOMAIN 18..58 FT /note="Saposin A-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00414" FT DOMAIN 59..142 FT /note="Saposin B-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 194..275 FT /note="Saposin B-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 311..392 FT /note="Saposin B-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 405..486 FT /note="Saposin B-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 488..524 FT /note="Saposin A-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00414" FT SITE 215 FT /note="Not glycosylated; in variant MLDSAPB Ile-217" FT CARBOHYD 80 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329, FT ECO:0000269|PubMed:2842863" FT CARBOHYD 101 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329, FT ECO:0000269|PubMed:2842863" FT CARBOHYD 215 FT /note="N-linked (GlcNAc...) (complex) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:11180632, ECO:0000269|PubMed:19167329" FT /id="CAR_000176" FT CARBOHYD 332 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329" FT CARBOHYD 426 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329" FT DISULFID 63..138 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 66..132 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 94..106 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 198..271 FT /evidence="ECO:0000269|PubMed:12510003" FT DISULFID 201..265 FT /evidence="ECO:0000269|PubMed:12510003" FT DISULFID 230..241 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 315..388 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 318..382 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 346..357 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 409..482 FT /evidence="ECO:0000269|PubMed:10406958" FT DISULFID 412..476 FT /evidence="ECO:0000269|PubMed:10406958" FT DISULFID 440..451 FT /evidence="ECO:0000269|PubMed:10406958" FT VAR_SEQ 259 FT /note="M -> MDQ (in isoform Sap-mu-6)" FT /evidence="ECO:0000305" FT /id="VSP_006014" FT VAR_SEQ 260 FT /note="Q -> QDQQ (in isoform Sap-mu-9)" FT /evidence="ECO:0000305" FT /id="VSP_006015" FT VARIANT 70 FT /note="Missing (in KRBSAPA)" FT /evidence="ECO:0000269|PubMed:15773042" FT /id="VAR_042440" FT VARIANT 215 FT /note="N -> H (in MLDSAPB; reduces the intracellular FT activity of the protein significantly; dbSNP:rs121918107)" FT /evidence="ECO:0000269|PubMed:10682309" FT /id="VAR_031823" FT VARIANT 215 FT /note="N -> K (in MLDSAPB; dbSNP:rs770171865)" FT /evidence="ECO:0000269|PubMed:10196694" FT /id="VAR_031899" FT VARIANT 217 FT /note="T -> I (in MLDSAPB; juvenile; affects glycosylation FT at N-215; dbSNP:rs121918103)" FT /evidence="ECO:0000269|PubMed:2302219, FT ECO:0000269|PubMed:2320574" FT /id="VAR_006943" FT VARIANT 241 FT /note="C -> S (in MLDSAPB; severe; dbSNP:rs121918104)" FT /evidence="ECO:0000269|PubMed:2019586" FT /id="VAR_006944" FT VARIANT 349 FT /note="L -> P (in GDSAPC; dbSNP:rs121918110)" FT /evidence="ECO:0000269|PubMed:17919309" FT /id="VAR_042441" FT VARIANT 388 FT /note="C -> F (in GDSAPC)" FT /evidence="ECO:0000269|PubMed:2060627" FT /id="VAR_006945" FT VARIANT 412 FT /note="C -> Y (in PARK24; associated with disease FT susceptibility; affects the intracellular trafficking, FT resulting in endoplasmic reticulum retention; affects the FT intracellular trafficking, resulting in endoplasmic FT reticulum retention; cells carrying this variant show FT accumulation of autophagic vacuoles, impaired autophagic FT flux and alpha-synuclein/SNCA aggregation; FT dbSNP:rs1842252448)" FT /evidence="ECO:0000269|PubMed:32201884" FT /id="VAR_086130" FT VARIANT 453 FT /note="Q -> P (in PARK24; associated with disease FT susceptibility; affects the intracellular trafficking, FT resulting in endoplasmic reticulum retention; cells FT carrying this variant show accumulation of autophagic FT vacuoles, impaired autophagic flux and alpha-synuclein/SNCA FT aggregation; dbSNP:rs2133029712)" FT /evidence="ECO:0000269|PubMed:32201884" FT /id="VAR_086131" FT MUTAGEN 240 FT /note="I->C: Strongly decreases stimulation of cerebroside FT sulfate hydrolysis." FT /evidence="ECO:0000269|PubMed:12518053" FT CONFLICT 369 FT /note="L -> P (in Ref. 4; CAG33027)" FT /evidence="ECO:0000305" FT HELIX 61..78 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 83..96 FT /evidence="ECO:0007829|PDB:4UEX" FT STRAND 97..99 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 100..122 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 128..134 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 196..214 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 218..229 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 230..233 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 237..257 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 261..267 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 314..330 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 335..345 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 346..348 FT /evidence="ECO:0007829|PDB:1M12" FT HELIX 351..373 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 378..384 FT /evidence="ECO:0007829|PDB:2GTG" FT TURN 386..388 FT /evidence="ECO:0007829|PDB:1SN6" FT HELIX 409..422 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 429..439 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 440..442 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 445..447 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 448..466 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 472..478 FT /evidence="ECO:0007829|PDB:3BQP" SQ SEQUENCE 524 AA; 58113 MW; 71977F7A8C9E1533 CRC64; MYALFLLASL LGAALAGPVL GLKECTRGSA VWCQNVKTAS DCGAVKHCLQ TVWNKPTVKS LPCDICKDVV TAAGDMLKDN ATEEEILVYL EKTCDWLPKP NMSASCKEIV DSYLPVILDI IKGEMSRPGE VCSALNLCES LQKHLAELNH QKQLESNKIP ELDMTEVVAP FMANIPLLLY PQDGPRSKPQ PKDNGDVCQD CIQMVTDIQT AVRTNSTFVQ ALVEHVKEEC DRLGPGMADI CKNYISQYSE IAIQMMMHMQ PKEICALVGF CDEVKEMPMQ TLVPAKVASK NVIPALELVE PIKKHEVPAK SDVYCEVCEF LVKEVTKLID NNKTEKEILD AFDKMCSKLP KSLSEECQEV VDTYGSSILS ILLEEVSPEL VCSMLHLCSG TRLPALTVHV TQPKDGGFCE VCKKLVGYLD RNLEKNSTKQ EILAALEKGC SFLPDPYQKQ CDQFVAEYEP VLIEILVEVM DPSFVCLKIG ACPSAHKPLL GTEKCIWGPS YWCQNTETAA QCNAVEHCKR HVWN // 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 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 //