ID ATX2_HUMAN Reviewed; 1313 AA. AC Q99700; A6NLD4; Q24JQ7; Q6ZQZ7; Q99493; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 204. DE RecName: Full=Ataxin-2; DE AltName: Full=Spinocerebellar ataxia type 2 protein; DE AltName: Full=Trinucleotide repeat-containing gene 13 protein; GN Name=ATXN2; Synonyms=ATX2, SCA2, TNRC13; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896555; DOI=10.1038/ng1196-269; RA Pulst S.-M., Nechiporuk A., Nechiporuk T., Gispert S., Chen X.-N., RA Lopes-Cendes I., Pearlman S., Starkman S., Orozco-Diaz G., Lunkes A., RA DeJong P., Rouleau G.A., Auburger G., Korenberg J.R., Figueroa C., RA Sahba S.; RT "Moderate expansion of a normally biallelic trinucleotide repeat in RT spinocerebellar ataxia type 2."; RL Nat. Genet. 14:269-276(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP AND TISSUE SPECIFICITY. RX PubMed=8896556; DOI=10.1038/ng1196-277; RA Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., RA Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T., Koide R., Saito M., RA Sato A., Tanaka T., Hanyu S., Takiyama Y., Nishizawa M., Shimizu N., RA Nomura Y., Segawa M., Iwabuchi K., Eguchi I., Tanaka H., Takahashi H., RA Tsuji S.; RT "Identification of the spinocerebellar ataxia type 2 gene using a direct RT identification of repeat expansion and cloning technique, DIRECT."; RL Nat. Genet. 14:277-284(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-1313 (ISOFORM 2), POLYMORPHISM, RP INVOLVEMENT IN SCA2, TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896557; DOI=10.1038/ng1196-285; RA Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Garnier J.-M., RA Weber C., Mandel J.-L., Cancel G., Abbas N., Duerr A., Didierjean O., RA Stevanin G., Agid Y., Brice A.; RT "Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high RT sensitivity to expanded CAG/glutamine repeats."; RL Nat. Genet. 14:285-291(1996). RN [7] RP ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY. RX PubMed=9480749; DOI=10.1006/geno.1997.5131; RA Sahba S., Nechiporuk A., Figueroa K.P., Nechiporuk T., Pulst S.-M.; RT "Genomic structure of the human gene for spinocerebellar ataxia type 2 RT (SCA2) on chromosome 12q24.1."; RL Genomics 47:359-364(1998). RN [8] RP INTERACTION WITH RBFOX1. RX PubMed=10814712; DOI=10.1093/hmg/9.9.1303; RA Shibata H., Huynh D.P., Pulst S.-M.; RT "A novel protein with RNA-binding motifs interacts with ataxin-2."; RL Hum. Mol. Genet. 9:1303-1313(2000). RN [9] RP INTERACTION WITH POLYRIBOSOMES. RX PubMed=16835262; DOI=10.1093/hmg/ddl173; RA Satterfield T.F., Pallanck L.J.; RT "Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with RT polyribosomes."; RL Hum. Mol. Genet. 15:2523-2532(2006). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [11] RP FUNCTION, AND INTERACTION WITH EGFR; SH3GL2 AND SH3GL3. RX PubMed=18602463; DOI=10.1016/j.cellsig.2008.05.018; RA Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J., RA Auburger G.; RT "Ataxin-2 associates with the endocytosis complex and affects EGF receptor RT trafficking."; RL Cell. Signal. 20:1725-1739(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-554; SER-684; RP THR-741; SER-857; SER-861; SER-888 AND SER-889, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-684, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP INTERACTION WITH TARDBP, INVOLVEMENT IN ALS13, AND POLY-GLN REPEAT RP EXPANSION. RX PubMed=20740007; DOI=10.1038/nature09320; RA Elden A.C., Kim H.J., Hart M.P., Chen-Plotkin A.S., Johnson B.S., Fang X., RA Armakola M., Geser F., Greene R., Lu M.M., Padmanabhan A., Clay-Falcone D., RA McCluskey L., Elman L., Juhr D., Gruber P.J., Rub U., Auburger G., RA Trojanowski J.Q., Lee V.M., Van Deerlin V.M., Bonini N.M., Gitler A.D.; RT "Ataxin-2 intermediate-length polyglutamine expansions are associated with RT increased risk for ALS."; RL Nature 466:1069-1075(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-393; SER-684 AND SER-784, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784; SER-861 AND SER-865, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [20] RP INTERACTION WITH ATXN2L. RX PubMed=23209657; DOI=10.1371/journal.pone.0050134; RA Kaehler C., Isensee J., Nonhoff U., Terrey M., Hucho T., Lehrach H., RA Krobitsch S.; RT "Ataxin-2-like is a regulator of stress granules and processing bodies."; RL PLoS ONE 7:E50134-E50134(2012). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-478; SER-508; RP SER-624; SER-642; SER-684; SER-772; SER-784 AND SER-889, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-624 AND SER-728, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-640, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [24] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-893, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). CC -!- FUNCTION: Involved in EGFR trafficking, acting as negative regulator of CC endocytic EGFR internalization at the plasma membrane. CC {ECO:0000269|PubMed:18602463}. CC -!- SUBUNIT: Monomer (By similarity). Can also form homodimers (By CC similarity). Interacts with TARDBP; the interaction is RNA-dependent CC (PubMed:20740007). Interacts with RBFOX1 (PubMed:10814712). Interacts CC with polyribosomes (PubMed:16835262). Interacts with SH3GL2 and SH3GL3 CC (PubMed:18602463). Interacts with SH3KBP1 and CBL (By similarity). CC Interacts with EGFR (PubMed:18602463). Interacts with ATXN2L CC (PubMed:23209657). {ECO:0000250|UniProtKB:O70305, CC ECO:0000269|PubMed:10814712, ECO:0000269|PubMed:16835262, CC ECO:0000269|PubMed:18602463, ECO:0000269|PubMed:20740007, CC ECO:0000269|PubMed:23209657}. CC -!- INTERACTION: CC Q99700; P54253: ATXN1; NbExp=4; IntAct=EBI-697691, EBI-930964; CC Q99700; P26196: DDX6; NbExp=14; IntAct=EBI-697691, EBI-351257; CC Q99700; Q13283: G3BP1; NbExp=4; IntAct=EBI-697691, EBI-1047359; CC Q99700; P11940: PABPC1; NbExp=8; IntAct=EBI-697691, EBI-81531; CC Q99700; Q99962: SH3GL2; NbExp=9; IntAct=EBI-697691, EBI-77938; CC Q99700; Q99963: SH3GL3; NbExp=11; IntAct=EBI-697691, EBI-473910; CC Q99700; Q13148: TARDBP; NbExp=3; IntAct=EBI-697691, EBI-372899; CC Q99700-5; P54253: ATXN1; NbExp=6; IntAct=EBI-25891409, EBI-930964; CC Q99700-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25891409, EBI-10988864; CC Q99700-5; Q9BTH3: BIN1; NbExp=3; IntAct=EBI-25891409, EBI-25891390; CC Q99700-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25891409, EBI-2837444; CC Q99700-5; P20963: CD247; NbExp=3; IntAct=EBI-25891409, EBI-1165705; CC Q99700-5; P11940: PABPC1; NbExp=3; IntAct=EBI-25891409, EBI-81531; CC Q99700-5; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-25891409, EBI-12123390; CC Q99700-5; Q8IVP1: SH3GL3; NbExp=3; IntAct=EBI-25891409, EBI-6503765; CC Q99700-5; Q9UJZ1: STOML2; NbExp=3; IntAct=EBI-25891409, EBI-1044428; CC Q99700-5; P55854: SUMO3; NbExp=3; IntAct=EBI-25891409, EBI-474067; CC Q99700-5; P40337-2: VHL; NbExp=3; IntAct=EBI-25891409, EBI-12157263; CC Q99700-5; Q96E88; NbExp=3; IntAct=EBI-25891409, EBI-10976904; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=Q99700-1; Sequence=Displayed; CC Name=2; CC IsoId=Q99700-2; Sequence=VSP_011575, VSP_011577; CC Name=3; CC IsoId=Q99700-3; Sequence=VSP_011574, VSP_011576, VSP_011578, CC VSP_011579, VSP_011580, VSP_011581; CC Name=4; CC IsoId=Q99700-4; Sequence=VSP_011582; CC Name=5; CC IsoId=Q99700-5; Sequence=VSP_057285, VSP_057286, VSP_057287; CC -!- TISSUE SPECIFICITY: Expressed in the brain, heart, liver, skeletal CC muscle, pancreas and placenta. Isoform 1 is predominant in the brain CC and spinal cord. Isoform 4 is more abundant in the cerebellum. In the CC brain, broadly expressed in the amygdala, caudate nucleus, corpus CC callosum, hippocampus, hypothalamus, substantia nigra, subthalamic CC nucleus and thalamus. {ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557, CC ECO:0000269|PubMed:9480749}. CC -!- POLYMORPHISM: The poly-Gln region of ATXN2 is polymorphic: 17 to 29 CC repeats are found in the normal population. Higher numbers of repeats CC result in different disease phenotypes depending on the length of the CC expansion. {ECO:0000269|PubMed:20740007, ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557}. CC -!- DISEASE: Spinocerebellar ataxia 2 (SCA2) [MIM:183090]: Spinocerebellar CC ataxia is a clinically and genetically heterogeneous group of CC cerebellar disorders. Patients show progressive incoordination of gait CC and often poor coordination of hands, speech and eye movements, due to CC cerebellum degeneration with variable involvement of the brainstem and CC spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias CC type I (ADCA I) which are characterized by cerebellar ataxia in CC combination with additional clinical features like optic atrophy, CC ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy CC and dementia. SCA2 is characterized by hyporeflexia, myoclonus and CC action tremor and dopamine-responsive parkinsonism. In some patients, CC SCA2 presents as pure familial parkinsonism without cerebellar signs. CC {ECO:0000269|PubMed:8896555, ECO:0000269|PubMed:8896556, CC ECO:0000269|PubMed:8896557}. Note=The disease is caused by variants CC affecting the gene represented in this entry. SCA2 is caused by CC expansion of a CAG repeat resulting in about 36 to 52 repeats in some CC patients. Longer expansions result in earlier the expansion, onset of CC the disease. CC -!- DISEASE: Amyotrophic lateral sclerosis 13 (ALS13) [MIM:183090]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:20740007}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC An increased risk for developing amyotrophic lateral sclerosis seems to CC be conferred by CAG repeat intermediate expansions greater than 23 but CC below the threshold for developing spinocerebellar ataxia. CC -!- SIMILARITY: Belongs to the ataxin-2 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U70323; AAB19200.1; -; mRNA. DR EMBL; AK128613; BAC87528.1; -; mRNA. DR EMBL; AC002395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137055; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF455720; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC114546; AAI14547.1; -; mRNA. DR EMBL; Y08262; CAA69589.1; -; mRNA. DR CCDS; CCDS81738.1; -. [Q99700-5] DR RefSeq; NP_001297052.1; NM_001310123.1. [Q99700-5] DR RefSeq; NP_002964.4; NM_002973.4. DR PDB; 3KTR; X-ray; 1.70 A; B=912-928. DR PDBsum; 3KTR; -. DR AlphaFoldDB; Q99700; -. DR SMR; Q99700; -. DR BioGRID; 112218; 327. DR DIP; DIP-33372N; -. DR ELM; Q99700; -. DR FunCoup; Q99700; 1901. DR IntAct; Q99700; 166. DR MINT; Q99700; -. DR STRING; 9606.ENSP00000446576; -. DR BindingDB; Q99700; -. DR ChEMBL; CHEMBL1795085; -. DR GlyCosmos; Q99700; 7 sites, 1 glycan. DR GlyGen; Q99700; 26 sites, 1 O-linked glycan (23 sites). DR iPTMnet; Q99700; -. DR MetOSite; Q99700; -. DR PhosphoSitePlus; Q99700; -. DR SwissPalm; Q99700; -. DR BioMuta; ATXN2; -. DR DMDM; 215273941; -. DR jPOST; Q99700; -. DR MassIVE; Q99700; -. DR PaxDb; 9606-ENSP00000366843; -. DR PeptideAtlas; Q99700; -. DR ProteomicsDB; 61268; -. DR ProteomicsDB; 78409; -. [Q99700-1] DR ProteomicsDB; 78410; -. [Q99700-2] DR ProteomicsDB; 78412; -. [Q99700-4] DR Pumba; Q99700; -. DR Antibodypedia; 18563; 277 antibodies from 36 providers. DR DNASU; 6311; -. DR Ensembl; ENST00000535949.5; ENSP00000439338.1; ENSG00000204842.19. [Q99700-5] DR Ensembl; ENST00000550104.5; ENSP00000446576.2; ENSG00000204842.19. [Q99700-1] DR Ensembl; ENST00000616825.4; ENSP00000481448.1; ENSG00000204842.19. [Q99700-5] DR GeneID; 6311; -. DR KEGG; hsa:6311; -. DR UCSC; uc001tsj.3; human. [Q99700-1] DR AGR; HGNC:10555; -. DR ClinPGx; PA34968; -. DR CTD; 6311; -. DR DisGeNET; 6311; -. DR GeneCards; ATXN2; -. DR GeneReviews; ATXN2; -. DR HGNC; HGNC:10555; ATXN2. DR HPA; ENSG00000204842; Low tissue specificity. DR MalaCards; ATXN2; -. DR MIM; 183090; phenotype. DR MIM; 601517; gene. DR OpenTargets; ENSG00000204842; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 98756; Spinocerebellar ataxia type 2. DR VEuPathDB; HostDB:ENSG00000204842; -. DR eggNOG; KOG2375; Eukaryota. DR GeneTree; ENSGT00940000156812; -. DR InParanoid; Q99700; -. DR OMA; RMQMSAS; -. DR OrthoDB; 2275718at2759; -. DR PAN-GO; Q99700; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q99700; -. DR PathwayCommons; Q99700; -. DR SignaLink; Q99700; -. DR SIGNOR; Q99700; -. DR Agora; ENSG00000204842; -. DR BioGRID-ORCS; 6311; 15 hits in 1159 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR ChiTaRS; ATXN2; human. DR GeneWiki; ATXN2; -. DR GenomeRNAi; 6311; -. DR Pharos; Q99700; Tbio. DR PRO; PR:Q99700; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q99700; protein. DR Bgee; ENSG00000204842; Expressed in buccal mucosa cell and 197 other cell types or tissues. DR ExpressionAtlas; Q99700; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002091; P:negative regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0033962; P:P-body assembly; IMP:UniProtKB. DR GO; GO:0006417; P:regulation of translation; NAS:UniProtKB. DR GO; GO:0016070; P:RNA metabolic process; NAS:UniProtKB. DR GO; GO:0050658; P:RNA transport; NAS:UniProtKB. DR GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB. DR CDD; cd00600; Sm_like; 1. DR IDEAL; IID00580; -. DR InterPro; IPR045117; ATXN2-like. DR InterPro; IPR010920; LSM_dom_sf. DR InterPro; IPR009604; LsmAD_domain. DR InterPro; IPR009818; PAM2_motif. DR InterPro; IPR047575; Sm. DR InterPro; IPR025852; SM_dom_ATX. DR PANTHER; PTHR12854; ATAXIN 2-RELATED; 1. DR PANTHER; PTHR12854:SF11; ATAXIN-2; 1. DR Pfam; PF06741; LsmAD; 1. DR Pfam; PF07145; PAM2; 1. DR Pfam; PF14438; SM-ATX; 1. DR SMART; SM01272; LsmAD; 1. DR SUPFAM; SSF81995; beta-sandwich domain of Sec23/24; 1. DR SUPFAM; SSF50182; Sm-like ribonucleoproteins; 1. DR PROSITE; PS52002; SM; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cytoplasm; Isopeptide bond; Methylation; Neurodegeneration; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Spinocerebellar ataxia; Triplet repeat expansion; Ubl conjugation. FT CHAIN 1..1313 FT /note="Ataxin-2" FT /id="PRO_0000064756" FT DOMAIN 267..344 FT /note="Sm" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01346" FT REGION 1..255 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 459..954 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1137..1219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..12 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 48..65 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 104..114 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 141..154 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 166..187 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 204..234 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 235..244 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 459..471 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 478..492 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 508..544 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 552..562 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 563..581 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 582..598 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 627..637 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 666..681 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 768..777 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 788..804 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 807..820 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 821..844 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 847..871 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 880..891 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 893..910 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 925..936 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1155..1192 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1206..1219 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 248 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 393 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 466 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 640 FT /note="Asymmetric dimethylarginine; alternate" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 640 FT /note="Omega-N-methylarginine; alternate" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 642 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 684 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 728 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 741 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 772 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 784 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 856 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 857 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 861 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692" FT MOD_RES 865 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692" FT MOD_RES 867 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 888 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 889 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 893 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..981 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011574" FT VAR_SEQ 1..265 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057285" FT VAR_SEQ 277..300 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057286" FT VAR_SEQ 980..995 FT /note="PLYPIPMTPMPVNQAK -> YQICPNSGKTSIIRVP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011575" FT VAR_SEQ 982..998 FT /note="YPIPMTPMPVNQAKTYR -> MYYAVEILFNRQSAFFS (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011576" FT VAR_SEQ 996..1313 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011577" FT VAR_SEQ 1106..1124 FT /note="ACPKLPYNKETSPSFYFAI -> V (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057287" FT VAR_SEQ 1106..1123 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011578" FT VAR_SEQ 1124 FT /note="I -> V (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011579" FT VAR_SEQ 1244..1313 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_011582" FT VAR_SEQ 1249..1257 FT /note="AHVQSGMVP -> VIPALANFL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011580" FT VAR_SEQ 1258..1313 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011581" FT VARIANT 107 FT /note="L -> V (in dbSNP:rs695871)" FT /evidence="ECO:0000269|PubMed:8896555, FT ECO:0000269|PubMed:8896557" FT /id="VAR_047629" FT VARIANT 248 FT /note="S -> N (in dbSNP:rs7969300)" FT /id="VAR_047630" FT CONFLICT 188 FT /note="Missing (in Ref. 1; AAB19200 and 6; CAA69589)" FT /evidence="ECO:0000305" SQ SEQUENCE 1313 AA; 140283 MW; 40A2883FF9D5D118 CRC64; MRSAAAAPRS PAVATESRRF AAARWPGWRS LQRPARRSGR GGGGAAPGPY PSAAPPPPGP GPPPSRQSSP PSASDCFGSN GNGGGAFRPG SRRLLGLGGP PRPFVVLLLP LASPGAPPAA PTRASPLGAR ASPPRSGVSL ARPAPGCPRP ACEPVYGPLT MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAV PNMPQQRQDQ HHQSAMMHPA SAAGPPIAAT PPAYSTQYVA YSPQQFPNQP LVQHVPHYQS QHPHVYSPVI QGNARMMAPP THAQPGLVSS SATQYGAHEQ THAMYACPKL PYNKETSPSF YFAISTGSLA QQYAHPNATL HPHTPHPQPS ATPTGQQQSQ HGGSHPAPSP VQHHQHQAAQ ALHLASPQQQ SAIYHAGLAP TPPSMTPASN TQSPQNSFPA AQQTVFTIHP SHVQPAYTNP PHMAHVPQAH VQSGMVPSHP TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM THPSVQAHHQ QQL // ID COASY_HUMAN Reviewed; 564 AA. AC Q13057; B2RA78; B4DLU0; Q6GS23; Q8NBM7; Q8NEW1; Q8WXD4; Q9NRM3; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 27-JUN-2003, sequence version 4. DT 28-JAN-2026, entry version 224. DE RecName: Full=Bifunctional coenzyme A synthase {ECO:0000305|PubMed:11923312}; DE Short=CoA synthase; DE AltName: Full=NBP; DE AltName: Full=POV-2; DE Includes: DE RecName: Full=Phosphopantetheine adenylyltransferase {ECO:0000305|PubMed:11923312}; DE EC=2.7.7.3 {ECO:0000269|PubMed:11923312, ECO:0000269|PubMed:24360804}; DE AltName: Full=Dephospho-CoA pyrophosphorylase; DE AltName: Full=Pantetheine-phosphate adenylyltransferase; DE Short=PPAT; DE Includes: DE RecName: Full=Dephospho-CoA kinase {ECO:0000305|PubMed:11923312}; DE Short=DPCK; DE EC=2.7.1.24 {ECO:0000269|PubMed:11923312, ECO:0000269|PubMed:24360804}; DE AltName: Full=Dephosphocoenzyme A kinase; DE Short=DPCOAK; GN Name=COASY {ECO:0000312|HGNC:HGNC:29932}; ORFNames=PSEC0106; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, TISSUE SPECIFICITY, VARIANT TYR-55, RP AND DOMAIN. RX PubMed=11923312; DOI=10.1074/jbc.m201708200; RA Daugherty M., Polanuyer B., Farrell M., Scholle M., Lykidis A., RA de Crecy-Lagard V., Osterman A.; RT "Complete reconstitution of the human coenzyme A biosynthetic pathway via RT comparative genomics."; RL J. Biol. Chem. 277:21431-21439(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SUBUNIT. RX PubMed=11994049; DOI=10.1042/bj20020569; RA Aghajanian S., Worrall D.M.; RT "Identification and characterization of the gene encoding the human RT phosphopantetheine adenylyltransferase and dephospho-CoA kinase RT bifunctional enzyme (CoA synthase)."; RL Biochem. J. 365:13-18(2002). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Teratocarcinoma; RA Ota T., Nishikawa T., Suzuki Y., Kawai-Hio Y., Hayashi K., Ishii S., RA Saito K., Yamamoto J., Wakamatsu A., Nagai T., Nakamura Y., Nagahari K., RA Sugano S., Isogai T.; RT "HRI human cDNA sequencing project."; RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP TYR-55. 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=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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT TYR-55. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT TYR-55. RC TISSUE=Colon, Muscle, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 165-564 (ISOFORMS 1/2). RA Zhu Y.-B., Han Y.; RT "Molecular cloning of a NBP gene cDNA."; RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 332-564 (ISOFORMS 1/2). RC TISSUE=Ovary; RX PubMed=8529999; DOI=10.1007/bf00197407; RA Montagna M., Serova O., Sylla B.S., Feunteun J., Lenoir G.M.; RT "A 100-kb physical and transcriptional map around the EDH17B2 gene: RT identification of three novel genes and a pseudogene of a human homologue RT of the rat PRL-1 tyrosine phosphatase."; RL Hum. Genet. 96:532-538(1995). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 340-564 (ISOFORMS 1/2). 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 [11] RP ALTERNATIVE SPLICING. RX PubMed=16460672; DOI=10.1016/j.bbrc.2006.01.051; RA Nemazanyy I., Panasyuk G., Breus O., Zhyvoloup A., Filonenko V., Gout I.T.; RT "Identification of a novel CoA synthase isoform, which is primarily RT expressed in the brain."; RL Biochem. Biophys. Res. Commun. 341:995-1000(2006). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-178, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-178, 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 [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-178 AND SER-183, 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 [15] 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 [16] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, VARIANTS NBIA6 RP 59-GLN--ASP-564 DEL AND CYS-499, AND CHARACTERIZATION OF VARIANTS NBIA6 RP 59-GLN--ASP-564 DEL AND CYS-499. RX PubMed=24360804; DOI=10.1016/j.ajhg.2013.11.008; RA Dusi S., Valletta L., Haack T.B., Tsuchiya Y., Venco P., Pasqualato S., RA Goffrini P., Tigano M., Demchenko N., Wieland T., Schwarzmayr T., RA Strom T.M., Invernizzi F., Garavaglia B., Gregory A., Sanford L., RA Hamada J., Bettencourt C., Houlden H., Chiapparini L., Zorzi G., RA Kurian M.A., Nardocci N., Prokisch H., Hayflick S., Gout I., Tiranti V.; RT "Exome sequence reveals mutations in CoA synthase as a cause of RT neurodegeneration with brain iron accumulation."; RL Am. J. Hum. Genet. 94:11-22(2014). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-178, 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 [18] RP INVOLVEMENT IN PCH12. RX PubMed=30089828; DOI=10.1038/s41431-018-0233-0; RA van Dijk T., Ferdinandusse S., Ruiter J.P.N., Alders M., Mathijssen I.B., RA Parboosingh J.S., Innes A.M., Meijers-Heijboer H., Poll-The B.T., RA Bernier F.P., Wanders R.J.A., Lamont R.E., Baas F.; RT "Biallelic loss of function variants in COASY cause prenatal onset RT pontocerebellar hypoplasia, microcephaly, and arthrogryposis."; RL Eur. J. Hum. Genet. 26:1752-1758(2018). RN [19] RP SUBCELLULAR LOCATION. RX PubMed=40925986; DOI=10.1038/s42255-025-01358-y; RA Liu R., Zhang Z., Kyaw A.K., Grabinska K.A., Shah H., Shen H.; RT "Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in RT mitochondrial CoA import and metabolism."; RL Nat. Metab. 0:0-0(2025). RN [20] RP VARIANTS NBIA6 VAL-214 AND CYS-499. RX PubMed=28489334; DOI=10.1002/ajmg.a.38252; RA Evers C., Seitz A., Assmann B., Opladen T., Karch S., Hinderhofer K., RA Granzow M., Paramasivam N., Eils R., Diessl N., Bartram C.R., Moog U.; RT "Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's RT eye."; RL Am. J. Med. Genet. A 173:1878-1886(2017). CC -!- FUNCTION: Bifunctional enzyme that catalyzes the fourth step of the CC coenzyme A biosynthetic pathway, the adenylation of 4'- CC phosphopantetheine, and the fifth step, the phosphorylation of CC dephospho-CoA to CoA. {ECO:0000269|PubMed:11923312, CC ECO:0000269|PubMed:24360804}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-4'-phosphopantetheine + ATP + H(+) = 3'-dephospho-CoA + CC diphosphate; Xref=Rhea:RHEA:19801, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57328, CC ChEBI:CHEBI:61723; EC=2.7.7.3; Evidence={ECO:0000269|PubMed:11923312, CC ECO:0000269|PubMed:24360804}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19802; CC Evidence={ECO:0000269|PubMed:24360804}; CC -!- CATALYTIC ACTIVITY: CC Reaction=3'-dephospho-CoA + ATP = ADP + CoA + H(+); CC Xref=Rhea:RHEA:18245, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57328, ChEBI:CHEBI:456216; CC EC=2.7.1.24; Evidence={ECO:0000269|PubMed:11923312, CC ECO:0000269|PubMed:24360804}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:18246; CC Evidence={ECO:0000269|PubMed:24360804}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=7.6 mM for 4'-phosphopantetheine {ECO:0000269|PubMed:11923312}; CC KM=145 mM for ATP (in the PPAT reaction) CC {ECO:0000269|PubMed:11923312}; CC KM=16.7 mM for dephospho-CoA {ECO:0000269|PubMed:11923312}; CC KM=34.4 mM for ATP (in the DPCK reaction) CC {ECO:0000269|PubMed:11923312}; CC -!- PATHWAY: Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)- CC pantothenate: step 4/5. {ECO:0000269|PubMed:11923312}. CC -!- PATHWAY: Cofactor biosynthesis; coenzyme A biosynthesis; CoA from (R)- CC pantothenate: step 5/5. {ECO:0000269|PubMed:11923312, CC ECO:0000269|PubMed:24360804}. CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:11994049}. CC -!- INTERACTION: CC Q13057; P13569: CFTR; NbExp=7; IntAct=EBI-745967, EBI-349854; CC Q13057; Q6P2E9: EDC4; NbExp=3; IntAct=EBI-745967, EBI-1006038; CC Q13057; P23443: RPS6KB1; NbExp=4; IntAct=EBI-745967, EBI-1775921; CC Q13057-2; Q8N137: CNTROB; NbExp=3; IntAct=EBI-10227704, EBI-947360; CC Q13057-2; Q8N8K9: KIAA1958; NbExp=3; IntAct=EBI-10227704, EBI-10181113; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:24360804, CC ECO:0000269|PubMed:40925986}. Mitochondrion matrix CC {ECO:0000269|PubMed:24360804}. Note=The protein is mainly cytosolic and CC active in the cytosol (PubMed:40925986). Present in the mitochondrial CC matrix, probably anchored to the inner mitochondrial membrane CC (PubMed:24360804). {ECO:0000269|PubMed:24360804, CC ECO:0000269|PubMed:40925986}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=CoASy alpha {ECO:0000303|PubMed:16460672}; CC IsoId=Q13057-1; Sequence=Displayed; CC Name=2; Synonyms=CoASy beta {ECO:0000303|PubMed:16460672}; CC IsoId=Q13057-2; Sequence=VSP_036404; CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including brain, CC heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small CC intestine, placenta, lung and peripheral blood leukocyte. Lowest CC expression in peripheral blood leukocytes and highest in kidney and CC liver. Isoform 2 is expressed mainly in the brain. CC {ECO:0000269|PubMed:11923312}. CC -!- DOMAIN: The phosphopantetheine adenylyltransferase domain catalyzes the CC fourth step of the coenzyme A biosynthetic pathway. CC {ECO:0000269|PubMed:11923312}. CC -!- DOMAIN: The DPCK domain catalyzes the fifth step of the coenzyme A CC biosynthetic pathway. {ECO:0000269|PubMed:11923312}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 6 (NBIA6) CC [MIM:615643]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. It is CC characterized by progressive motor and cognitive dysfunction beginning CC in childhood or young adulthood. Patients show extrapyramidal motor CC signs, such as spasticity, dystonia, and parkinsonism. CC {ECO:0000269|PubMed:24360804, ECO:0000269|PubMed:28489334}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Pontocerebellar hypoplasia 12 (PCH12) [MIM:618266]: A form of CC pontocerebellar hypoplasia, a disorder characterized by structural CC defects of the pons and cerebellum, evident upon brain imaging. PCH12 CC is an autosomal recessive form characterized by onset in utero and CC death in infancy. Brain imaging shows microcephaly, cerebellar CC hypoplasia, micrognathia, and multiple contractures. CC {ECO:0000269|PubMed:30089828}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform which is active in the CC cytosol. {ECO:0000269|PubMed:40925986}. CC -!- MISCELLANEOUS: [Isoform 2]: The physiological significance of this CC isoform is uncertain. {ECO:0000269|PubMed:40925986}. CC -!- SIMILARITY: In the central section; belongs to the eukaryotic CoaD CC family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA69699.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAF87955.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH06354.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH20985.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AK075415; 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; AF453478; AAL50813.1; -; mRNA. DR EMBL; AY094602; AAM19996.1; -; mRNA. DR EMBL; AK075415; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK297153; BAG59652.1; -; mRNA. DR EMBL; AK314076; BAG36775.1; -; mRNA. DR EMBL; AC067852; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471152; EAW60840.1; -; Genomic_DNA. DR EMBL; BC006354; AAH06354.1; ALT_INIT; mRNA. DR EMBL; BC020985; AAH20985.1; ALT_INIT; mRNA. DR EMBL; BC067254; AAH67254.1; -; mRNA. DR EMBL; AF208536; AAF87955.1; ALT_INIT; mRNA. DR EMBL; U18919; AAA69699.1; ALT_FRAME; mRNA. DR EMBL; BT007168; AAP35832.1; -; mRNA. DR CCDS; CCDS11429.1; -. [Q13057-1] DR CCDS; CCDS45685.1; -. [Q13057-2] DR RefSeq; NP_001035994.1; NM_001042529.3. [Q13057-1] DR RefSeq; NP_001035997.2; NM_001042532.4. [Q13057-2] DR RefSeq; NP_079509.5; NM_025233.6. [Q13057-1] DR RefSeq; XP_006722179.1; XM_006722116.5. [Q13057-2] DR RefSeq; XP_011523602.1; XM_011525300.2. [Q13057-1] DR RefSeq; XP_054173386.1; XM_054317411.1. [Q13057-1] DR RefSeq; XP_054173389.1; XM_054317414.1. [Q13057-2] DR AlphaFoldDB; Q13057; -. DR BioGRID; 123254; 117. DR FunCoup; Q13057; 1266. DR IntAct; Q13057; 53. DR MINT; Q13057; -. DR STRING; 9606.ENSP00000464814; -. DR BindingDB; Q13057; -. DR ChEMBL; CHEMBL4105867; -. DR GlyGen; Q13057; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q13057; -. DR PhosphoSitePlus; Q13057; -. DR SwissPalm; Q13057; -. DR BioMuta; COASY; -. DR DMDM; 32363505; -. DR jPOST; Q13057; -. DR MassIVE; Q13057; -. DR PaxDb; 9606-ENSP00000464814; -. DR PeptideAtlas; Q13057; -. DR ProteomicsDB; 59124; -. [Q13057-1] DR ProteomicsDB; 59125; -. [Q13057-2] DR Pumba; Q13057; -. DR Antibodypedia; 16973; 327 antibodies from 30 providers. DR DNASU; 80347; -. DR Ensembl; ENST00000393818.3; ENSP00000377406.1; ENSG00000068120.15. [Q13057-1] DR Ensembl; ENST00000421097.6; ENSP00000393564.2; ENSG00000068120.15. [Q13057-1] DR Ensembl; ENST00000590958.5; ENSP00000464814.1; ENSG00000068120.15. [Q13057-2] DR GeneID; 80347; -. DR KEGG; hsa:80347; -. DR MANE-Select; ENST00000393818.3; ENSP00000377406.1; NM_025233.7; NP_079509.5. DR UCSC; uc002hzz.5; human. [Q13057-1] DR AGR; HGNC:29932; -. DR ClinPGx; PA134867942; -. DR CTD; 80347; -. DR DisGeNET; 80347; -. DR GeneCards; COASY; -. DR GeneReviews; COASY; -. DR HGNC; HGNC:29932; COASY. DR HPA; ENSG00000068120; Low tissue specificity. DR MalaCards; COASY; -. DR MIM; 609855; gene. DR MIM; 615643; phenotype. DR MIM; 618266; phenotype. DR OpenTargets; ENSG00000068120; -. DR Orphanet; 397725; COASY protein-associated neurodegeneration. DR VEuPathDB; HostDB:ENSG00000068120; -. DR eggNOG; KOG3220; Eukaryota. DR eggNOG; KOG3351; Eukaryota. DR GeneTree; ENSGT00550000075078; -. DR HOGENOM; CLU_027827_1_0_1; -. DR InParanoid; Q13057; -. DR OMA; TQCLQSY; -. DR OrthoDB; 330671at2759; -. DR PAN-GO; Q13057; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q13057; -. DR BioCyc; MetaCyc:HS00931-MONOMER; -. DR BRENDA; 2.7.1.24; 2681. DR BRENDA; 2.7.7.3; 2681. DR PathwayCommons; Q13057; -. DR Reactome; R-HSA-196783; Coenzyme A biosynthesis. DR SABIO-RK; Q13057; -. DR SignaLink; Q13057; -. DR UniPathway; UPA00241; UER00355. DR UniPathway; UPA00241; UER00356. DR Agora; ENSG00000068120; -. DR BioGRID-ORCS; 80347; 445 hits in 1171 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; COASY; human. DR GeneWiki; COASY; -. DR GenomeRNAi; 80347; -. DR Pharos; Q13057; Tbio. DR PRO; PR:Q13057; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q13057; protein. DR Bgee; ENSG00000068120; Expressed in mucosa of transverse colon and 190 other cell types or tissues. DR ExpressionAtlas; Q13057; baseline and differential. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0120212; C:sperm head-tail coupling apparatus; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004140; F:dephospho-CoA kinase activity; IDA:UniProtKB. DR GO; GO:0004595; F:pantetheine-phosphate adenylyltransferase activity; IDA:UniProtKB. DR GO; GO:0015937; P:coenzyme A biosynthetic process; IDA:UniProtKB. DR CDD; cd02022; DPCK; 1. DR CDD; cd02164; PPAT_CoAS; 1. DR FunFam; 3.40.50.300:FF:000899; Bifunctional coenzyme A synthase; 1. DR FunFam; 3.40.50.620:FF:000089; Bifunctional coenzyme A synthase; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR HAMAP; MF_00376; Dephospho_CoA_kinase; 1. DR InterPro; IPR004821; Cyt_trans-like. DR InterPro; IPR001977; Depp_CoAkinase. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR NCBIfam; TIGR00152; dephospho-CoA kinase; 1. DR PANTHER; PTHR10695:SF46; BIFUNCTIONAL COENZYME A SYNTHASE-RELATED; 1. DR PANTHER; PTHR10695; DEPHOSPHO-COA KINASE-RELATED; 1. DR Pfam; PF01121; CoaE; 1. DR Pfam; PF01467; CTP_transf_like; 1. DR SUPFAM; SSF52374; Nucleotidylyl transferase; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51219; DPCK; 1. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Coenzyme A biosynthesis; Cytoplasm; KW Disease variant; Kinase; Mitochondrion; Multifunctional enzyme; KW Neurodegeneration; Nucleotide-binding; Nucleotidyltransferase; KW Phosphoprotein; Proteomics identification; Reference proteome; Transferase. FT CHAIN 1..564 FT /note="Bifunctional coenzyme A synthase" FT /id="PRO_0000173039" FT DOMAIN 360..563 FT /note="DPCK" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00564" FT REGION 180..358 FT /note="Phosphopantetheine adenylyltransferase domain" FT /evidence="ECO:0000305|PubMed:11923312" FT BINDING 365..372 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00564" FT BINDING 389 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT BINDING 393 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT BINDING 396 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT BINDING 423 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT BINDING 445 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT BINDING 514 FT /ligand="acetyl-CoA" FT /ligand_id="ChEBI:CHEBI:57288" FT /evidence="ECO:0000250|UniProtKB:Q9DBL7" FT MOD_RES 178 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18088087, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:24275569" FT MOD_RES 183 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT VAR_SEQ 1 FT /note="M -> MRTPRLRAQPRGAVYQAPSPPPAPVGLGSM (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_036404" FT VARIANT 55 FT /note="S -> Y (in dbSNP:rs615942)" FT /evidence="ECO:0000269|PubMed:11923312, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334, FT ECO:0000269|Ref.6" FT /id="VAR_030299" FT VARIANT 59..564 FT /note="Missing (in NBIA6; reduced protein abundance)" FT /evidence="ECO:0000269|PubMed:24360804" FT /id="VAR_082222" FT VARIANT 214 FT /note="A -> V (in NBIA6; uncertain significance)" FT /evidence="ECO:0000269|PubMed:28489334" FT /id="VAR_082223" FT VARIANT 499 FT /note="R -> C (in NBIA6; reduced protein abundance; loss of FT dephospho-CoA kinase activity; dbSNP:rs140709867)" FT /evidence="ECO:0000269|PubMed:24360804, FT ECO:0000269|PubMed:28489334" FT /id="VAR_070975" FT CONFLICT 41 FT /note="L -> P (in Ref. 4; BAG36775)" FT /evidence="ECO:0000305" SQ SEQUENCE 564 AA; 62329 MW; 7DC9E93B356C5DB7 CRC64; MAVFRSGLLV LTTPLASLAP RLASILTSAA RLVNHTLYVH LQPGMSLEGP AQPQSSPVQA TFEVLDFITH LYAGADVHRH LDVRILLTNI RTKSTFLPPL PTSVQNLAHP PEVVLTDFQT LDGSQYNPVK QQLVRYATSC YSCCPRLASV LLYSDYGIGE VPVEPLDVPL PSTIRPASPV AGSPKQPVRG YYRGAVGGTF DRLHNAHKVL LSVACILAQE QLVVGVADKD LLKSKLLPEL LQPYTERVEH LSEFLVDIKP SLTFDVIPLL DPYGPAGSDP SLEFLVVSEE TYRGGMAINR FRLENDLEEL ALYQIQLLKD LRHTENEEDK VSSSSFRQRM LGNLLRPPYE RPELPTCLYV IGLTGISGSG KSSIAQRLKG LGAFVIDSDH LGHRAYAPGG PAYQPVVEAF GTDILHKDGI INRKVLGSRV FGNKKQLKIL TDIMWPIIAK LAREEMDRAV AEGKRVCVID AAVLLEAGWQ NLVHEVWTAV IPETEAVRRI VERDGLSEAA AQSRLQSQMS GQQLVEQSHV VLSTLWEPHI TQRQVEKAWA LLQKRIPKTH QALD // ID CS012_HUMAN Reviewed; 141 AA. AC Q9NSK7; B3KQ16; Q0D2Q0; Q6P4C5; Q9BSL7; DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot. DT 29-MAY-2024, sequence version 4. DT 28-JAN-2026, entry version 140. DE RecName: Full=Protein C19orf12; GN Name=C19orf12; 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] {ECO:0000312|EMBL:BAG51878.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Stomach, and Teratocarcinoma; 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] {ECO:0000312|EMBL:AC010513} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [3] {ECO:0000312|EMBL:AAH04957.1, ECO:0000312|EMBL:AAH09946.1, ECO:0000312|EMBL:AAH17211.2, ECO:0000312|EMBL:AAH63518.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Brain, Lymph, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] {ECO:0000312|EMBL:CAB82403.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 23-130 (ISOFORMS 1/2). RC TISSUE=Melanoma; 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 [5] RP INVOLVEMENT IN NBIA4. RX PubMed=23521069; DOI=10.1111/cge.12137; RA Schottmann G., Stenzel W., Lutzkendorf S., Schuelke M., Knierim E.; RT "A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar RT atrophy and manifests with severe peripheral motor axonal neuropathy."; RL Clin. Genet. 85:290-292(2014). RN [6] RP VARIANTS NBIA4 ARG-42; GLU-54 AND ARG-58, VARIANT NBIA4 MET-11 (ISOFORM 4), RP VARIANTS GLU-131 AND THR-131, SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=21981780; DOI=10.1016/j.ajhg.2011.09.007; RA Hartig M.B., Iuso A., Haack T., Kmiec T., Jurkiewicz E., Heim K., RA Roeber S., Tarabin V., Dusi S., Krajewska-Walasek M., Jozwiak S., RA Hempel M., Winkelmann J., Elstner M., Oexle K., Klopstock T., RA Mueller-Felber W., Gasser T., Trenkwalder C., Tiranti V., Kretzschmar H., RA Schmitz G., Strom T.M., Meitinger T., Prokisch H.; RT "Absence of an orphan mitochondrial protein, c19orf12, causes a distinct RT clinical subtype of neurodegeneration with brain iron accumulation."; RL Am. J. Hum. Genet. 89:543-550(2011). RN [7] RP VARIANT NBIA4 GLY-55 DEL, AND VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=22584950; DOI=10.1007/s00415-012-6521-7; RA Deschauer M., Gaul C., Behrmann C., Prokisch H., Zierz S., Haack T.B.; RT "C19orf12 mutations in neurodegeneration with brain iron accumulation RT mimicking juvenile amyotrophic lateral sclerosis."; RL J. Neurol. 259:2434-2439(2012). RN [8] RP VARIANT NBIA4 GLN-110. RX PubMed=22508347; DOI=10.1002/mds.24980; RA Horvath R., Holinski-Feder E., Neeve V.C., Pyle A., Griffin H., Ashok D., RA Foley C., Hudson G., Rautenstrauss B., Nurnberg G., Nurnberg P., RA Kortler J., Neitzel B., Bassmann I., Rahman T., Keavney B., Loughlin J., RA Hambleton S., Schoser B., Lochmuller H., Santibanez-Koref M., RA Chinnery P.F.; RT "A new phenotype of brain iron accumulation with dystonia, optic atrophy, RT and peripheral neuropathy."; RL Mov. Disord. 27:789-793(2012). RN [9] RP VARIANTS NBIA4 SER-47 AND PRO-85. RX PubMed=22704260; DOI=10.1016/j.spen.2012.03.006; RA Panteghini C., Zorzi G., Venco P., Dusi S., Reale C., Brunetti D., RA Chiapparini L., Zibordi F., Siegel B., Siegel B., Garavaglia B., RA Simonati A., Bertini E., Nardocci N., Tiranti V.; RT "C19orf12 and FA2H mutations are rare in Italian patients with RT neurodegeneration with brain iron accumulation."; RL Semin. Pediatr. Neurol. 19:75-81(2012). RN [10] RP VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=23278385; DOI=10.1111/cge.12079; RA Dogu O., Krebs C.E., Kaleagasi H., Demirtas Z., Oksuz N., Walker R.H., RA Paisan-Ruiz C.; RT "Rapid disease progression in adult-onset mitochondrial membrane protein- RT associated neurodegeneration."; RL Clin. Genet. 84:350-355(2013). RN [11] RP VARIANTS NBIA4 PHE-28; PRO-37; ARG-42; LEU-49; GLU-54; VAL-54; ARG-58; RP LEU-72; SER-87 AND PRO-123, AND VARIANTS GLU-131; THR-131 AND ARG-138. RX PubMed=23269600; DOI=10.1212/wnl.0b013e31827e07be; RA Hogarth P., Gregory A., Kruer M.C., Sanford L., Wagoner W., Natowicz M.R., RA Egel R.T., Subramony S.H., Goldman J.G., Berry-Kravis E., Foulds N.C., RA Hammans S.R., Desguerre I., Rodriguez D., Wilson C., Diedrich A., Green S., RA Tran H., Reese L., Woltjer R.L., Hayflick S.J.; RT "New NBIA subtype: genetic, clinical, pathologic, and radiographic features RT of MPAN."; RL Neurology 80:268-275(2013). RN [12] RP VARIANT SPG43 PRO-52, VARIANTS NBIA4 PRO-52 AND GLY-55 DEL, SUBCELLULAR RP LOCATION, CHARACTERIZATION OF VARIANTS SPG43 PRO-52, AND CHARACTERIZATION RP OF VARIANTS NBIA4 PRO-52; GLY-55 DEL AND ARG-58. RX PubMed=23857908; DOI=10.1002/humu.22378; RA Landoure G., Zhu P.P., Lourenco C.M., Johnson J.O., Toro C., Bricceno K.V., RA Rinaldi C., Meilleur K.G., Sangare M., Diallo O., Pierson T.M., Ishiura H., RA Tsuji S., Hein N., Fink J.K., Stoll M., Nicholson G., Gonzalez M.A., RA Speziani F., Durr A., Stevanin G., Biesecker L.G., Accardi J., Landis D.M., RA Gahl W.A., Traynor B.J., Marques W. Jr., Zuchner S., Blackstone C., RA Fischbeck K.H., Burnett B.G.; RT "Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in RT C19orf12."; RL Hum. Mutat. 34:1357-1360(2013). RN [13] RP CHARACTERIZATION OF VARIANTS NBIA4 SER-47 AND PRO-85, AND SUBCELLULAR RP LOCATION. RX PubMed=26136767; DOI=10.3389/fgene.2015.00185; RA Venco P., Bonora M., Giorgi C., Papaleo E., Iuso A., Prokisch H., RA Pinton P., Tiranti V.; RT "Mutations of C19orf12, coding for a transmembrane glycine zipper RT containing mitochondrial protein, cause mis-localization of the protein, RT inability to respond to oxidative stress and increased mitochondrial RT Ca(2)(+)."; RL Front. Genet. 6:185-185(2015). RN [14] RP VARIANT NBIA4 ARG-58, AND VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=25592411; DOI=10.1016/j.jns.2014.12.036; RA Tschentscher A., Dekomien G., Ross S., Cremer K., Kukuk G.M., Epplen J.T., RA Hoffjan S.; RT "Analysis of the C19orf12 and WDR45 genes in patients with RT neurodegeneration with brain iron accumulation."; RL J. Neurol. Sci. 349:105-109(2015). RN [15] RP VARIANT NBIA4 LEU-72. RX PubMed=26187298; DOI=10.1016/j.jns.2015.07.009; RA Kleffner I., Wessling C., Gess B., Korsukewitz C., Allkemper T., RA Schirmacher A., Young P., Senderek J., Husstedt I.W.; RT "Behr syndrome with homozygous C19ORF12 mutation."; RL J. Neurol. Sci. 357:115-118(2015). CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:22508347, ECO:0000269|PubMed:26136767}. CC Mitochondrion membrane {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:26136767}; Single-pass membrane protein CC {ECO:0000255}. Endoplasmic reticulum {ECO:0000269|PubMed:22508347}. CC Cytoplasm, cytosol {ECO:0000269|PubMed:26136767}. Note=In response to CC oxidative stress, relocates to the cytosol forming aggregates that CC partially co-localize with mitochondria. {ECO:0000269|PubMed:26136767}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q9NSK7-4; Sequence=Displayed; CC Name=4; CC IsoId=Q9NSK7-1; Sequence=VSP_062333; CC Name=2; CC IsoId=Q9NSK7-2; Sequence=VSP_062332; CC Name=3; CC IsoId=Q9NSK7-3; Sequence=VSP_062334, VSP_062335; CC -!- INDUCTION: Up-regulated during adipocyte differentiation in an in vitro CC preadipocyte differentiation model. {ECO:0000269|PubMed:21981780}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 4 (NBIA4) CC [MIM:614298]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. NBIA4 CC results in speech difficulty, extrapyramidal signs, oromandibular and CC generalized dystonia, and parkinsonism. Most patients have progressive CC involvement of the corticospinal tract, with spasticity, hyperreflexia, CC and extensor plantar responses. {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:22508347, ECO:0000269|PubMed:22584950, CC ECO:0000269|PubMed:22704260, ECO:0000269|PubMed:23269600, CC ECO:0000269|PubMed:23278385, ECO:0000269|PubMed:23521069, CC ECO:0000269|PubMed:23857908, ECO:0000269|PubMed:25592411, CC ECO:0000269|PubMed:26136767, ECO:0000269|PubMed:26187298}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Spastic paraplegia 43, autosomal recessive (SPG43) CC [MIM:615043]: 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. SP43 is characterized CC by childhood onset of progressive spasticity affecting the lower and CC upper limbs. {ECO:0000269|PubMed:23857908}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the C19orf12 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH17211.2; Type=Erroneous initiation; Note=Extended 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; AK057185; BAG51878.1; -; mRNA. DR EMBL; DA708831; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AC010513; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC004957; AAH04957.1; -; mRNA. DR EMBL; BC009946; AAH09946.1; -; mRNA. DR EMBL; BC017211; AAH17211.2; ALT_INIT; mRNA. DR EMBL; BC063518; AAH63518.1; -; mRNA. DR EMBL; AL162066; CAB82403.1; -; mRNA. DR CCDS; CCDS12418.2; -. [Q9NSK7-4] DR CCDS; CCDS59373.1; -. [Q9NSK7-3] DR CCDS; CCDS74325.1; -. [Q9NSK7-2] DR PIR; T47169; T47169. DR RefSeq; NP_001026896.3; NM_001031726.4. [Q9NSK7-4] DR RefSeq; NP_001242975.1; NM_001256046.3. [Q9NSK7-3] DR RefSeq; NP_001242976.1; NM_001256047.2. [Q9NSK7-4] DR RefSeq; NP_001269858.1; NM_001282929.1. [Q9NSK7-2] DR RefSeq; NP_001269859.1; NM_001282930.3. [Q9NSK7-2] DR RefSeq; NP_001269860.1; NM_001282931.3. [Q9NSK7-2] DR RefSeq; NP_113636.2; NM_031448.6. [Q9NSK7-4] DR RefSeq; XP_024307503.1; XM_024451735.2. [Q9NSK7-4] DR RefSeq; XP_047295453.1; XM_047439497.1. [Q9NSK7-2] DR RefSeq; XP_054178270.1; XM_054322295.1. [Q9NSK7-4] DR RefSeq; XP_054178271.1; XM_054322296.1. [Q9NSK7-2] DR AlphaFoldDB; Q9NSK7; -. DR SMR; Q9NSK7; -. DR BioGRID; 123700; 2. DR FunCoup; Q9NSK7; 1030. DR IntAct; Q9NSK7; 2. DR STRING; 9606.ENSP00000376103; -. DR iPTMnet; Q9NSK7; -. DR PhosphoSitePlus; Q9NSK7; -. DR BioMuta; C19orf12; -. DR DMDM; 374095505; -. DR jPOST; Q9NSK7; -. DR MassIVE; Q9NSK7; -. DR PaxDb; 9606-ENSP00000376103; -. DR PeptideAtlas; Q9NSK7; -. DR ProteomicsDB; 82566; -. [Q9NSK7-1] DR ProteomicsDB; 82567; -. [Q9NSK7-2] DR ProteomicsDB; 82568; -. [Q9NSK7-3] DR ProteomicsDB; 82569; -. [Q9NSK7-4] DR Pumba; Q9NSK7; -. DR Antibodypedia; 47936; 39 antibodies from 14 providers. DR DNASU; 83636; -. DR Ensembl; ENST00000323670.14; ENSP00000313332.9; ENSG00000131943.21. [Q9NSK7-4] DR Ensembl; ENST00000392275.1; ENSP00000507573.1; ENSG00000131943.21. [Q9NSK7-2] DR Ensembl; ENST00000392276.1; ENSP00000376102.1; ENSG00000131943.21. [Q9NSK7-2] DR Ensembl; ENST00000592153.5; ENSP00000467117.1; ENSG00000131943.21. [Q9NSK7-3] DR Ensembl; ENST00000623113.3; ENSP00000485413.2; ENSG00000131943.21. [Q9NSK7-4] DR GeneID; 83636; -. DR KEGG; hsa:83636; -. DR MANE-Select; ENST00000323670.14; ENSP00000313332.9; NM_031448.6; NP_113636.2. DR UCSC; uc002nsj.4; human. [Q9NSK7-4] DR AGR; HGNC:25443; -. DR ClinPGx; PA134981038; -. DR CTD; 83636; -. DR DisGeNET; 83636; -. DR GeneCards; C19orf12; -. DR GeneReviews; C19orf12; -. DR HGNC; HGNC:25443; C19orf12. DR HPA; ENSG00000131943; Tissue enhanced (adipose tissue, tongue). DR MalaCards; C19orf12; -. DR MIM; 614297; gene. DR MIM; 614298; phenotype. DR MIM; 615043; phenotype. DR OpenTargets; ENSG00000131943; -. DR Orphanet; 320370; Autosomal recessive spastic paraplegia type 43. DR Orphanet; 289560; Mitochondrial membrane protein-associated neurodegeneration. DR VEuPathDB; HostDB:ENSG00000131943; -. DR eggNOG; ENOG502RZQC; Eukaryota. DR GeneTree; ENSGT00390000009077; -. DR HOGENOM; CLU_2460310_0_0_1; -. DR InParanoid; Q9NSK7; -. DR OrthoDB; 5976774at2759; -. DR PAN-GO; Q9NSK7; 0 GO annotations based on evolutionary models. DR PhylomeDB; Q9NSK7; -. DR PathwayCommons; Q9NSK7; -. DR SignaLink; Q9NSK7; -. DR Agora; ENSG00000131943; -. DR BioGRID-ORCS; 83636; 24 hits in 1143 CRISPR screens. DR ChiTaRS; C19orf12; human. DR GenomeRNAi; 83636; -. DR Pharos; Q9NSK7; Tbio. DR PRO; PR:Q9NSK7; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q9NSK7; protein. DR Bgee; ENSG00000131943; Expressed in endothelial cell and 186 other cell types or tissues. DR ExpressionAtlas; Q9NSK7; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IMP:UniProtKB. DR GO; GO:0006979; P:response to oxidative stress; IMP:UniProtKB. DR InterPro; IPR033369; C19orf12. DR PANTHER; PTHR31493; NAZO FAMILY MEMBER; 1. DR PANTHER; PTHR31493:SF1; PROTEIN C19ORF12; 1. DR Pfam; PF20721; C19orf12; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Disease variant; Endoplasmic reticulum; KW Hereditary spastic paraplegia; Membrane; Mitochondrion; Neurodegeneration; KW Proteomics identification; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..141 FT /note="Protein C19orf12" FT /id="PRO_0000296662" FT TRANSMEM 40..60 FT /note="Helical" FT /evidence="ECO:0000255" FT VAR_SEQ 1..64 FT /note="Missing (in isoform 2)" FT /id="VSP_062332" FT VAR_SEQ 1 FT /note="M -> MERLKSHKPATM (in isoform 4)" FT /id="VSP_062333" FT VAR_SEQ 98..107 FT /note="HLEWTDAVQL -> PCSSSCWPCW (in isoform 3)" FT /id="VSP_062334" FT VAR_SEQ 108..141 FT /note="Missing (in isoform 3)" FT /id="VSP_062335" FT VARIANT 28 FT /note="S -> F (in NBIA4; dbSNP:rs1204865094)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069756" FT VARIANT 37 FT /note="A -> P (in NBIA4)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069757" FT VARIANT 42 FT /note="G -> R (in NBIA4; dbSNP:rs200133991)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066618" FT VARIANT 47 FT /note="G -> S (in NBIA4; predominantly cytosolic FT distribution with a localization also seen in the FT mitochondrial matrix; no cytosolic redistribution seen in FT response to oxidative stress; patient fibroblasts FT accumulate high levels of mitochondrial calcium and are FT more prone to oxidative stress-induced apoptosis; FT dbSNP:rs1358503478)" FT /evidence="ECO:0000269|PubMed:22704260, FT ECO:0000269|PubMed:26136767" FT /id="VAR_076803" FT VARIANT 49 FT /note="P -> L (in NBIA4; dbSNP:rs1424999393)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069758" FT VARIANT 52 FT /note="A -> P (in NBIA4 and SPG43; impairs subcellular FT localization to the endoplasmic reticulum or mitochondrion; FT dbSNP:rs376103979)" FT /evidence="ECO:0000269|PubMed:23857908" FT /id="VAR_070668" FT VARIANT 54 FT /note="G -> E (in NBIA4; dbSNP:rs752450983)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066619" FT VARIANT 54 FT /note="G -> V (in NBIA4; dbSNP:rs752450983)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069759" FT VARIANT 55 FT /note="Missing (in NBIA4; impairs subcellular localization FT to the endoplasmic reticulum or mitochondrion)" FT /evidence="ECO:0000269|PubMed:22584950, FT ECO:0000269|PubMed:23857908" FT /id="VAR_070669" FT VARIANT 58 FT /note="G -> R (in NBIA4; impairs subcellular localization FT to the endoplasmic reticulum or mitochondrion; FT dbSNP:rs515726205)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600, ECO:0000269|PubMed:23857908, FT ECO:0000269|PubMed:25592411" FT /id="VAR_066620" FT VARIANT 72 FT /note="P -> L (in NBIA4; dbSNP:rs201987973)" FT /evidence="ECO:0000269|PubMed:23269600, FT ECO:0000269|PubMed:26187298" FT /id="VAR_069760" FT VARIANT 85 FT /note="Q -> P (in NBIA4; no effect on its subcellular FT localization; no cytosolic redistribution seen in response FT to oxidative stress)" FT /evidence="ECO:0000269|PubMed:22704260, FT ECO:0000269|PubMed:26136767" FT /id="VAR_076804" FT VARIANT 87 FT /note="R -> S (in NBIA4; dbSNP:rs1384930997)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069761" FT VARIANT 110 FT /note="L -> Q (in NBIA4)" FT /evidence="ECO:0000269|PubMed:22508347" FT /id="VAR_069762" FT VARIANT 123 FT /note="A -> P (in NBIA4; uncertain significance; FT dbSNP:rs1264612218)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069763" FT VARIANT 131 FT /note="K -> E (found in families with neurodegeneration FT with brain iron accumulation; uncertain significance; FT dbSNP:rs146170087)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066621" FT VARIANT 131 FT /note="K -> T (in dbSNP:rs79915936)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066622" FT VARIANT 138 FT /note="Q -> R (in dbSNP:rs73023451)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069764" FT VARIANT Q9NSK7-1:11 FT /note="T -> M (in NBIA4; dbSNP:rs397514477)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:22584950, ECO:0000269|PubMed:23278385, FT ECO:0000269|PubMed:25592411" FT /id="VAR_089160" SQ SEQUENCE 141 AA; 15007 MW; C6EEA8C17A909E7F CRC64; MTIMVEDIMK LLCSLSGERK MKAAVKHSGK GALVTGAMAF VGGLVGGPPG LAVGGAVGGL LGAWMTSGQF KPVPQILMEL PPAEQQRLFN EAAAIIRHLE WTDAVQLTAL VMGSEALQQQ LLAMLVNYVT KELRAEIQYD D // ID HTRA2_HUMAN Reviewed; 458 AA. AC O43464; Q9HBZ4; Q9P0Y3; Q9P0Y4; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 2. DT 28-JAN-2026, entry version 241. DE RecName: Full=Serine protease HTRA2, mitochondrial; DE EC=3.4.21.108; DE AltName: Full=High temperature requirement protein A2; DE Short=HtrA2; DE AltName: Full=Omi stress-regulated endoprotease; DE AltName: Full=Serine protease 25; DE AltName: Full=Serine proteinase OMI; DE Flags: Precursor; GN Name=HTRA2; Synonyms=OMI, PRSS25; 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), SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF SER-306. RX PubMed=10644717; DOI=10.1074/jbc.275.4.2581; RA Faccio L., Fusco C., Chen A., Martinotti S., Bonventre J.V., Zervos A.S.; RT "Characterization of a novel human serine protease that has extensive RT homology to bacterial heat shock endoprotease HtrA and is regulated by RT kidney ischemia."; RL J. Biol. Chem. 275:2581-2588(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4), AND CHARACTERIZATION. RC TISSUE=Brain; RX PubMed=10971580; DOI=10.1046/j.1432-1327.2000.01589.x; RA Gray C.W., Ward R.V., Karran E.H., Turconi S., Rowles A., Viglienghi D., RA Southan C., Barton A., Fantom K.G., West A., Savopoulos J.W., Hassan N.J., RA Clinkenbeard H., Hanning C., Amegadzie B., Davis J.B., Dingwall C., RA Livi G.P., Creasy C.L.; RT "Characterization of human HtrA2, a novel serine protease involved in the RT mammalian cellular stress response."; RL Eur. J. Biochem. 267:5699-5710(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Kidney; RX PubMed=10995577; DOI=10.1006/geno.2000.6263; RA Faccio L., Fusco C., Viel A., Zervos A.S.; RT "Tissue-specific splicing of Omi stress-regulated endoprotease leads to an RT inactive protease with a modified PDZ motif."; RL Genomics 68:343-347(2000). RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 134-458, INTERACTION WITH XIAP, AND MUTAGENESIS OF RP ALA-134. RX PubMed=11583623; DOI=10.1016/s1097-2765(01)00341-0; RA Suzuki Y., Imai Y., Nakayama H., Takahashi K., Takio K., Takahashi R.; RT "A serine protease, HtrA2, is released from the mitochondria and interacts RT with XIAP, inducing cell death."; RL Mol. Cell 8:613-621(2001). RN [7] RP CHARACTERIZATION, AND PHOSPHORYLATION. RX PubMed=10873535; DOI=10.1006/prep.2000.1240; RA Savopoulos J.W., Carter P.S., Turconi S., Pettman G.R., Karran E.H., RA Gray C.W., Ward R.V., Jenkins O., Creasy C.L.; RT "Expression, purification, and functional analysis of the human serine RT protease HtrA2."; RL Protein Expr. Purif. 19:227-234(2000). RN [8] RP FUNCTION, AND INTERACTION WITH BIRC6/BRUCE. RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018; RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.; RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin RT ligase."; RL Mol. Cell 14:801-811(2004). RN [9] RP FUNCTION, AND INTERACTION WITH THAP5. RX PubMed=19502560; DOI=10.1152/ajpheart.00234.2009; RA Balakrishnan M.P., Cilenti L., Mashak Z., Popat P., Alnemri E.S., RA Zervos A.S.; RT "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved RT by the proapoptotic Omi/HtrA2 protease during cell death."; RL Am. J. Physiol. 297:H643-H653(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP INTERACTION WITH AREL1. RX PubMed=23479728; DOI=10.1074/jbc.m112.436113; RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y., RA Chae H.D., Shin D.Y.; RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, RT and ARTS."; RL J. Biol. Chem. 288:12014-12021(2013). RN [12] 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 [13] 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 [14] {ECO:0007744|PDB:1LCY} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 134-458, SUBUNIT, AND ACTIVE SITE. RX PubMed=11967569; DOI=10.1038/nsb795; RA Li W., Srinivasula S.M., Chai J., Li P., Wu J.W., Zhang Z., Alnemri E.S., RA Shi Y.; RT "Structural insights into the pro-apoptotic function of mitochondrial RT serine protease HtrA2/Omi."; RL Nat. Struct. Biol. 9:436-441(2002). RN [15] {ECO:0007744|PDB:8E2K} RP STRUCTURE BY ELECTRON MICROSCOPY (3.21 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758104; DOI=10.1126/science.ade5750; RA Hunkeler M., Jin C.Y., Fischer E.S.; RT "Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated RT release of caspases."; RL Science 379:1105-1111(2023). RN [16] {ECO:0007744|PDB:8AUK} RP STRUCTURE BY ELECTRON MICROSCOPY (6.20 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758105; DOI=10.1126/science.ade8873; RA Ehrmann J.F., Grabarczyk D.B., Heinke M., Deszcz L., Kurzbauer R., RA Hudecz O., Shulkina A., Gogova R., Meinhart A., Versteeg G.A., Clausen T.; RT "Structural basis for regulation of apoptosis and autophagy by the RT BIRC6/SMAC complex."; RL Science 379:1117-1123(2023). RN [17] RP INVOLVEMENT IN PARK13, VARIANTS SER-141 AND SER-399, AND CHARACTERIZATION RP OF VARIANTS SER-141 AND SER-399. RX PubMed=15961413; DOI=10.1093/hmg/ddi215; RA Strauss K.M., Martins L.M., Plun-Favreau H., Marx F.P., Kautzmann S., RA Berg D., Gasser T., Wszolek Z., Mueller T., Bornemann A., Wolburg H., RA Downward J., Riess O., Schulz J.B., Krueger R.; RT "Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's RT disease."; RL Hum. Mol. Genet. 14:2099-2111(2005). RN [18] RP INVOLVEMENT IN PARK13, VARIANTS PRO-72 AND SER-141, AND VARIANT PARK13 RP TRP-404. RX PubMed=18401856; DOI=10.1002/humu.20713; RA Bogaerts V., Nuytemans K., Reumers J., Pals P., Engelborghs S., Pickut B., RA Corsmit E., Peeters K., Schymkowitz J., De Deyn P.P., Cras P., Rousseau F., RA Theuns J., Van Broeckhoven C.; RT "Genetic variability in the mitochondrial serine protease HTRA2 contributes RT to risk for Parkinson disease."; RL Hum. Mutat. 29:832-840(2008). RN [19] RP VARIANTS CYS-12; LEU-128; SER-141; SER-227 AND SER-399. RX PubMed=18364387; DOI=10.1093/hmg/ddn096; RA Simon-Sanchez J., Singleton A.B.; RT "Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic RT mutations in neurologically normal controls."; RL Hum. Mol. Genet. 17:1988-1993(2008). RN [20] RP VARIANT SER-399. RX PubMed=25422467; DOI=10.1073/pnas.1419581111; RA Unal Gulsuner H., Gulsuner S., Mercan F.N., Onat O.E., Walsh T., Shahin H., RA Lee M.K., Dogu O., Kansu T., Topaloglu H., Elibol B., Akbostanci C., RA King M.C., Ozcelik T., Tekinay A.B.; RT "Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential RT tremor and Parkinson disease."; RL Proc. Natl. Acad. Sci. U.S.A. 111:18285-18290(2014). RN [21] RP INVOLVEMENT IN MGCA8, VARIANT MGCA8 GLN-404, AND CHARACTERIZATION OF RP VARIANT MGCA8 GLN-404. RX PubMed=27208207; DOI=10.1136/jmedgenet-2016-103922; RA Mandel H., Saita S., Edvardson S., Jalas C., Shaag A., Goldsher D., RA Vlodavsky E., Langer T., Elpeleg O.; RT "Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and RT 3-methylglutaconic aciduria."; RL J. Med. Genet. 53:690-696(2016). RN [22] RP VARIANT SER-399. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [23] RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER, AND CHARACTERIZATION OF RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER. RX PubMed=27696117; DOI=10.1007/s10545-016-9977-2; RA Olahova M., Thompson K., Hardy S.A., Barbosa I.A., Besse A., RA Anagnostou M.E., White K., Davey T., Simpson M.A., Champion M., Enns G., RA Schelley S., Lightowlers R.N., Chrzanowska-Lightowlers Z.M., McFarland R., RA Deshpande C., Bonnen P.E., Taylor R.W.; RT "Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome RT associated with 3-methylglutaconic aciduria."; RL J. Inherit. Metab. Dis. 40:121-130(2017). CC -!- FUNCTION: [Isoform 1]: Serine protease that shows proteolytic activity CC against a non-specific substrate beta-casein (PubMed:10873535). CC Promotes apoptosis by either relieving the inhibition of BIRC proteins CC on caspases, leading to an increase in caspase activity; or by a BIRC CC inhibition-independent, caspase-independent and serine protease CC activity-dependent mechanism (PubMed:15200957). Cleaves BIRC6 and CC relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone CC to inhibition by BIRC6 (PubMed:36758104, PubMed:36758105). Cleaves CC THAP5 and promotes its degradation during apoptosis (PubMed:19502560). CC {ECO:0000269|PubMed:10873535, ECO:0000269|PubMed:15200957, CC ECO:0000269|PubMed:19502560, ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- FUNCTION: [Isoform 2]: Seems to be proteolytically inactive. CC {ECO:0000269|PubMed:10995577}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Cleavage of non-polar aliphatic amino-acids at the P1 CC position, with a preference for Val, Ile and Met. At the P2 and P3 CC positions, Arg is selected most strongly with a secondary preference CC for other hydrophilic residues.; EC=3.4.21.108; CC -!- ACTIVITY REGULATION: Inhibited by BIRC6. {ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- SUBUNIT: Homotrimer (PubMed:36758104, PubMed:36758105). Interacts with CC MXI2. Interacts with THAP5 under apoptotic conditions. The mature CC protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and CC XIAP/BIRC4. Interacts with AREL1 (via HECT domain); in the cytoplasm CC following induction of apoptosis (PubMed:23479728). CC {ECO:0000269|PubMed:11583623, ECO:0000269|PubMed:11967569, CC ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560, CC ECO:0000269|PubMed:23479728}. CC -!- INTERACTION: CC O43464; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-517086, EBI-25840993; CC O43464; Q8IUR7: ARMC8; NbExp=6; IntAct=EBI-517086, EBI-1049469; CC O43464; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-517086, EBI-25844820; CC O43464; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-517086, EBI-14199987; CC O43464; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-517086, EBI-25843552; CC O43464; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-517086, EBI-9089489; CC O43464; Q13490: BIRC2; NbExp=4; IntAct=EBI-517086, EBI-514538; CC O43464; Q96CA5: BIRC7; NbExp=5; IntAct=EBI-517086, EBI-517623; CC O43464; Q7Z7K6: CENPV; NbExp=3; IntAct=EBI-517086, EBI-1210604; CC O43464; P02489: CRYAA; NbExp=3; IntAct=EBI-517086, EBI-6875961; CC O43464; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-517086, EBI-25842815; CC O43464; O00303: EIF3F; NbExp=3; IntAct=EBI-517086, EBI-711990; CC O43464; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-517086, EBI-9246952; CC O43464; Q13216-2: ERCC8; NbExp=3; IntAct=EBI-517086, EBI-16466949; CC O43464; Q99871: HAUS7; NbExp=3; IntAct=EBI-517086, EBI-395719; CC O43464; Q02363: ID2; NbExp=3; IntAct=EBI-517086, EBI-713450; CC O43464; Q8IY31-2: IFT20; NbExp=3; IntAct=EBI-517086, EBI-11742277; CC O43464; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-517086, EBI-743960; CC O43464; Q6P597: KLC3; NbExp=3; IntAct=EBI-517086, EBI-1643885; CC O43464; P57682: KLF3; NbExp=3; IntAct=EBI-517086, EBI-8472267; CC O43464; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-517086, EBI-714379; CC O43464; P08727: KRT19; NbExp=3; IntAct=EBI-517086, EBI-742756; CC O43464; Q14525: KRT33B; NbExp=3; IntAct=EBI-517086, EBI-1049638; CC O43464; Q1L5Z9: LONRF2; NbExp=3; IntAct=EBI-517086, EBI-2510853; CC O43464; Q99683: MAP3K5; NbExp=3; IntAct=EBI-517086, EBI-476263; CC O43464; Q8NA82: MARCHF10; NbExp=3; IntAct=EBI-517086, EBI-2341554; CC O43464; Q8N594: MPND; NbExp=3; IntAct=EBI-517086, EBI-2512452; CC O43464; Q8WY64: MYLIP; NbExp=3; IntAct=EBI-517086, EBI-6952711; CC O43464; Q9P0J0: NDUFA13; NbExp=8; IntAct=EBI-517086, EBI-372742; CC O43464; Q13562: NEUROD1; NbExp=3; IntAct=EBI-517086, EBI-3908303; CC O43464; O15381-5: NVL; NbExp=3; IntAct=EBI-517086, EBI-18577082; CC O43464; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-517086, EBI-1058491; CC O43464; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-517086, EBI-25830200; CC O43464; Q9NUU6: OTULINL; NbExp=3; IntAct=EBI-517086, EBI-6916492; CC O43464; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-517086, EBI-11022007; CC O43464; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-517086, EBI-6309018; CC O43464; O14813: PHOX2A; NbExp=3; IntAct=EBI-517086, EBI-25844430; CC O43464; O75925: PIAS1; NbExp=3; IntAct=EBI-517086, EBI-629434; CC O43464; Q8WWB5: PIH1D2; NbExp=3; IntAct=EBI-517086, EBI-10232538; CC O43464; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-517086, EBI-10293968; CC O43464; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-517086, EBI-25835994; CC O43464; P17980: PSMC3; NbExp=3; IntAct=EBI-517086, EBI-359720; CC O43464; P57052: RBM11; NbExp=3; IntAct=EBI-517086, EBI-741332; CC O43464; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-517086, EBI-749039; CC O43464; Q96D59: RNF183; NbExp=3; IntAct=EBI-517086, EBI-743938; CC O43464; Q15287: RNPS1; NbExp=2; IntAct=EBI-517086, EBI-395959; CC O43464; Q96GQ5: RUSF1; NbExp=3; IntAct=EBI-517086, EBI-8636004; CC O43464; Q8N488: RYBP; NbExp=3; IntAct=EBI-517086, EBI-752324; CC O43464; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-517086, EBI-11528848; CC O43464; Q9NR46: SH3GLB2; NbExp=3; IntAct=EBI-517086, EBI-749607; CC O43464; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-517086, EBI-358489; CC O43464; Q16637-3: SMN2; NbExp=3; IntAct=EBI-517086, EBI-395447; CC O43464; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-517086, EBI-3942425; CC O43464; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-517086, EBI-745958; CC O43464; Q86WV5: TEN1; NbExp=3; IntAct=EBI-517086, EBI-2562799; CC O43464; O95150: TNFSF15; NbExp=3; IntAct=EBI-517086, EBI-16355546; CC O43464; Q6DKK2: TTC19; NbExp=4; IntAct=EBI-517086, EBI-948354; CC O43464; Q495M9: USH1G; NbExp=3; IntAct=EBI-517086, EBI-8601749; CC O43464; O75604-3: USP2; NbExp=3; IntAct=EBI-517086, EBI-10696113; CC O43464; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-517086, EBI-2850578; CC O43464; Q15007-2: WTAP; NbExp=3; IntAct=EBI-517086, EBI-25840023; CC O43464; O00308: WWP2; NbExp=3; IntAct=EBI-517086, EBI-743923; CC O43464; P98170: XIAP; NbExp=23; IntAct=EBI-517086, EBI-517127; CC O43464; P24278: ZBTB25; NbExp=3; IntAct=EBI-517086, EBI-739899; CC O43464; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-517086, EBI-749023; CC O43464; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-517086, EBI-12010736; CC O43464; O60304: ZNF500; NbExp=3; IntAct=EBI-517086, EBI-18234077; CC O43464; O15535: ZSCAN9; NbExp=3; IntAct=EBI-517086, EBI-751531; CC O43464; Q86V28; NbExp=3; IntAct=EBI-517086, EBI-10259496; CC O43464; P02666: CSN2; Xeno; NbExp=7; IntAct=EBI-517086, EBI-5260183; CC O43464; Q60855: Ripk1; Xeno; NbExp=2; IntAct=EBI-517086, EBI-529119; CC PRO_0000026946; P02666: CSN2; Xeno; NbExp=2; IntAct=EBI-5271862, EBI-5260183; CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space. Mitochondrion CC membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}. CC Note=Predominantly present in the intermembrane space. Released into CC the cytosol following apoptotic stimuli, such as UV treatment, and CC stimulation of mitochondria with caspase-8 truncated BID/tBID. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum CC {ECO:0000269|PubMed:10644717}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=13B; CC IsoId=O43464-1; Sequence=Displayed; CC Name=2; Synonyms=D-Omi; CC IsoId=O43464-2; Sequence=VSP_005359, VSP_005361; CC Name=3; Synonyms=p7; CC IsoId=O43464-3; Sequence=VSP_005360, VSP_005361; CC Name=4; Synonyms=p4; CC IsoId=O43464-4; Sequence=VSP_005362; CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed. CC {ECO:0000269|PubMed:10644717}. CC -!- DOMAIN: The mature N-terminus is involved in the interaction with XIAP. CC -!- DOMAIN: The PDZ domain mediates interaction with MXI2. CC -!- PTM: Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. CC {ECO:0000269|PubMed:36758104, ECO:0000269|PubMed:36758105}. CC -!- PTM: Autoproteolytically activated. {ECO:0000269|PubMed:10873535}. CC -!- DISEASE: 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248]: An CC autosomal recessive inborn error of metabolism resulting in early CC death. Clinical features include extreme hypertonia observed at birth, CC alternating with hypotonia, subsequent appearance of extrapyramidal CC symptoms, lack of psychomotor development, microcephaly, and CC intractable seizures. Patients show lactic acidemia, 3-methylglutaconic CC aciduria, intermittent neutropenia, and progressive brain atrophy. CC {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 13 (PARK13) [MIM:610297]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC 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. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41879/HTRA2"; 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; AF020760; AAB94569.2; -; mRNA. DR EMBL; AF141305; AAF66596.1; -; mRNA. DR EMBL; AF141306; AAF66597.1; -; mRNA. DR EMBL; AF141307; AAF66598.1; -; mRNA. DR EMBL; AF184911; AAG13126.1; -; mRNA. DR EMBL; AC006544; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000096; AAH00096.1; -; mRNA. DR CCDS; CCDS1951.1; -. [O43464-1] DR CCDS; CCDS1952.1; -. [O43464-2] DR CCDS; CCDS92785.1; -. [O43464-3] DR RefSeq; NP_001308656.1; NM_001321727.1. [O43464-3] DR RefSeq; NP_037379.1; NM_013247.5. [O43464-1] DR RefSeq; NP_659540.1; NM_145074.2. [O43464-2] DR PDB; 1LCY; X-ray; 2.00 A; A=134-458. DR PDB; 2PZD; X-ray; 2.75 A; A/B=359-458. DR PDB; 5FHT; X-ray; 1.95 A; A=134-458. DR PDB; 5M3N; X-ray; 1.65 A; A=134-458. DR PDB; 5M3O; X-ray; 1.70 A; A=134-458. DR PDB; 5TNY; X-ray; 1.70 A; A=134-458. DR PDB; 5TNZ; X-ray; 1.75 A; A=134-458. DR PDB; 5TO0; X-ray; 1.90 A; A=134-458. DR PDB; 5TO1; X-ray; 1.69 A; A=134-458. DR PDB; 5WYN; X-ray; 2.05 A; A=134-458. DR PDB; 7VGE; X-ray; 4.00 A; A/B/C=140-342, D/F=140-341, E=140-340. DR PDB; 8AUK; EM; 6.20 A; C/D/E=134-458. DR PDB; 8E2K; EM; 3.21 A; X/Y/Z=134-458. DR PDBsum; 1LCY; -. DR PDBsum; 2PZD; -. DR PDBsum; 5FHT; -. DR PDBsum; 5M3N; -. DR PDBsum; 5M3O; -. DR PDBsum; 5TNY; -. DR PDBsum; 5TNZ; -. DR PDBsum; 5TO0; -. DR PDBsum; 5TO1; -. DR PDBsum; 5WYN; -. DR PDBsum; 7VGE; -. DR PDBsum; 8AUK; -. DR PDBsum; 8E2K; -. DR AlphaFoldDB; O43464; -. DR EMDB; EMD-15672; -. DR EMDB; EMD-27841; -. DR SASBDB; O43464; -. DR SMR; O43464; -. DR BioGRID; 118165; 304. DR CORUM; O43464; -. DR ELM; O43464; -. DR FunCoup; O43464; 1709. DR IntAct; O43464; 313. DR MINT; O43464; -. DR STRING; 9606.ENSP00000258080; -. DR BindingDB; O43464; -. DR ChEMBL; CHEMBL4523137; -. DR MEROPS; S01.278; -. DR MoonDB; O43464; Predicted. DR TCDB; 8.A.217.1.1; the apoptosis cell death regulator (acdr) family. DR iPTMnet; O43464; -. DR PhosphoSitePlus; O43464; -. DR BioMuta; HTRA2; -. DR OGP; O43464; -. DR jPOST; O43464; -. DR MassIVE; O43464; -. DR PaxDb; 9606-ENSP00000258080; -. DR PeptideAtlas; O43464; -. DR ProteomicsDB; 48958; -. [O43464-1] DR ProteomicsDB; 48959; -. [O43464-2] DR ProteomicsDB; 48960; -. [O43464-3] DR ProteomicsDB; 48961; -. [O43464-4] DR Pumba; O43464; -. DR TopDownProteomics; O43464-2; -. [O43464-2] DR ABCD; O43464; 1 sequenced antibody. DR Antibodypedia; 3554; 772 antibodies from 43 providers. DR DNASU; 27429; -. DR Ensembl; ENST00000258080.8; ENSP00000258080.3; ENSG00000115317.14. [O43464-1] DR Ensembl; ENST00000352222.7; ENSP00000312893.3; ENSG00000115317.14. [O43464-2] DR Ensembl; ENST00000437202.2; ENSP00000399166.2; ENSG00000115317.14. [O43464-3] DR GeneID; 27429; -. DR KEGG; hsa:27429; -. DR MANE-Select; ENST00000258080.8; ENSP00000258080.3; NM_013247.5; NP_037379.1. DR UCSC; uc002smi.2; human. [O43464-1] DR AGR; HGNC:14348; -. DR ClinPGx; PA33836; -. DR CTD; 27429; -. DR DisGeNET; 27429; -. DR GeneCards; HTRA2; -. DR HGNC; HGNC:14348; HTRA2. DR HPA; ENSG00000115317; Low tissue specificity. DR MalaCards; HTRA2; -. DR MIM; 168600; phenotype. DR MIM; 606441; gene. DR MIM; 610297; phenotype. DR MIM; 617248; phenotype. DR OpenTargets; ENSG00000115317; -. DR Orphanet; 505208; 3-methylglutaconic aciduria type 8. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000115317; -. DR eggNOG; KOG1320; Eukaryota. DR GeneTree; ENSGT00940000155108; -. DR HOGENOM; CLU_020120_6_0_1; -. DR InParanoid; O43464; -. DR OMA; MDNYRDE; -. DR OrthoDB; 4217619at2759; -. DR PAN-GO; O43464; 5 GO annotations based on evolutionary models. DR PhylomeDB; O43464; -. DR BRENDA; 3.4.21.108; 2681. DR PathwayCommons; O43464; -. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9841251; Mitochondrial unfolded protein response (UPRmt). DR SignaLink; O43464; -. DR SIGNOR; O43464; -. DR Agora; ENSG00000115317; -. DR BioGRID-ORCS; 27429; 97 hits in 1167 CRISPR screens. DR ChiTaRS; HTRA2; human. DR EvolutionaryTrace; O43464; -. DR GeneWiki; HtrA_serine_peptidase_2; -. DR GenomeRNAi; 27429; -. DR Pharos; O43464; Tbio. DR PRO; PR:O43464; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O43464; protein. DR Bgee; ENSG00000115317; Expressed in cortical plate and 199 other cell types or tissues. DR ExpressionAtlas; O43464; baseline and differential. DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; NAS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:MGI. DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:1905370; C:serine-type endopeptidase complex; IMP:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:CAFA. DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB. DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB. DR GO; GO:1990948; F:ubiquitin ligase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IDA:UniProtKB. DR GO; GO:0035458; P:cellular response to interferon-beta; IDA:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0071300; P:cellular response to retinoic acid; IDA:ParkinsonsUK-UCL. DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl. DR GO; GO:0097194; P:execution phase of apoptosis; TAS:UniProtKB. DR GO; GO:0030900; P:forebrain development; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:ParkinsonsUK-UCL. DR GO; GO:0035694; P:mitochondrial protein catabolic process; TAS:Reactome. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0045786; P:negative regulation of cell cycle; TAS:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:1905090; P:negative regulation of type 2 mitophagy; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0019742; P:pentacyclic triterpenoid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IDA:ParkinsonsUK-UCL. DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL. DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central. DR GO; GO:0016540; P:protein autoprocessing; TAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl. DR CDD; cd06785; cpPDZ_HtrA-like; 1. DR DisProt; DP00315; -. DR FunFam; 2.40.10.120:FF:000004; Serine protease HTRA2, mitochondrial; 1. DR FunFam; 2.30.42.10:FF:000145; serine protease HTRA2, mitochondrial; 1. DR Gene3D; 2.30.42.10; -; 1. DR Gene3D; 2.40.10.120; -; 1. DR InterPro; IPR001478; PDZ. DR InterPro; IPR041489; PDZ_6. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR001940; Peptidase_S1C. DR PANTHER; PTHR22939; SERINE PROTEASE FAMILY S1C HTRA-RELATED; 1. DR PANTHER; PTHR22939:SF127; SERINE PROTEASE HTRA2, MITOCHONDRIAL; 1. DR Pfam; PF17820; PDZ_6; 1. DR Pfam; PF13365; Trypsin_2; 1. DR PRINTS; PR00834; PROTEASES2C. DR SMART; SM00228; PDZ; 1. DR SUPFAM; SSF50156; PDZ domain-like; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS50106; PDZ; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Epilepsy; Hydrolase; Membrane; Mitochondrion; Neurodegeneration; KW Parkinson disease; Parkinsonism; Protease; Proteomics identification; KW Reference proteome; Serine protease; Transit peptide; Transmembrane; KW Transmembrane helix; Ubl conjugation; Zymogen. FT TRANSIT 1..31 FT /note="Mitochondrion" FT PROPEP 32..133 FT /evidence="ECO:0000269|PubMed:11583623" FT /id="PRO_0000026945" FT CHAIN 134..458 FT /note="Serine protease HTRA2, mitochondrial" FT /id="PRO_0000026946" FT TRANSMEM 105..125 FT /note="Helical" FT /evidence="ECO:0000255" FT DOMAIN 364..445 FT /note="PDZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT REGION 166..342 FT /note="Serine protease" FT MOTIF 134..137 FT /note="IAP-binding motif" FT ACT_SITE 198 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 228 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 306 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT VAR_SEQ 238..302 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10995577" FT /id="VSP_005359" FT VAR_SEQ 313 FT /note="L -> LARELGAVSLQ (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005360" FT VAR_SEQ 314..458 FT /note="DGEVIGVNTMKVTAGISFAIPSDRLREFLHRGEKKNSSSGISGSQRRYIGVM FT MLTLSPSILAELQLREPSFPDVQHGVLIHKVILGSPAHRAGLRPGDVILAIGEQMVQNA FT EDVYEAVRTQSQLAVQIRRGRETLTLYVTPEVTE -> VSETSFLPRIPAPGQCGKGRF FT PLIQGCLVKFLSSSLLAISQYPTRSPQHLLVLLFGCPHPLLFV (in isoform 4)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005362" FT VAR_SEQ 372..403 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580, FT ECO:0000303|PubMed:10995577" FT /id="VSP_005361" FT VARIANT 12 FT /note="W -> C (in dbSNP:rs775840965)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076967" FT VARIANT 72 FT /note="L -> P (in dbSNP:rs150047108)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046134" FT VARIANT 128 FT /note="P -> L (in dbSNP:rs757704467)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076968" FT VARIANT 141 FT /note="A -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470544)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:18401856" FT /id="VAR_027349" FT VARIANT 227 FT /note="A -> S (in dbSNP:rs375322953)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076969" FT VARIANT 243..244 FT /note="LP -> PS (in MGCA8; loss of protein expression; FT dbSNP:rs1057519082)" FT /evidence="ECO:0000269|PubMed:27696117" FT /id="VAR_077960" FT VARIANT 399 FT /note="G -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470545)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:25422467, FT ECO:0000269|PubMed:27535533" FT /id="VAR_027350" FT VARIANT 404 FT /note="R -> Q (in MGCA8; may lead to skipping of exon 7 and FT the resultant protein may be truncated; loss of protein FT expression in patient cells homozygous for the mutation; FT dbSNP:rs767006508)" FT /evidence="ECO:0000269|PubMed:27208207" FT /id="VAR_077961" FT VARIANT 404 FT /note="R -> W (in PARK13; dbSNP:rs1380794702)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046135" FT MUTAGEN 134 FT /note="A->M: Loss of interaction with XIAP. Loss of FT inhibition of XIAP activity." FT /evidence="ECO:0000269|PubMed:11583623" FT MUTAGEN 306 FT /note="S->A: Loss of protease activity." FT /evidence="ECO:0000269|PubMed:10644717" FT HELIX 143..147 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 149..157 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 158..160 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 161..170 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 171..174 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 175..188 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 192..195 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 198..200 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 204..209 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 211..213 FT /evidence="ECO:0007829|PDB:5TO0" FT STRAND 215..224 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 225..228 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 229..233 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 256..259 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 265..268 FT /evidence="ECO:0007829|PDB:5FHT" FT STRAND 271..275 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 295..299 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 303..307 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 308..311 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 317..326 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 329..334 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 335..342 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 359..361 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 364..368 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 371..380 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:5WYN" FT STRAND 391..396 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 401..405 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 412..416 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 424..433 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 435..443 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 446..452 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 455..457 FT /evidence="ECO:0007829|PDB:5M3N" SQ SEQUENCE 458 AA; 48841 MW; CEA955A7D0DD8C0D CRC64; MAAPRAGRGA GWSLRAWRAL GGIRWGRRPR LTPDLRALLT SGTSDPRARV TYGTPSLWAR LSVGVTEPRA CLTSGTPGPR AQLTAVTPDT RTREASENSG TRSRAWLAVA LGAGGAVLLL LWGGGRGPPA VLAAVPSPPP ASPRSQYNFI ADVVEKTAPA VVYIEILDRH PFLGREVPIS NGSGFVVAAD GLIVTNAHVV ADRRRVRVRL LSGDTYEAVV TAVDPVADIA TLRIQTKEPL PTLPLGRSAD VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQT NVEYIQTDAA IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS SSGISGSQRR YIGVMMLTLS PSILAELQLR EPSFPDVQHG VLIHKVILGS PAHRAGLRPG DVILAIGEQM VQNAEDVYEA VRTQSQLAVQ IRRGRETLTL YVTPEVTE // ID PLPL9_HUMAN Reviewed; 806 AA. AC O60733; A8K597; B0QYE8; O75645; Q8N452; Q9UG29; Q9UIT0; Q9Y671; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2000, sequence version 2. DT 28-JAN-2026, entry version 228. DE RecName: Full=85/88 kDa calcium-independent phospholipase A2; DE Short=CaI-PLA2; DE EC=3.1.1.4 {ECO:0000269|PubMed:20886109}; DE AltName: Full=2-lysophosphatidylcholine acylhydrolase; DE EC=3.1.1.5 {ECO:0000269|PubMed:20886109}; DE AltName: Full=Group VI phospholipase A2; DE Short=GVI PLA2; DE AltName: Full=Intracellular membrane-associated calcium-independent phospholipase A2 beta; DE Short=iPLA2-beta; DE AltName: Full=Palmitoyl-CoA hydrolase; DE EC=3.1.2.2 {ECO:0000269|PubMed:20886109}; DE AltName: Full=Patatin-like phospholipase domain-containing protein 9; DE Short=PNPLA9; GN Name=PLA2G6; Synonyms=PLPLA9; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LH-IPLA2; ANKYRIN-IPLA2-1 AND RP ANKYRIN-IPLA2-2), AND FUNCTION. RC TISSUE=B-cell, and Testis; RX PubMed=9417066; DOI=10.1074/jbc.273.1.207; RA Larsson P.K.A., Claesson H.-E., Kennedy B.P.; RT "Multiple splice variants of the human calcium-independent phospholipase A2 RT and their effect on enzyme activity."; RL J. Biol. Chem. 273:207-214(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS LH-IPLA2 AND SH-IPLA2), RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RC TISSUE=Pancreatic islet; RX PubMed=10092647; DOI=10.1074/jbc.274.14.9607; RA Ma Z., Wang X., Nowatzke W., Ramanadham S., Turk J.; RT "Human pancreatic islets express mRNA species encoding two distinct RT catalytically active isoforms of group VI phospholipase A2 (iPLA2) that RT arise from an exon-skipping mechanism of alternative splicing of the RT transcript from the iPLA2 gene on chromosome 22q13.1."; RL J. Biol. Chem. 274:9607-9616(1999). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND FUNCTION. RX PubMed=10336645; DOI=10.1046/j.1432-1327.1999.00418.x; RA Larsson Forsell P.K.A., Kennedy B.P., Claesson H.-E.; RT "The human calcium-independent phospholipase A2 gene. Multiple enzymes with RT distinct properties from a single gene."; RL Eur. J. Biochem. 262:575-585(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LH-IPLA2). RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LH-IPLA2). RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84; RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A., RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J., RA Beare D.M., Dunham I.; RT "A genome annotation-driven approach to cloning the human ORFeome."; RL Genome Biol. 5:R84.1-R84.11(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-58; GLY-63; GLN-70; RP ASN-183 AND THR-343. RG NIEHS SNPs program; RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LH-IPLA2). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10591208; DOI=10.1038/990031; RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M., RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C., RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E., RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C., RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G., RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V., RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E., RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F., RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M., RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A., RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D., RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S., RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E., RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A., RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L., RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P., RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P., RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q., RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J., RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J., RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D., RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T., RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L., RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J., RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E., RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P., RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y., RA Wright H.; RT "The DNA sequence of human chromosome 22."; RL Nature 402:489-495(1999). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LH-IPLA2 AND SH-IPLA2). 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 [11] RP FUNCTION IN CHEMOTAXIS, AND SUBCELLULAR LOCATION. RX PubMed=18208975; DOI=10.1084/jem.20071243; RA Mishra R.S., Carnevale K.A., Cathcart M.K.; RT "iPLA2beta: front and center in human monocyte chemotaxis to MCP-1."; RL J. Exp. Med. 205:347-359(2008). RN [12] RP REVIEW ON FAMILY. RX PubMed=19029121; DOI=10.1194/jlr.r800082-jlr200; RA Kienesberger P.C., Oberer M., Lass A., Zechner R.; RT "Mammalian patatin domain containing proteins: a family with diverse RT lipolytic activities involved in multiple biological functions."; RL J. Lipid Res. 50:S63-S68(2009). RN [13] RP FUNCTION, AND PHARMACEUTICAL USE. RX PubMed=19164547; DOI=10.1073/pnas.0811224106; RA Malhotra A., Edelman-Novemsky I., Xu Y., Plesken H., Ma J., Schlame M., RA Ren M.; RT "Role of calcium-independent phospholipase A2 in the pathogenesis of Barth RT syndrome."; RL Proc. Natl. Acad. Sci. U.S.A. 106:2337-2341(2009). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS THR-341; CYS-517; TRP-632; ARG-638; RP VAL-691 DEL; GLN-741; TRP-741; TRP-747 AND 790-TYR--PRO-806 DEL, AND RP MUTAGENESIS OF SER-519. RX PubMed=20886109; DOI=10.1371/journal.pone.0012897; RA Engel L.A., Jing Z., O'Brien D.E., Sun M., Kotzbauer P.T.; RT "Catalytic function of PLA2G6 is impaired by mutations associated with RT infantile neuroaxonal dystrophy but not dystonia-parkinsonism."; RL PLoS ONE 5:e12897-e12897(2010). RN [15] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=23533611; DOI=10.1371/journal.pone.0059267; RA Hsu Y.H., Dumlao D.S., Cao J., Dennis E.A.; RT "Assessing phospholipase A2 activity toward cardiolipin by mass RT spectrometry."; RL PLoS ONE 8:E59267-E59267(2013). RN [16] RP ERRATUM OF PUBMED:23533611. RX DOI=10.1371/annotation/47607b18-ed69-4a08-8619-60c39bd83a13; RA Hsu Y.H., Dumlao D.S., Cao J., Dennis E.A.; RL PLoS ONE 8:59267-59267(2013). RN [17] RP VARIANT NBIA2A VAL-691 DEL. RX PubMed=17033970; DOI=10.1086/508572; RA Khateeb S., Flusser H., Ofir R., Shelef I., Narkis G., Vardi G., Shorer Z., RA Levy R., Galil A., Elbedour K., Birk O.S.; RT "PLA2G6 mutation underlies infantile neuroaxonal dystrophy."; RL Am. J. Hum. Genet. 79:942-948(2006). RN [18] RP VARIANTS NBIA2B THR-545; TRP-632 AND VAL-691 DEL, AND VARIANTS NBIA2A RP GLU-310; THR-341; CYS-517; ARG-638; TRP-741 AND 790-TYR--PRO-806 DEL. RX PubMed=16783378; DOI=10.1038/ng1826; RA Morgan N.V., Westaway S.K., Morton J.E., Gregory A., Gissen P., Sonek S., RA Cangul H., Coryell J., Canham N., Nardocci N., Zorzi G., Pasha S., RA Rodriguez D., Desguerre I., Mubaidin A., Bertini E., Trembath R.C., RA Simonati A., Schanen C., Johnson C.A., Levinson B., Woods C.G., Wilmot B., RA Kramer P., Gitschier J., Maher E.R., Hayflick S.J.; RT "PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative RT disorders with high brain iron."; RL Nat. Genet. 38:752-754(2006). RN [19] RP ERRATUM OF PUBMED:16783378. RA Morgan N.V., Westaway S.K., Morton J.E., Gregory A., Gissen P., Sonek S., RA Cangul H., Coryell J., Canham N., Nardocci N., Zorzi G., Pasha S., RA Rodriguez D., Desguerre I., Mubaidin A., Bertini E., Trembath R.C., RA Simonati A., Schanen C., Johnson C.A., Levinson B., Woods C.G., Wilmot B., RA Kramer P., Gitschier J., Maher E.R., Hayflick S.J.; RL Nat. Genet. 38:957-957(2006). RN [20] RP VARIANTS PARK14 GLN-741 AND TRP-747. RX PubMed=18570303; DOI=10.1002/ana.21415; RA Paisan-Ruiz C., Bhatia K.P., Li A., Hernandez D., Davis M., Wood N.W., RA Hardy J., Houlden H., Singleton A., Schneider S.A.; RT "Characterization of PLA2G6 as a locus for dystonia-parkinsonism."; RL Ann. Neurol. 65:19-23(2009). RN [21] RP VARIANTS NBIA2A GLY-484 AND MET-661. RX PubMed=23749988; DOI=10.1136/jmedgenet-2013-101634; RA Koeroglu C., Seven M., Tolun A.; RT "Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy RT with facial dysmorphism."; RL J. Med. Genet. 50:515-520(2013). RN [22] RP VARIANT TRP-550. RX PubMed=28887846; DOI=10.1002/humu.23335; RA Zhou X.L., He L.X., Yu L.J., Wang Y., Wang X.J., Wang E.D., Yang T.; RT "Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: RT Potential pathogenic mechanism."; RL Hum. Mutat. 38:1740-1750(2017). RN [23] RP VARIANT NBIA2A ASN-366. RX PubMed=39796207; DOI=10.3390/ijms26010352; RA Cheema A.N., Shi R., Kamboh M.I.; RT "Association of Novel Pathogenic Variant (p. Ile366Asn) in PLA2G6 Gene with RT Infantile Neuroaxonal Dystrophy."; RL Int. J. Mol. Sci. 26:0-0(2025). CC -!- FUNCTION: Calcium-independent phospholipase involved in phospholipid CC remodeling with implications in cellular membrane homeostasis, CC mitochondrial integrity and signal transduction. Hydrolyzes the ester CC bond of the fatty acyl group attached at sn-1 or sn-2 position of CC phospholipids (phospholipase A1 and A2 activity respectively), CC producing lysophospholipids that are used in deacylation-reacylation CC cycles (PubMed:10092647, PubMed:10336645, PubMed:20886109, CC PubMed:9417066). Hydrolyzes both saturated and unsaturated long fatty CC acyl chains in various glycerophospholipid classes such as CC phosphatidylcholines, phosphatidylethanolamines and phosphatidates, CC with a preference for hydrolysis at sn-2 position (PubMed:10092647, CC PubMed:10336645, PubMed:20886109). Can further hydrolyze CC lysophospholipids carrying saturated fatty acyl chains CC (lysophospholipase activity) (PubMed:20886109). Upon oxidative stress, CC contributes to remodeling of mitochondrial phospholipids in pancreatic CC beta cells, in a repair mechanism to reduce oxidized lipid content CC (PubMed:23533611). Preferentially hydrolyzes oxidized polyunsaturated CC fatty acyl chains from cardiolipins, yielding monolysocardiolipins that CC can be reacylated with unoxidized fatty acyls to regenerate native CC cardiolipin species (By similarity). Hydrolyzes oxidized CC glycerophosphoethanolamines present in pancreatic islets, releasing CC oxidized polyunsaturated fatty acids such as hydroxyeicosatetraenoates CC (HETEs) (By similarity). Has thioesterase activity toward fatty-acyl CC CoA releasing CoA-SH known to facilitate fatty acid transport and beta- CC oxidation in mitochondria particularly in skeletal muscle CC (PubMed:20886109). Plays a role in regulation of membrane dynamics and CC homeostasis. Selectively hydrolyzes sn-2 arachidonoyl group in CC plasmalogen phospholipids, structural components of lipid rafts and CC myelin (By similarity). Regulates F-actin polymerization at the CC pseudopods, which is required for both speed and directionality of CC MCP1/CCL2-induced monocyte chemotaxis (PubMed:18208975). Targets CC membrane phospholipids to produce potent lipid signaling messengers. CC Generates lysophosphatidate (LPA, 1-acyl-glycerol-3-phosphate), which CC acts via G-protein receptors in various cell types (By similarity). Has CC phospholipase A2 activity toward platelet-activating factor (PAF, 1-O- CC alkyl-2-acetyl-sn-glycero-3-phosphocholine), likely playing a role in CC inactivation of this potent pro-inflammatory signaling lipid (By CC similarity). In response to glucose, amplifies calcium influx in CC pancreatic beta cells to promote INS secretion (By similarity). CC {ECO:0000250|UniProtKB:A0A3L7I2I8, ECO:0000250|UniProtKB:P97570, CC ECO:0000250|UniProtKB:P97819, ECO:0000269|PubMed:10092647, CC ECO:0000269|PubMed:10336645, ECO:0000269|PubMed:18208975, CC ECO:0000269|PubMed:20886109, ECO:0000269|PubMed:23533611, CC ECO:0000269|PubMed:9417066}. CC -!- FUNCTION: [Isoform Ankyrin-iPLA2-1]: Lacks the catalytic domain and may CC act as a negative regulator of the catalytically active isoforms. CC {ECO:0000269|PubMed:9417066}. CC -!- FUNCTION: [Isoform Ankyrin-iPLA2-2]: Lacks the catalytic domain and may CC act as a negative regulator of the catalytically active isoforms. CC {ECO:0000269|PubMed:9417066}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn- CC glycero-3-phosphocholine + a fatty acid + H(+); Xref=Rhea:RHEA:15801, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:28868, CC ChEBI:CHEBI:57643, ChEBI:CHEBI:58168; EC=3.1.1.4; CC Evidence={ECO:0000269|PubMed:20886109}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15802; CC Evidence={ECO:0000305|PubMed:20886109}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine + H2O = a 1-O- CC alkyl-sn-glycero-3-phosphocholine + a fatty acid + H(+); CC Xref=Rhea:RHEA:36231, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:28868, ChEBI:CHEBI:30909, ChEBI:CHEBI:36702; EC=3.1.1.4; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36232; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1- CC hexadecanoyl-sn-glycero-3-phosphocholine + hexadecanoate + H(+); CC Xref=Rhea:RHEA:41223, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:72998, ChEBI:CHEBI:72999; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41224; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine CC + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (9Z)- CC octadecenoate + H(+); Xref=Rhea:RHEA:38779, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:72998, CC ChEBI:CHEBI:73001; Evidence={ECO:0000269|PubMed:20886109}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38780; CC Evidence={ECO:0000305|PubMed:20886109}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3- CC phosphocholine + H2O = (9Z,12Z)-octadecadienoate + 1-hexadecanoyl-sn- CC glycero-3-phosphocholine + H(+); Xref=Rhea:RHEA:40811, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30245, CC ChEBI:CHEBI:72998, ChEBI:CHEBI:73002; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8, CC ECO:0000250|UniProtKB:P97819}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40812; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8, CC ECO:0000250|UniProtKB:P97819}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero- CC 3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + CC (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+); Xref=Rhea:RHEA:40427, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:32395, CC ChEBI:CHEBI:72998, ChEBI:CHEBI:73003; CC Evidence={ECO:0000269|PubMed:10092647, ECO:0000269|PubMed:23533611}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40428; CC Evidence={ECO:0000305|PubMed:10092647, ECO:0000305|PubMed:23533611}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero- CC 3-phosphocholine + H2O = 1-octadecanoyl-sn-glycero-3-phosphocholine + CC (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+); Xref=Rhea:RHEA:40519, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:32395, CC ChEBI:CHEBI:73858, ChEBI:CHEBI:74965; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40520; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero- CC 3-phosphoethanolamine + H2O = 1-hexadecanoyl-sn-glycero-3- CC phosphoethanolamine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+); CC Xref=Rhea:RHEA:40431, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:32395, ChEBI:CHEBI:73004, ChEBI:CHEBI:73009; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8, CC ECO:0000250|UniProtKB:P97819}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40432; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8, CC ECO:0000250|UniProtKB:P97819}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphate + H2O = 1- CC hexadecanoyl-sn-glycero-3-phosphate + hexadecanoate + H(+); CC Xref=Rhea:RHEA:63304, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57518, ChEBI:CHEBI:72859; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63305; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1-acyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3- CC phosphocholine + a fatty acid + H(+); Xref=Rhea:RHEA:15177, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16870, CC ChEBI:CHEBI:28868, ChEBI:CHEBI:58168; EC=3.1.1.5; CC Evidence={ECO:0000269|PubMed:20886109}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15178; CC Evidence={ECO:0000305|PubMed:20886109}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol CC 3-phosphocholine + hexadecanoate + H(+); Xref=Rhea:RHEA:40435, CC ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16870, ChEBI:CHEBI:72998; CC Evidence={ECO:0000269|PubMed:20886109}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40436; CC Evidence={ECO:0000305|PubMed:20886109}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine CC + H2O = sn-glycerol 3-phosphocholine + (5Z,8Z,11Z,14Z)- CC eicosatetraenoate + H(+); Xref=Rhea:RHEA:40831, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16870, ChEBI:CHEBI:32395, CC ChEBI:CHEBI:74344; Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40832; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphocholine CC + H2O = sn-glycerol 3-phosphocholine + (5Z,8Z,11Z,14Z)- CC eicosatetraenoate + H(+); Xref=Rhea:RHEA:40827, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16870, ChEBI:CHEBI:32395, CC ChEBI:CHEBI:76079; Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40828; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-O-hexadecyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3- CC phosphocholine + H2O = 1-O-hexadecyl-sn-glycero-3-phosphocholine + CC (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+); Xref=Rhea:RHEA:41067, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:32395, CC ChEBI:CHEBI:55430, ChEBI:CHEBI:64496; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41068; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine + H2O = 1- CC O-hexadecyl-sn-glycero-3-phosphocholine + acetate + H(+); CC Xref=Rhea:RHEA:40479, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30089, ChEBI:CHEBI:44811, ChEBI:CHEBI:64496; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40480; CC Evidence={ECO:0000250|UniProtKB:A0A3L7I2I8}; CC -!- CATALYTIC ACTIVITY: CC Reaction=hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+); CC Xref=Rhea:RHEA:16645, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379; EC=3.1.2.2; CC Evidence={ECO:0000269|PubMed:20886109}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16646; CC Evidence={ECO:0000305|PubMed:20886109}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1',3'-bis[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]- CC glycerol + H2O = 1'-[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]- CC 3'-[1-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + (9Z)- CC octadecenoate + H(+); Xref=Rhea:RHEA:40463, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:77253, CC ChEBI:CHEBI:77259; Evidence={ECO:0000269|PubMed:23533611}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40464; CC Evidence={ECO:0000305|PubMed:23533611}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1'-[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]-3'-[1-(9Z- CC octadecenoyl)-sn-glycero-3-phospho]-glycerol + H2O = 1',3'-bis-[1- CC (9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + (9Z)-octadecenoate CC + H(+); Xref=Rhea:RHEA:40467, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30823, ChEBI:CHEBI:77256, ChEBI:CHEBI:77259; CC Evidence={ECO:0000269|PubMed:23533611}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40468; CC Evidence={ECO:0000305|PubMed:23533611}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1',3'-bis-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3- CC phospho]-glycerol + H2O = 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn- CC glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-sn-glycero-3- CC phospho]-glycerol + (9Z,12Z)-octadecadienoate + H(+); CC Xref=Rhea:RHEA:52812, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30245, ChEBI:CHEBI:83580, ChEBI:CHEBI:83581; CC Evidence={ECO:0000250|UniProtKB:P97819}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:52814; CC Evidence={ECO:0000250|UniProtKB:P97819}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-octadecanoyl-2-(15-hydroxy-(5Z,8Z,11Z,13E)- CC eicosatetraenoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1- CC octadecanoyl-sn-glycero-3-phosphoethanolamine + 15-hydroxy- CC (5Z,8Z,11Z,13E)-eicosatetraenoate + H(+); Xref=Rhea:RHEA:63256, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:75036, CC ChEBI:CHEBI:78832, ChEBI:CHEBI:146277; CC Evidence={ECO:0000250|UniProtKB:P97570}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63257; CC Evidence={ECO:0000250|UniProtKB:P97570}; CC -!- ACTIVITY REGULATION: Activated by ATP (PubMed:10092647). Inhibited by CC calcium-activated calmodulin (By similarity). Inhibited by bromoenol CC lactone (BEL) (By similarity). {ECO:0000250|UniProtKB:P97570, CC ECO:0000269|PubMed:10092647}. CC -!- SUBUNIT: Homodimer formed by catalytic domains tightly interacting CC through a large hydrophobic interface. The contact area involves 3 CC alpha helices, several loops and a part of the beta sheet from each CC monomer. Both active sites of the dimer are in close proximity adopting CC an open conformation that provide sufficient space for phospholipid CC access and favoring cooperativity in deacylation-reacylation reactions. CC Each monomer has 9 ankyrin repeats stacked side-by-side in an elongated CC structure oriented outwards from the catalytic core. CC {ECO:0000250|UniProtKB:A0A3L7I2I8}. CC -!- INTERACTION: CC O60733; Q8TAP6: CEP76; NbExp=3; IntAct=EBI-12089905, EBI-742887; CC O60733; Q9NZL9: MAT2B; NbExp=3; IntAct=EBI-12089905, EBI-10317491; CC O60733; Q8N1F7: NUP93; NbExp=3; IntAct=EBI-12089905, EBI-1042703; CC O60733; O60733: PLA2G6; NbExp=3; IntAct=EBI-12089905, EBI-12089905; CC O60733; O95199: RCBTB2; NbExp=3; IntAct=EBI-12089905, EBI-742404; CC O60733; Q9BVN2: RUSC1; NbExp=3; IntAct=EBI-12089905, EBI-6257312; CC O60733; Q14140: SERTAD2; NbExp=3; IntAct=EBI-12089905, EBI-2822051; CC O60733; Q86XT4: TRIM50; NbExp=3; IntAct=EBI-12089905, EBI-9867283; CC O60733; Q70EL1-9: USP54; NbExp=3; IntAct=EBI-12089905, EBI-11975223; CC O60733; B2RXF5: ZBTB42; NbExp=3; IntAct=EBI-12089905, EBI-12287587; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18208975}. Cell CC membrane {ECO:0000269|PubMed:18208975}. Mitochondrion CC {ECO:0000250|UniProtKB:P97819}. Cell projection, pseudopodium CC {ECO:0000269|PubMed:18208975}. Note=Recruited to the membrane-enriched CC pseudopods upon MCP1/CCL2 stimulation in monocytes. CC {ECO:0000269|PubMed:18208975}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=LH-iPLA2; CC IsoId=O60733-1; Sequence=Displayed; CC Name=SH-iPLA2; CC IsoId=O60733-2; Sequence=VSP_000278; CC Name=Ankyrin-iPLA2-1; CC IsoId=O60733-3; Sequence=VSP_000281, VSP_000282; CC Name=Ankyrin-iPLA2-2; CC IsoId=O60733-4; Sequence=VSP_000277, VSP_000279, VSP_000280; CC -!- TISSUE SPECIFICITY: Four different transcripts were found to be CC expressed in a distinct tissue distribution. CC -!- DOMAIN: Has two putative calmodulin binding domains, the 1-9-14 and IQ CC motifs. One calmodulin molecule interacts with PLA2G6 dimer, likely CC through 1-9-14 motif on each monomer (By similarity). Binds calmodulin CC in a calcium-dependent way (By similarity). CC {ECO:0000250|UniProtKB:A0A3L7I2I8, ECO:0000250|UniProtKB:P97570}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 2B (NBIA2B) CC [MIM:610217]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. It is CC characterized by progressive extrapyramidal dysfunction leading to CC rigidity, dystonia, dysarthria and sensorimotor impairment. CC {ECO:0000269|PubMed:16783378}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 2A (NBIA2A) CC [MIM:256600]: A neurodegenerative disease characterized by pathologic CC axonal swelling and spheroid bodies in the central nervous system. CC Onset is within the first 2 years of life with death by age 10 years. CC {ECO:0000269|PubMed:16783378, ECO:0000269|PubMed:17033970, CC ECO:0000269|PubMed:23749988, ECO:0000269|PubMed:39796207}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 14 (PARK14) [MIM:612953]: An adult-onset CC progressive neurodegenerative disorder characterized by parkinsonism, CC dystonia, severe cognitive decline, cerebral and cerebellar atrophy and CC absent iron in the basal ganglia on magnetic resonance imaging. CC {ECO:0000269|PubMed:18570303}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- PHARMACEUTICAL: Potential target for therapeutic intervention of Barth CC syndrome. 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; AF064594; AAC97486.1; -; mRNA. DR EMBL; AF102988; AAD41722.1; -; mRNA. DR EMBL; AF102989; AAD41723.1; -; mRNA. DR EMBL; AF117692; AAD30424.1; -; Genomic_DNA. DR EMBL; AF117677; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117678; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117679; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117680; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117681; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117682; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117683; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117684; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117685; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117686; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117687; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117688; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117689; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117690; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF117691; AAD30424.1; JOINED; Genomic_DNA. DR EMBL; AF116267; AAF34728.1; -; Genomic_DNA. DR EMBL; AF116252; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116253; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116254; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116255; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116256; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116257; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116258; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116259; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116260; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116261; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116262; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116263; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116264; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116265; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AF116266; AAF34728.1; JOINED; Genomic_DNA. DR EMBL; AL080187; CAB45768.2; -; mRNA. DR EMBL; CR456543; CAG30429.1; -; mRNA. DR EMBL; AY522921; AAR92478.1; -; Genomic_DNA. DR EMBL; AK291212; BAF83901.1; -; mRNA. DR EMBL; AL022322; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471095; EAW60219.1; -; Genomic_DNA. DR EMBL; CH471095; EAW60220.1; -; Genomic_DNA. DR EMBL; BC036742; AAH36742.2; -; mRNA. DR EMBL; BC051904; AAH51904.1; -; mRNA. DR CCDS; CCDS13967.1; -. [O60733-1] DR CCDS; CCDS33645.1; -. [O60733-2] DR RefSeq; NP_001004426.1; NM_001004426.3. [O60733-2] DR RefSeq; NP_001186491.1; NM_001199562.3. [O60733-2] DR RefSeq; NP_001336793.1; NM_001349864.2. [O60733-1] DR RefSeq; NP_001336794.1; NM_001349865.2. [O60733-2] DR RefSeq; NP_001336795.1; NM_001349866.2. [O60733-2] DR RefSeq; NP_003551.2; NM_003560.2. [O60733-1] DR AlphaFoldDB; O60733; -. DR SMR; O60733; -. DR BioGRID; 113986; 31. DR FunCoup; O60733; 1469. DR IntAct; O60733; 15. DR MINT; O60733; -. DR STRING; 9606.ENSP00000333142; -. DR BindingDB; O60733; -. DR ChEMBL; CHEMBL3213; -. DR DrugBank; DB01103; Quinacrine. DR SwissLipids; SLP:000000618; -. DR iPTMnet; O60733; -. DR PhosphoSitePlus; O60733; -. DR BioMuta; PLA2G6; -. DR jPOST; O60733; -. DR MassIVE; O60733; -. DR PaxDb; 9606-ENSP00000333142; -. DR PeptideAtlas; O60733; -. DR ProteomicsDB; 49578; -. [O60733-1] DR ProteomicsDB; 49579; -. [O60733-2] DR ProteomicsDB; 49580; -. [O60733-3] DR ProteomicsDB; 49581; -. [O60733-4] DR Antibodypedia; 225; 244 antibodies from 32 providers. DR DNASU; 8398; -. DR Ensembl; ENST00000332509.8; ENSP00000333142.3; ENSG00000184381.21. [O60733-1] DR Ensembl; ENST00000335539.7; ENSP00000335149.3; ENSG00000184381.21. [O60733-2] DR Ensembl; ENST00000402064.5; ENSP00000386100.1; ENSG00000184381.21. [O60733-2] DR Ensembl; ENST00000660610.1; ENSP00000499555.1; ENSG00000184381.21. [O60733-1] DR Ensembl; ENST00000663895.1; ENSP00000499712.1; ENSG00000184381.21. [O60733-1] DR Ensembl; ENST00000667521.1; ENSP00000499665.1; ENSG00000184381.21. [O60733-1] DR GeneID; 8398; -. DR KEGG; hsa:8398; -. DR MANE-Select; ENST00000332509.8; ENSP00000333142.3; NM_003560.4; NP_003551.2. DR UCSC; uc003auy.2; human. [O60733-1] DR AGR; HGNC:9039; -. DR ClinPGx; PA33367; -. DR CTD; 8398; -. DR DisGeNET; 8398; -. DR GeneCards; PLA2G6; -. DR GeneReviews; PLA2G6; -. DR HGNC; HGNC:9039; PLA2G6. DR HPA; ENSG00000184381; Low tissue specificity. DR MalaCards; PLA2G6; -. DR MIM; 256600; phenotype. DR MIM; 603604; gene. DR MIM; 610217; phenotype. DR MIM; 612953; phenotype. DR OpenTargets; ENSG00000184381; -. DR Orphanet; 199351; Adult-onset dystonia-parkinsonism. DR Orphanet; 35069; Infantile neuroaxonal dystrophy. DR VEuPathDB; HostDB:ENSG00000184381; -. DR eggNOG; KOG0513; Eukaryota. DR GeneTree; ENSGT00940000158756; -. DR HOGENOM; CLU_010817_0_0_1; -. DR InParanoid; O60733; -. DR OMA; VVYSHTH; -. DR OrthoDB; 10021675at2759; -. DR PAN-GO; O60733; 5 GO annotations based on evolutionary models. DR PhylomeDB; O60733; -. DR BRENDA; 3.1.1.4; 2681. DR PathwayCommons; O60733; -. DR Reactome; R-HSA-1482788; Acyl chain remodelling of PC. DR Reactome; R-HSA-1482798; Acyl chain remodeling of CL. DR Reactome; R-HSA-1482839; Acyl chain remodelling of PE. DR Reactome; R-HSA-2029485; Role of phospholipids in phagocytosis. DR Reactome; R-HSA-6811436; COPI-independent Golgi-to-ER retrograde traffic. DR SignaLink; O60733; -. DR Agora; ENSG00000184381; -. DR BioGRID-ORCS; 8398; 8 hits in 1163 CRISPR screens. DR ChiTaRS; PLA2G6; human. DR GeneWiki; PLA2G6; -. DR GenomeRNAi; 8398; -. DR Pharos; O60733; Tchem. DR PRO; PR:O60733; -. DR Proteomes; UP000005640; Chromosome 22. DR RNAct; O60733; protein. DR Bgee; ENSG00000184381; Expressed in right uterine tube and 158 other cell types or tissues. DR ExpressionAtlas; O60733; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IDA:FlyBase. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0031143; C:pseudopodium; IEA:UniProtKB-SubCell. DR GO; GO:0003847; F:1-alkyl-2-acetylglycerophosphocholine esterase activity; ISS:UniProtKB. DR GO; GO:0047499; F:calcium-independent phospholipase A2 activity; IDA:UniProtKB. DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW. DR GO; GO:0016787; F:hydrolase activity; TAS:Reactome. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0052816; F:long-chain fatty acyl-CoA hydrolase activity; IDA:UniProtKB. DR GO; GO:0004622; F:phosphatidylcholine lysophospholipase activity; IDA:UniProtKB. DR GO; GO:0004623; F:phospholipase A2 activity; TAS:ProtInc. DR GO; GO:0017171; F:serine hydrolase activity; IEA:Ensembl. DR GO; GO:0019731; P:antibacterial humoral response; IDA:UniProtKB. DR GO; GO:0035965; P:cardiolipin acyl-chain remodeling; IDA:UniProtKB. DR GO; GO:0006935; P:chemotaxis; IEA:UniProtKB-KW. DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome. DR GO; GO:0046473; P:phosphatidic acid metabolic process; ISS:UniProtKB. DR GO; GO:0034638; P:phosphatidylcholine catabolic process; IDA:UniProtKB. DR GO; GO:0046338; P:phosphatidylethanolamine catabolic process; ISS:UniProtKB. DR GO; GO:0046469; P:platelet activating factor metabolic process; ISS:UniProtKB. DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; IBA:GO_Central. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB. DR CDD; cd07212; Pat_PNPLA9; 1. DR FunFam; 1.25.40.20:FF:000338; 85/88 kDa calcium-independent phospholipase A2; 1. DR FunFam; 3.40.1090.10:FF:000006; 85/88 kDa calcium-independent phospholipase A2; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 3.40.1090.10; Cytosolic phospholipase A2 catalytic domain; 1. DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR047148; PLPL9. DR InterPro; IPR002641; PNPLA_dom. DR PANTHER; PTHR24139:SF34; 85_88 KDA CALCIUM-INDEPENDENT PHOSPHOLIPASE A2; 1. DR PANTHER; PTHR24139; CALCIUM-INDEPENDENT PHOSPHOLIPASE A2; 1. DR Pfam; PF00023; Ank; 1. DR Pfam; PF12796; Ank_2; 2. DR Pfam; PF01734; Patatin; 1. DR PRINTS; PR01415; ANKYRIN. DR SMART; SM00248; ANK; 6. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR SUPFAM; SSF52151; FabD/lysophospholipase-like; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 4. DR PROSITE; PS51635; PNPLA; 1. PE 1: Evidence at protein level; KW Alternative splicing; ANK repeat; Calmodulin-binding; Cell membrane; KW Cell projection; Chemotaxis; Cytoplasm; Disease variant; Dystonia; KW Hydrolase; Lipid metabolism; Membrane; Mitochondrion; Neurodegeneration; KW Parkinson disease; Parkinsonism; Pharmaceutical; Phospholipid metabolism; KW Proteomics identification; Reference proteome; Repeat; Transmembrane; KW Transmembrane helix. FT CHAIN 1..806 FT /note="85/88 kDa calcium-independent phospholipase A2" FT /id="PRO_0000067037" FT TRANSMEM 480..500 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 511..531 FT /note="Helical" FT /evidence="ECO:0000255" FT REPEAT 120..147 FT /note="ANK 1" FT /evidence="ECO:0000250|UniProtKB:A0A3L7I2I8" FT REPEAT 151..181 FT /note="ANK 1" FT /evidence="ECO:0000255" FT REPEAT 185..215 FT /note="ANK 2" FT /evidence="ECO:0000255" FT REPEAT 219..248 FT /note="ANK 3" FT /evidence="ECO:0000255" FT REPEAT 251..281 FT /note="ANK 4" FT /evidence="ECO:0000255" FT REPEAT 286..312 FT /note="ANK 5" FT /evidence="ECO:0000255" FT REPEAT 316..345 FT /note="ANK 6" FT /evidence="ECO:0000255" FT REPEAT 349..378 FT /note="ANK 7" FT /evidence="ECO:0000255" FT REPEAT 382..403 FT /note="ANK 9" FT /evidence="ECO:0000250|UniProtKB:A0A3L7I2I8" FT DOMAIN 481..665 FT /note="PNPLA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT REGION 677..686 FT /note="Calmodulin-binding (1-9-14 motif)" FT /evidence="ECO:0000250|UniProtKB:A0A3L7I2I8" FT REGION 748..759 FT /note="Calmodulin-binding (IQ motif)" FT /evidence="ECO:0000250|UniProtKB:A0A3L7I2I8" FT MOTIF 485..490 FT /note="GXGXXG" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT MOTIF 517..521 FT /note="GXSXG" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT MOTIF 652..654 FT /note="DGA/G" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT ACT_SITE 519 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT ACT_SITE 652 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01161" FT VAR_SEQ 71..142 FT /note="Missing (in isoform Ankyrin-iPLA2-2)" FT /evidence="ECO:0000303|PubMed:9417066" FT /id="VSP_000277" FT VAR_SEQ 396..450 FT /note="LVTRKAILTLLRTVGAEYCFPPIHGVPAEQGSAAPHHPFSLERAQPPPISLN FT NLE -> Q (in isoform SH-iPLA2)" FT /evidence="ECO:0000303|PubMed:10092647, FT ECO:0000303|PubMed:15489334" FT /id="VSP_000278" FT VAR_SEQ 450..499 FT /note="ELQDLMHISRARKPAFILGSMRDEKRTHDHLLCLDGGGVKGLIIIQLLIA FT -> GSHPSQAGWWAWGAVSDGTTGSHAHLTGPEASVHPGLHEGREADMQNLSP (in FT isoform Ankyrin-iPLA2-2)" FT /evidence="ECO:0000303|PubMed:9417066" FT /id="VSP_000279" FT VAR_SEQ 477..479 FT /note="HDH -> CRT (in isoform Ankyrin-iPLA2-1)" FT /evidence="ECO:0000303|PubMed:9417066" FT /id="VSP_000281" FT VAR_SEQ 480..806 FT /note="Missing (in isoform Ankyrin-iPLA2-1)" FT /evidence="ECO:0000303|PubMed:9417066" FT /id="VSP_000282" FT VAR_SEQ 500..806 FT /note="Missing (in isoform Ankyrin-iPLA2-2)" FT /evidence="ECO:0000303|PubMed:9417066" FT /id="VSP_000280" FT VARIANT 58 FT /note="V -> I (in dbSNP:rs11570605)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_018961" FT VARIANT 63 FT /note="R -> G (in dbSNP:rs11570606)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_018962" FT VARIANT 70 FT /note="R -> Q (in dbSNP:rs11570607)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_018963" FT VARIANT 183 FT /note="D -> N (in dbSNP:rs11570646)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_018964" FT VARIANT 310 FT /note="V -> E (in NBIA2A; dbSNP:rs121908682)" FT /evidence="ECO:0000269|PubMed:16783378" FT /id="VAR_029371" FT VARIANT 341 FT /note="A -> T (in NBIA2A; complete loss of phospholipase FT and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_083527" FT VARIANT 343 FT /note="A -> T (in dbSNP:rs11570680)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_018965" FT VARIANT 366 FT /note="I -> N (in NBIA2A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:39796207" FT /id="VAR_091088" FT VARIANT 484 FT /note="D -> G (in NBIA2A)" FT /evidence="ECO:0000269|PubMed:23749988" FT /id="VAR_070600" FT VARIANT 517 FT /note="G -> C (in NBIA2A; complete loss of phospholipase FT and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_083528" FT VARIANT 545 FT /note="K -> T (in NBIA2B; dbSNP:rs121908681)" FT /evidence="ECO:0000269|PubMed:16783378" FT /id="VAR_029372" FT VARIANT 550 FT /note="R -> W (in dbSNP:rs1004616610)" FT /evidence="ECO:0000269|PubMed:28887846" FT /id="VAR_079753" FT VARIANT 632 FT /note="R -> W (in NBIA2B; increases phospholipase, FT lysophospholipase and thioesterase activities; FT dbSNP:rs121908683)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_029373" FT VARIANT 638 FT /note="G -> R (in NBIA2A; complete loss of phospholipase FT and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_083529" FT VARIANT 661 FT /note="T -> M (in NBIA2A; dbSNP:rs767689496)" FT /evidence="ECO:0000269|PubMed:23749988" FT /id="VAR_070601" FT VARIANT 691 FT /note="Missing (in NBIA2A and NBIA2B; significantly reduces FT phospholipase and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:17033970, ECO:0000269|PubMed:20886109" FT /id="VAR_029374" FT VARIANT 741 FT /note="R -> Q (in PARK14; has no effect on phospholipase, FT lysophospholipase and thioesterase activities; FT dbSNP:rs121908686)" FT /evidence="ECO:0000269|PubMed:18570303, FT ECO:0000269|PubMed:20886109" FT /id="VAR_062530" FT VARIANT 741 FT /note="R -> W (in NBIA2A; significantly reduces FT phospholipase and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_083530" FT VARIANT 747 FT /note="R -> W (in PARK14; has no effect on phospholipase, FT lysophospholipase and thioesterase activities; FT dbSNP:rs121908687)" FT /evidence="ECO:0000269|PubMed:18570303, FT ECO:0000269|PubMed:20886109" FT /id="VAR_062531" FT VARIANT 774 FT /note="S -> T (in dbSNP:rs34184838)" FT /id="VAR_037903" FT VARIANT 790..806 FT /note="Missing (in NBIA2A; complete loss of phospholipase FT and lysophospholipase activities)" FT /evidence="ECO:0000269|PubMed:16783378, FT ECO:0000269|PubMed:20886109" FT /id="VAR_083531" FT MUTAGEN 519 FT /note="S->A: Abolishes phospholipase and lysophospholipase FT activities." FT /evidence="ECO:0000269|PubMed:20886109" FT CONFLICT 11 FT /note="F -> S (in Ref. 3; AAD30424)" FT /evidence="ECO:0000305" FT CONFLICT 64 FT /note="N -> D (in Ref. 2; AAD41722/AAD41723)" FT /evidence="ECO:0000305" FT CONFLICT 579 FT /note="K -> I (in Ref. 3; AAD30424)" FT /evidence="ECO:0000305" FT CONFLICT 686 FT /note="K -> I (in Ref. 3; AAD30424)" FT /evidence="ECO:0000305" FT CONFLICT 801 FT /note="Q -> H (in Ref. 1; AAC97486)" FT /evidence="ECO:0000305" SQ SEQUENCE 806 AA; 89903 MW; 8E55CD4EB9ACAD8B CRC64; MQFFGRLVNT FSGVTNLFSN PFRVKEVAVA DYTSSDRVRE EGQLILFQNT PNRTWDCVLV NPRNSQSGFR LFQLELEADA LVNFHQYSSQ LLPFYESSPQ VLHTEVLQHL TDLIRNHPSW SVAHLAVELG IRECFHHSRI ISCANCAENE EGCTPLHLAC RKGDGEILVE LVQYCHTQMD VTDYKGETVF HYAVQGDNSQ VLQLLGRNAV AGLNQVNNQG LTPLHLACQL GKQEMVRVLL LCNARCNIMG PNGYPIHSAM KFSQKGCAEM IISMDSSQIH SKDPRYGASP LHWAKNAEMA RMLLKRGCNV NSTSSAGNTA LHVAVMRNRF DCAIVLLTHG ANADARGEHG NTPLHLAMSK DNVEMIKALI VFGAEVDTPN DFGETPTFLA SKIGRLVTRK AILTLLRTVG AEYCFPPIHG VPAEQGSAAP HHPFSLERAQ PPPISLNNLE LQDLMHISRA RKPAFILGSM RDEKRTHDHL LCLDGGGVKG LIIIQLLIAI EKASGVATKD LFDWVAGTST GGILALAILH SKSMAYMRGM YFRMKDEVFR GSRPYESGPL EEFLKREFGE HTKMTDVRKP KVMLTGTLSD RQPAELHLFR NYDAPETVRE PRFNQNVNLR PPAQPSDQLV WRAARSSGAA PTYFRPNGRF LDGGLLANNP TLDAMTEIHE YNQDLIRKGQ ANKVKKLSIV VSLGTGRSPQ VPVTCVDVFR PSNPWELAKT VFGAKELGKM VVDCCTDPDG RAVDRARAWC EMVGIQYFRL NPQLGTDIML DEVSDTVLVN ALWETEVYIY EHREEFQKLI QLLLSP // 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 WIPI4_HUMAN Reviewed; 360 AA. AC Q9Y484; A6NGH5; B7WPI2; Q5MNZ5; Q6IBS7; Q6NT94; Q96H03; DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 187. DE RecName: Full=WD repeat domain phosphoinositide-interacting protein 4; DE Short=WIPI-4; DE AltName: Full=WD repeat-containing protein 45; GN Name=WDR45; Synonyms=WDRX1, WDRXI4, WIPI4; ORFNames=JM5; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Testis; RX PubMed=15602573; DOI=10.1038/sj.onc.1208331; RA Proikas-Cezanne T., Waddell S., Gaugel A., Frickey T., Lupas A., RA Nordheim A.; RT "WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, RT is aberrantly expressed in human cancer and is linked to starvation-induced RT autophagy."; RL Oncogene 23:9314-9325(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Strom T.M., Nyakatura G., Hellebrand H., Drescher B., Rosenthal A., RA Meindl A.; RT "Transcription map in Xp11.23."; RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 69-360 (ISOFORM 2). RC TISSUE=Brain, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP SUBCELLULAR LOCATION. RX PubMed=21802374; DOI=10.1016/j.devcel.2011.06.024; RA Lu Q., Yang P., Huang X., Hu W., Guo B., Wu F., Lin L., Kovacs A.L., Yu L., RA Zhang H.; RT "The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of RT omegasomes to autophagosomes."; RL Dev. Cell 21:343-357(2011). RN [8] RP INVOLVEMENT IN NBIA5, AND FUNCTION. RX PubMed=23435086; DOI=10.1038/ng.2562; RA Saitsu H., Nishimura T., Muramatsu K., Kodera H., Kumada S., Sugai K., RA Kasai-Yoshida E., Sawaura N., Nishida H., Hoshino A., Ryujin F., RA Yoshioka S., Nishiyama K., Kondo Y., Tsurusaki Y., Nakashima M., Miyake N., RA Arakawa H., Kato M., Mizushima N., Matsumoto N.; RT "De novo mutations in the autophagy gene WDR45 cause static encephalopathy RT of childhood with neurodegeneration in adulthood."; RL Nat. Genet. 45:445-449(2013). RN [9] RP INTERACTION WITH ATG2A AND ATG2B. RX PubMed=28820312; DOI=10.1080/15548627.2017.1359381; RA Zheng J.X., Li Y., Ding Y.H., Liu J.J., Zhang M.J., Dong M.Q., Wang H.W., RA Yu L.; RT "Architecture of the ATG2B-WDR45 complex and an aromatic Y/HF motif crucial RT for complex formation."; RL Autophagy 13:1870-1883(2017). RN [10] RP FUNCTION, PHOSPHOINOSITIDES-BINDING, ACTIVITY REGULATION, INTERACTION WITH RP AMPK; ATG2A; NUDC; ULK1; WIPI1 AND WIPI2, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF ASN-15; GLN-16; ASP-17; GLU-55; ARG-109; ARG-111; HIS-112; RP ASP-113; LYS-114 AND 232-ARG-ARG-233. RX PubMed=28561066; DOI=10.1038/ncomms15637; RA Bakula D., Mueller A.J., Zuleger T., Takacs Z., Franz-Wachtel M., RA Thost A.K., Brigger D., Tschan M.P., Frickey T., Robenek H., Macek B., RA Proikas-Cezanne T.; RT "WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling RT circuits in the control of autophagy."; RL Nat. Commun. 8:15637-15637(2017). RN [11] RP FUNCTION. RX PubMed=31271352; DOI=10.7554/elife.45777; RA Maeda S., Otomo C., Otomo T.; RT "The autophagic membrane tether ATG2A transfers lipids between membranes."; RL Elife 8:0-0(2019). RN [12] RP INTERACTION WITH ATG2A. RX PubMed=32483132; DOI=10.1038/s41467-020-16523-y; RA Ren J., Liang R., Wang W., Zhang D., Yu L., Feng W.; RT "Multi-site-mediated entwining of the linear WIR-motif around WIPI beta- RT propellers for autophagy."; RL Nat. Commun. 11:2702-2702(2020). RN [13] RP VARIANT NBIA5 7-ARG--PHE-360 DEL. RX PubMed=25356899; DOI=10.1371/journal.pgen.1004772; RA Hamdan F.F., Srour M., Capo-Chichi J.M., Daoud H., Nassif C., Patry L., RA Massicotte C., Ambalavanan A., Spiegelman D., Diallo O., Henrion E., RA Dionne-Laporte A., Fougerat A., Pshezhetsky A.V., Venkateswaran S., RA Rouleau G.A., Michaud J.L.; RT "De novo mutations in moderate or severe intellectual disability."; RL PLoS Genet. 10:E1004772-E1004772(2014). RN [14] RP VARIANT NBIA5 ASP-208. RX PubMed=25592411; DOI=10.1016/j.jns.2014.12.036; RA Tschentscher A., Dekomien G., Ross S., Cremer K., Kukuk G.M., Epplen J.T., RA Hoffjan S.; RT "Analysis of the C19orf12 and WDR45 genes in patients with RT neurodegeneration with brain iron accumulation."; RL J. Neurol. Sci. 349:105-109(2015). CC -!- FUNCTION: Component of the autophagy machinery that controls the major CC intracellular degradation process by which cytoplasmic materials are CC packaged into autophagosomes and delivered to lysosomes for degradation CC (PubMed:23435086, PubMed:28561066). Binds phosphatidylinositol 3- CC phosphate (PtdIns3P) (PubMed:28561066). Activated by the STK11/AMPK CC signaling pathway upon starvation, WDR45 is involved in autophagosome CC assembly downstream of WIPI2, regulating the size of forming CC autophagosomes (PubMed:28561066). Together with WIPI1, promotes ATG2 CC (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association CC with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes CC (PubMed:31271352). Probably recruited to membranes through its PtdIns3P CC activity (PubMed:28561066). {ECO:0000269|PubMed:23435086, CC ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:31271352}. CC -!- ACTIVITY REGULATION: Activated upon amino-acid starvation. CC {ECO:0000269|PubMed:28561066}. CC -!- SUBUNIT: Interacts with WIPI1 (PubMed:28561066). Interacts with WIPI2 CC (PubMed:28561066). Interacts with ATG2A and ATG2B (PubMed:28561066, CC PubMed:28820312, PubMed:32483132). Interacts with ULK1 CC (PubMed:28561066). May interact with the PRKAA1, PRKAA2, PRKAB1 and CC PRKAG1 subunits of the AMPK kinase (PubMed:28561066). May interact with CC NUDC (PubMed:28561066). {ECO:0000269|PubMed:28561066, CC ECO:0000269|PubMed:28820312, ECO:0000269|PubMed:32483132}. CC -!- SUBCELLULAR LOCATION: Preautophagosomal structure CC {ECO:0000269|PubMed:21802374, ECO:0000269|PubMed:28561066}. Cytoplasm CC {ECO:0000269|PubMed:21802374}. Note=Diffusely localized in the CC cytoplasm under nutrient-rich conditions. Localizes to autophagic CC structures during starvation-induced autophagy. CC {ECO:0000269|PubMed:21802374}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9Y484-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9Y484-2; Sequence=VSP_016976; CC Name=3; CC IsoId=Q9Y484-3; Sequence=VSP_016975; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with high expression in CC skeletal muscle and heart. Weakly expressed in liver and placenta. CC Expression is down-regulated in pancreatic and in kidney tumors. CC {ECO:0000269|PubMed:15602573}. CC -!- DOMAIN: The L/FRRG motif is required for recruitment to PtdIns3P. CC {ECO:0000250|UniProtKB:Q9Y4P8}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 5 (NBIA5) CC [MIM:300894]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. NBIA5 is CC characterized by global developmental delay in early childhood that is CC essentially static, with slow motor and cognitive gains until CC adolescence or early adulthood. In young adulthood, affected CC individuals develop progressive dystonia, parkinsonism, extrapyramidal CC signs, and dementia resulting in severe disability. CC {ECO:0000269|PubMed:23435086, ECO:0000269|PubMed:25356899, CC ECO:0000269|PubMed:25592411}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the WD repeat PROPPIN family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY691428; AAV80764.1; -; mRNA. DR EMBL; AJ005897; CAA06754.1; -; mRNA. DR EMBL; CR456725; CAG33006.1; -; mRNA. DR EMBL; AF196779; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471224; EAW50697.1; -; Genomic_DNA. DR EMBL; CH471224; EAW50702.1; -; Genomic_DNA. DR EMBL; BC000464; AAH00464.1; -; mRNA. DR EMBL; BC003037; AAH03037.1; -; mRNA. DR EMBL; BC009027; AAH09027.1; -; mRNA. DR EMBL; BC069206; AAH69206.1; -; mRNA. DR CCDS; CCDS14318.1; -. [Q9Y484-3] DR CCDS; CCDS35250.1; -. [Q9Y484-1] DR RefSeq; NP_001025067.1; NM_001029896.2. [Q9Y484-1] DR RefSeq; NP_009006.2; NM_007075.3. [Q9Y484-3] DR PDB; 8KBX; EM; 3.23 A; A=1-360. DR PDB; 8KC3; EM; 7.00 A; D=1-360. DR PDB; 8Y1L; EM; 7.05 A; A=1-360. DR PDBsum; 8KBX; -. DR PDBsum; 8KC3; -. DR PDBsum; 8Y1L; -. DR AlphaFoldDB; Q9Y484; -. DR EMDB; EMD-37086; -. DR EMDB; EMD-37091; -. DR EMDB; EMD-38839; -. DR SMR; Q9Y484; -. DR BioGRID; 116323; 52. DR CORUM; Q9Y484; -. DR FunCoup; Q9Y484; 883. DR STRING; 9606.ENSP00000348848; -. DR TCDB; 9.A.15.2.1; the autophagy-related phagophore-formation transporter (apt) family. DR GlyGen; Q9Y484; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9Y484; -. DR PhosphoSitePlus; Q9Y484; -. DR SwissPalm; Q9Y484; -. DR BioMuta; WDR45; -. DR DMDM; 74762056; -. DR jPOST; Q9Y484; -. DR MassIVE; Q9Y484; -. DR PaxDb; 9606-ENSP00000348848; -. DR PeptideAtlas; Q9Y484; -. DR ProteomicsDB; 86126; -. [Q9Y484-1] DR ProteomicsDB; 86127; -. [Q9Y484-2] DR ProteomicsDB; 86128; -. [Q9Y484-3] DR Pumba; Q9Y484; -. DR ABCD; Q9Y484; 2 sequenced antibodies. DR Antibodypedia; 34945; 170 antibodies from 21 providers. DR DNASU; 11152; -. DR Ensembl; ENST00000322995.13; ENSP00000365543.5; ENSG00000196998.20. [Q9Y484-2] DR Ensembl; ENST00000356463.7; ENSP00000348848.3; ENSG00000196998.20. [Q9Y484-3] DR Ensembl; ENST00000376368.7; ENSP00000365546.2; ENSG00000196998.20. [Q9Y484-3] DR Ensembl; ENST00000376372.9; ENSP00000365551.3; ENSG00000196998.20. [Q9Y484-1] DR Ensembl; ENST00000634944.1; ENSP00000488972.1; ENSG00000196998.20. [Q9Y484-1] DR Ensembl; ENST00000710219.1; ENSP00000518130.1; ENSG00000292221.1. [Q9Y484-1] DR Ensembl; ENST00000710220.1; ENSP00000518131.1; ENSG00000292221.1. [Q9Y484-1] DR Ensembl; ENST00000710225.1; ENSP00000518136.1; ENSG00000292221.1. [Q9Y484-2] DR Ensembl; ENST00000710226.1; ENSP00000518137.1; ENSG00000292221.1. [Q9Y484-3] DR Ensembl; ENST00000710231.1; ENSP00000518141.1; ENSG00000292221.1. [Q9Y484-3] DR GeneID; 11152; -. DR KEGG; hsa:11152; -. DR MANE-Select; ENST00000376372.9; ENSP00000365551.3; NM_001029896.2; NP_001025067.1. DR UCSC; uc004dmk.2; human. [Q9Y484-1] DR AGR; HGNC:28912; -. DR ClinPGx; PA134927673; -. DR CTD; 11152; -. DR DisGeNET; 11152; -. DR GeneCards; WDR45; -. DR GeneReviews; WDR45; -. DR HGNC; HGNC:28912; WDR45. DR HPA; ENSG00000196998; Low tissue specificity. DR MalaCards; WDR45; -. DR MIM; 300526; gene. DR MIM; 300894; phenotype. DR OpenTargets; ENSG00000196998; -. DR Orphanet; 329284; Beta-propeller protein-associated neurodegeneration. DR Orphanet; 697160; Infantile epileptic spasms syndrome. DR VEuPathDB; HostDB:ENSG00000196998; -. DR eggNOG; KOG2111; Eukaryota. DR GeneTree; ENSGT00940000155657; -. DR InParanoid; Q9Y484; -. DR OMA; YAVCENG; -. DR OrthoDB; 1667587at2759; -. DR PAN-GO; Q9Y484; 9 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y484; -. DR PathwayCommons; Q9Y484; -. DR Reactome; R-HSA-1632852; Macroautophagy. DR SignaLink; Q9Y484; -. DR SIGNOR; Q9Y484; -. DR Agora; ENSG00000196998; -. DR BioGRID-ORCS; 11152; 21 hits in 778 CRISPR screens. DR ChiTaRS; WDR45; human. DR GeneWiki; WDR45; -. DR GenomeRNAi; 11152; -. DR Pharos; Q9Y484; Tbio. DR PRO; PR:Q9Y484; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q9Y484; protein. DR Bgee; ENSG00000196998; Expressed in apex of heart and 209 other cell types or tissues. DR ExpressionAtlas; Q9Y484; baseline and differential. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0000407; C:phagophore assembly site; IDA:UniProtKB. DR GO; GO:0034045; C:phagophore assembly site membrane; IBA:GO_Central. DR GO; GO:1901981; F:phosphatidylinositol phosphate binding; IDA:UniProtKB. DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IBA:GO_Central. DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IBA:GO_Central. DR GO; GO:0000045; P:autophagosome assembly; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; IBA:GO_Central. DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB. DR GO; GO:0061723; P:glycophagy; IBA:GO_Central. DR GO; GO:0044804; P:nucleophagy; IBA:GO_Central. DR GO; GO:0000425; P:pexophagy; IBA:GO_Central. DR GO; GO:2000786; P:positive regulation of autophagosome assembly; IDA:UniProtKB. DR GO; GO:0034497; P:protein localization to phagophore assembly site; IBA:GO_Central. DR FunFam; 2.130.10.10:FF:000154; WD repeat domain phosphoinositide-interacting protein 4; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR048720; PROPPIN. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR InterPro; IPR036322; WD40_repeat_dom_sf. DR InterPro; IPR001680; WD40_rpt. DR PANTHER; PTHR11227; WD-REPEAT PROTEIN INTERACTING WITH PHOSPHOINOSIDES WIPI -RELATED; 1. DR Pfam; PF21032; PROPPIN; 1. DR SMART; SM00320; WD40; 4. DR SUPFAM; SSF50978; WD40 repeat-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cytoplasm; Disease variant; KW Lipid-binding; Neurodegeneration; Proteomics identification; KW Reference proteome; Repeat; WD repeat. FT CHAIN 1..360 FT /note="WD repeat domain phosphoinositide-interacting FT protein 4" FT /id="PRO_0000051452" FT REPEAT 1..34 FT /note="WD 1" FT REPEAT 40..84 FT /note="WD 2" FT REPEAT 92..128 FT /note="WD 3" FT REPEAT 133..174 FT /note="WD 4" FT REPEAT 183..222 FT /note="WD 5" FT REPEAT 227..266 FT /note="WD 6" FT REPEAT 284..329 FT /note="WD 7" FT MOTIF 231..234 FT /note="L/FRRG motif" FT /evidence="ECO:0000250|UniProtKB:Q9Y4P8" FT VAR_SEQ 78 FT /note="S -> SA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_016975" FT VAR_SEQ 145 FT /note="K -> KAAHPTPHLHTL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_016976" FT VARIANT 7..360 FT /note="Missing (in NBIA5)" FT /evidence="ECO:0000269|PubMed:25356899" FT /id="VAR_078645" FT VARIANT 208 FT /note="A -> D (in NBIA5; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25592411" FT /id="VAR_080430" FT MUTAGEN 15 FT /note="N->A: Decreased interaction with ATG2A. Loss of FT interaction with ATG2A; when associated with A-17." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 16 FT /note="Q->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 17 FT /note="D->A: Decreased interaction with ATG2A. Loss of FT interaction with ATG2A; when associated with A-15." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 55 FT /note="E->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 109 FT /note="R->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 111 FT /note="R->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 112 FT /note="H->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 113 FT /note="D->A: Loss of interaction with AMPK. No effect on FT interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 114 FT /note="K->A: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT MUTAGEN 232..233 FT /note="RR->AA: No effect on interaction with ATG2A." FT /evidence="ECO:0000269|PubMed:28561066" FT CONFLICT 217 FT /note="I -> T (in Ref. 3; CAG33006)" FT /evidence="ECO:0000305" FT CONFLICT 300..302 FT /note="FTV -> YTA (in Ref. 1; AAV80764)" FT /evidence="ECO:0000305" FT HELIX 6..8 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 9..14 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 18..25 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 28..33 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 34..37 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 38..43 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 45..48 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 49..56 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 60..74 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 78..83 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 91..94 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 95..100 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 105..111 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 114..127 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 134..139 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 158..162 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 168..173 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 174..176 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 186..189 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 195..200 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 204..211 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 215..221 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 222..224 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 227..232 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 240..245 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 249..256 FT /evidence="ECO:0007829|PDB:8KBX" FT TURN 257..259 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 260..268 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 269..271 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 272..274 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 276..278 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 288..291 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 297..301 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 308..312 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 320..327 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 330..337 FT /evidence="ECO:0007829|PDB:8KBX" FT STRAND 343..350 FT /evidence="ECO:0007829|PDB:8KBX" FT HELIX 351..353 FT /evidence="ECO:0007829|PDB:8KBX" SQ SEQUENCE 360 AA; 39868 MW; E1A6746277182AF9 CRC64; MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS NLLALVGGGS SPKFSEISVL IWDDAREGKD SKEKLVLEFT FTKPVLSVRM RHDKIVIVLK NRIYVYSFPD NPRKLFEFDT RDNPKGLCDL CPSLEKQLLV FPGHKCGSLQ LVDLASTKPG TSSAPFTINA HQSDIACVSL NQPGTVVASA SQKGTLIRLF DTQSKEKLVE LRRGTDPATL YCINFSHDSS FLCASSDKGT VHIFALKDTR LNRRSALARV GKVGPMIGQY VDSQWSLASF TVPAESACIC AFGRNTSKNV NSVIAICVDG TFHKYVFTPD GNCNREAFDV YLDICDDDDF // ID ZNT10_HUMAN Reviewed; 485 AA. AC Q6XR72; Q49AL9; Q9NPW0; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 156. DE RecName: Full=Calcium/manganese antiporter SLC30A10 {ECO:0000305|PubMed:30755481}; DE AltName: Full=Solute carrier family 30 member 10 {ECO:0000312|HGNC:HGNC:25355}; DE AltName: Full=Zinc transporter 10; DE Short=ZnT-10; GN Name=SLC30A10 {ECO:0000312|HGNC:HGNC:25355}; GN Synonyms=ZNT10 {ECO:0000303|PubMed:22706290}, ZNT8 {ECO:0000303|Ref.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 [MRNA] (ISOFORM 1). RA Huang L., Zhou B., Gitschier J.; RT "Characterization of a novel mammalian zinc transporter, ZNT8."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 90-485 (ISOFORM 3). 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 [5] RP TISSUE SPECIFICITY. RX PubMed=15154973; DOI=10.1186/1471-2164-5-32; RA Seve M., Chimienti F., Devergnas S., Favier A.; RT "In silico identification and expression of SLC30 family genes: an RT expressed sequence tag data mining strategy for the characterization of RT zinc transporters' tissue expression."; RL BMC Genomics 5:32-32(2004). RN [6] RP FUNCTION, INVOLVEMENT IN HMNDYT1, VARIANTS HMNDYT1 PRO-89; 105-ALA--PRO-107 RP DEL; VAL-256 DEL AND PRO-349, AND CHARACTERIZATION OF VARIANTS HMNDYT1 RP PRO-89. RX PubMed=22341972; DOI=10.1016/j.ajhg.2012.01.018; RA Tuschl K., Clayton P.T., Gospe S.M. Jr., Gulab S., Ibrahim S., Singhi P., RA Aulakh R., Ribeiro R.T., Barsottini O.G., Zaki M.S., Del Rosario M.L., RA Dyack S., Price V., Rideout A., Gordon K., Wevers R.A., Chong W.K., RA Mills P.B.; RT "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and RT hypermanganesemia caused by mutations in SLC30A10, a manganese transporter RT in man."; RL Am. J. Hum. Genet. 90:457-466(2012). RN [7] RP INVOLVEMENT IN HMNDYT1, VARIANT SER-167, INDUCTION BY MANGANESE, AND TISSUE RP SPECIFICITY. RX PubMed=22341971; DOI=10.1016/j.ajhg.2012.01.017; RA Quadri M., Federico A., Zhao T., Breedveld G.J., Battisti C., Delnooz C., RA Severijnen L.A., Di Toro Mammarella L., Mignarri A., Monti L., Sanna A., RA Lu P., Punzo F., Cossu G., Willemsen R., Rasi F., Oostra B.A., RA van de Warrenburg B.P., Bonifati V.; RT "Mutations in SLC30A10 cause parkinsonism and dystonia with RT hypermanganesemia, polycythemia, and chronic liver disease."; RL Am. J. Hum. Genet. 90:467-477(2012). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22706290; DOI=10.1039/c2mt20088k; RA Bosomworth H.J., Thornton J.K., Coneyworth L.J., Ford D., Valentine R.A.; RT "Efflux function, tissue-specific expression and intracellular trafficking RT of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis."; RL Metallomics 4:771-779(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH RP SLC30A3, AND INDUCTION. RX PubMed=22427991; DOI=10.1371/journal.pone.0033211; RA Patrushev N., Seidel-Rogol B., Salazar G.; RT "Angiotensin II requires zinc and downregulation of the zinc transporters RT ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells."; RL PLoS ONE 7:E33211-E33211(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP THR-196, AND CHARACTERIZATION OF VARIANTS HMNDYT1 PRO-89 AND RP 105-ALA--PRO-107 DEL. RX PubMed=25319704; DOI=10.1523/jneurosci.2329-14.2014; RA Leyva-Illades D., Chen P., Zogzas C.E., Hutchens S., Mercado J.M., RA Swaim C.D., Morrisett R.A., Bowman A.B., Aschner M., Mukhopadhyay S.; RT "SLC30A10 is a cell surface-localized manganese efflux transporter, and RT parkinsonism-causing mutations block its intracellular trafficking and RT efflux activity."; RL J. Neurosci. 34:14079-14095(2014). RN [11] RP INDUCTION. RX PubMed=25582195; DOI=10.1128/mcb.01298-14; RA Ogo O.A., Tyson J., Cockell S.J., Howard A., Valentine R.A., Ford D.; RT "The zinc finger protein ZNF658 regulates the transcription of genes RT involved in zinc homeostasis and affects ribosome biogenesis through the RT zinc transcriptional regulatory element."; RL Mol. Cell. Biol. 35:977-987(2015). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASN-43; CYS-52 AND LEU-242. RX PubMed=27226609; DOI=10.1074/jbc.m116.728014; RA Nishito Y., Tsuji N., Fujishiro H., Takeda T.A., Yamazaki T., Teranishi F., RA Okazaki F., Matsunaga A., Tuschl K., Rao R., Kono S., Miyajima H., RA Narita H., Himeno S., Kambe T.; RT "Direct comparison of manganese detoxification/efflux proteins and RT molecular characterization of ZnT10 protein as a manganese transporter."; RL J. Biol. Chem. 291:14773-14787(2016). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-25; ASP-40; ASN-43; ASP-47; ASN-127; HIS-244; ASP-248; HIS-333 AND RP HIS-350. RX PubMed=27307044; DOI=10.1074/jbc.m116.726935; RA Zogzas C.E., Aschner M., Mukhopadhyay S.; RT "Structural elements in the transmembrane and cytoplasmic domains of the RT metal transporter SLC30A10 are required for its manganese efflux RT activity."; RL J. Biol. Chem. 291:15940-15957(2016). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, INTERACTION WITH SLC30A2; SLC30A3 RP AND SLC30A4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-4. RX PubMed=26728129; DOI=10.1111/tra.12371; RA Zhao Y., Feresin R.G., Falcon-Perez J.M., Salazar G.; RT "Differential targeting of SLC30A10/ZnT10 heterodimers to endolysosomal RT compartments modulates EGF-induced MEK/ERK1/2 activity."; RL Traffic 17:267-288(2016). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, MUTAGENESIS OF ASN-43; ASP-47; HIS-244 AND RP ASP-248, AND SITE. RX PubMed=30755481; DOI=10.1074/jbc.ra118.006816; RA Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., RA Hershfinkel M., Sekler I.; RT "Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2+ is driven RT by an active Ca2+-coupled exchange."; RL J. Biol. Chem. 294:5879-5889(2019). CC -!- FUNCTION: Calcium:manganese antiporter of the plasma membrane mediating CC the efflux of intracellular manganese coupled to an active CC extracellular calcium exchange (PubMed:30755481). Required for CC intracellular manganese homeostasis, an essential cation for the CC function of several enzymes, including some crucially important for the CC metabolism of neurotransmitters and other neuronal metabolic pathways. CC Manganese can also be cytotoxic and induce oxidative stress, CC mitochondrial dysfunction and apoptosis (PubMed:22341972, CC PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). CC Could also have an intracellular zinc ion transporter activity, CC directly regulating intracellular zinc ion homeostasis and more CC indirectly various signaling pathway and biological processes CC (PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, CC ECO:0000269|PubMed:26728129, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + Ca(2+)(in) = Mn(2+)(in) + Ca(2+)(out); CC Xref=Rhea:RHEA:73059, ChEBI:CHEBI:29035, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; CC -!- SUBUNIT: Forms homodimers. Forms heterodimers and high-molecular weight CC oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is CC mediated by covalent-bound tyrosine residues, occurs probably in a CC tissue-specific manner and could mediate the intracellular zinc CC transport activity into early endosomes and recycling endosomes. CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. CC -!- INTERACTION: CC Q6XR72; Q9BRI3: SLC30A2; NbExp=4; IntAct=EBI-13917996, EBI-8644112; CC Q6XR72; Q99726: SLC30A3; NbExp=3; IntAct=EBI-13917996, EBI-10294651; CC Q6XR72; O14863: SLC30A4; NbExp=2; IntAct=EBI-13917996, EBI-13918058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22706290, CC ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:26728129, CC ECO:0000269|PubMed:27226609, ECO:0000269|PubMed:27307044}; Multi-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:27226609}; Multi-pass CC membrane protein {ECO:0000255}. Recycling endosome membrane CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. Early CC endosome membrane {ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localization to the Golgi and plasma membrane is CC regulated by zinc. {ECO:0000269|PubMed:22706290}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6XR72-4; Sequence=Displayed; CC Name=2; CC IsoId=Q6XR72-2; Sequence=VSP_029863; CC Name=3; CC IsoId=Q6XR72-3; Sequence=VSP_029864, VSP_029865; CC -!- TISSUE SPECIFICITY: Specifically expressed in fetal liver and fetal CC brain (PubMed:15154973). Expressed in adult tissues with relative CC levels small intestine > liver > testes > brain > ovary > colon > CC cervix > prostate > placenta (PubMed:22706290). Expressed in liver and CC neurons of the nervous system (at protein level) (PubMed:22341971). CC {ECO:0000269|PubMed:15154973, ECO:0000269|PubMed:22341971, CC ECO:0000269|PubMed:22706290}. CC -!- INDUCTION: Down-regulated by zinc (PubMed:22427991, PubMed:22706290, CC PubMed:25582195). Down-regulated by angiotensin-2 (PubMed:22427991). CC Up-regulated by manganese (PubMed:22341971). CC {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:25582195}. CC -!- DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A CC metabolic autosomal recessive disorder characterized by dystonia, CC parkinsonism, extrapyramidal signs, severe hypermanganesemia, CC polycythemia, and chronic hepatic disease, including steatosis and CC cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:25319704}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: 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 cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; 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; AY212919; AAP44332.1; ALT_SEQ; mRNA. DR EMBL; AL359609; CAB94880.1; -; mRNA. DR EMBL; AC093562; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036078; AAH36078.1; -; mRNA. DR CCDS; CCDS31026.1; -. [Q6XR72-4] DR PIR; T50628; T50628. DR RefSeq; NP_061183.2; NM_018713.2. [Q6XR72-4] DR AlphaFoldDB; Q6XR72; -. DR SMR; Q6XR72; -. DR BioGRID; 120703; 181. DR ComplexPortal; CPX-8462; ZNT10 calcium-coupled manganese antiporter homodimer. DR ComplexPortal; CPX-8463; ZNT2-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8464; ZNT3-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8465; ZNT4-ZNT10 proton-coupled zinc antiporter complex. DR FunCoup; Q6XR72; 245. DR IntAct; Q6XR72; 179. DR STRING; 9606.ENSP00000355893; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.2.5; the cation diffusion facilitator (cdf) family. DR GlyGen; Q6XR72; 1 site. DR iPTMnet; Q6XR72; -. DR PhosphoSitePlus; Q6XR72; -. DR BioMuta; SLC30A10; -. DR DMDM; 311033506; -. DR jPOST; Q6XR72; -. DR MassIVE; Q6XR72; -. DR PaxDb; 9606-ENSP00000355893; -. DR PeptideAtlas; Q6XR72; -. DR ProteomicsDB; 67813; -. [Q6XR72-4] DR ProteomicsDB; 67814; -. [Q6XR72-2] DR ProteomicsDB; 67815; -. [Q6XR72-3] DR Antibodypedia; 3072; 116 antibodies from 18 providers. DR DNASU; 55532; -. DR Ensembl; ENST00000356609.2; ENSP00000349018.2; ENSG00000196660.13. [Q6XR72-3] DR Ensembl; ENST00000366926.4; ENSP00000355893.4; ENSG00000196660.13. [Q6XR72-4] DR GeneID; 55532; -. DR KEGG; hsa:55532; -. DR MANE-Select; ENST00000366926.4; ENSP00000355893.4; NM_018713.3; NP_061183.2. DR UCSC; uc001hlw.4; human. [Q6XR72-4] DR AGR; HGNC:25355; -. DR ClinPGx; PA142670903; -. DR CTD; 55532; -. DR DisGeNET; 55532; -. DR GeneCards; SLC30A10; -. DR GeneReviews; SLC30A10; -. DR HGNC; HGNC:25355; SLC30A10. DR HPA; ENSG00000196660; Group enriched (intestine, liver). DR MalaCards; SLC30A10; -. DR MIM; 611146; gene. DR MIM; 613280; phenotype. DR OpenTargets; ENSG00000196660; -. DR Orphanet; 309854; Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000196660; -. DR eggNOG; KOG1483; Eukaryota. DR GeneTree; ENSGT00940000159967; -. DR HOGENOM; CLU_1239780_0_0_1; -. DR InParanoid; Q6XR72; -. DR OMA; FQDCASW; -. DR OrthoDB; 29444at2759; -. DR PAN-GO; Q6XR72; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6XR72; -. DR PathwayCommons; Q6XR72; -. DR Reactome; R-HSA-425410; Metal ion SLC transporters. DR SignaLink; Q6XR72; -. DR Agora; ENSG00000196660; -. DR BioGRID-ORCS; 55532; 11 hits in 1155 CRISPR screens. DR ChiTaRS; SLC30A10; human. DR GenomeRNAi; 55532; -. DR Pharos; Q6XR72; Tbio. DR PRO; PR:Q6XR72; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q6XR72; protein. DR Bgee; ENSG00000196660; Expressed in jejunal mucosa and 75 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0140983; F:calcium:manganese antiporter activity; IDA:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IDA:UniProtKB. DR GO; GO:0010312; P:detoxification of zinc ion; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030026; P:intracellular manganese ion homeostasis; IDA:UniProtKB. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:UniProtKB. DR GO; GO:0140048; P:manganese ion export across plasma membrane; IDA:UniProtKB. DR GO; GO:0006828; P:manganese ion transport; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0062111; P:zinc ion import into organelle; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR027470; Cation_efflux_CTD. DR InterPro; IPR058533; Cation_efflux_TM. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR45820:SF3; CALCIUM_MANGANESE ANTIPORTER SLC30A10; 1. DR PANTHER; PTHR45820; FI23527P1; 1. DR Pfam; PF01545; Cation_efflux; 1. DR Pfam; PF16916; ZT_dimer; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Cell membrane; Disease variant; Dystonia; KW Endosome; Golgi apparatus; Ion transport; Manganese; Membrane; KW Neurodegeneration; Parkinsonism; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; Zinc; KW Zinc transport. FT CHAIN 1..485 FT /note="Calcium/manganese antiporter SLC30A10" FT /id="PRO_0000312580" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..40 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 41..61 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 62..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..113 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 114..134 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 135..244 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 245..265 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 266..278 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 300..485 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 167..196 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 308..485 FT /note="Required for plasma membrane localization" FT /evidence="ECO:0000269|PubMed:25319704" FT SITE 43 FT /note="Important for coupling of manganese to calcium FT transport" FT /evidence="ECO:0000269|PubMed:30755481" FT VAR_SEQ 1..245 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_029863" FT VAR_SEQ 214..223 FT /note="GDSFNTQNEP -> ELIHNTRFLL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029864" FT VAR_SEQ 224..485 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029865" FT VARIANT 89 FT /note="L -> P (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; loss of function in FT intracellular manganese ion homeostasis; FT dbSNP:rs281860284)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072573" FT VARIANT 105..107 FT /note="Missing (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; decreased function in FT intracellular manganese ion homeostasis)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072574" FT VARIANT 167 FT /note="F -> S (in dbSNP:rs281860286)" FT /evidence="ECO:0000269|PubMed:22341971" FT /id="VAR_072575" FT VARIANT 256 FT /note="Missing (in HMNDYT1)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072576" FT VARIANT 349 FT /note="L -> P (in HMNDYT1; dbSNP:rs281860291)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072577" FT MUTAGEN 4 FT /note="Y->F: Decreased interaction with SLC30A3. No effect FT on self-association. Decreased zinc ion transmembrane FT transporter activity. Decreased EGF-induced ERK1/2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26728129" FT MUTAGEN 25 FT /note="E->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 40 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 43 FT /note="N->A: No effect on localization to the plasma FT membrane. Changed calcium:manganese antiporter activity. FT Enhanced coupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:27307044, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->H: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity. FT Loss of calcium:manganese antiporter activity and increased FT zinc ion transmembrane transporter activity; when FT associated with V-52 and F-242." FT /evidence="ECO:0000269|PubMed:27226609, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->T: Loss of calcium:manganese antiporter activity. FT Uncoupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 47 FT /note="D->A: No effect on localization to the plasma FT membrane. No effect on calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 47 FT /note="D->E: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 52 FT /note="C->V: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and F-242." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 127 FT /note="N->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-244." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 196 FT /note="T->P: Loss of localization to the plasma membrane." FT /evidence="ECO:0000269|PubMed:25319704" FT MUTAGEN 242 FT /note="L->F: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and V-52." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 244 FT /note="H->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-127." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 244 FT /note="H->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 248 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of manganese ion export across plasma FT membrane." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 333 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 350 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" SQ SEQUENCE 485 AA; 52684 MW; 96A3495EF026DE94 CRC64; MGRYSGKTCR LLFMLVLTVA FFVAELVSGY LGNSIALLSD SFNMLSDLIS LCVGLSAGYI ARRPTRGFSA TYGYARAEVV GALSNAVFLT ALCFTIFVEA VLRLARPERI DDPELVLIVG VLGLLVNVVG LLIFQDCAAW FACCLRGRSR RLQQRQQLAE GCVPGAFGGP QGAEDPRRAA DPTAPGSDSA VTLRGTSVER KREKGATVFA NVAGDSFNTQ NEPEDMMKKE KKSEALNIRG VLLHVMGDAL GSVVVVITAI IFYVLPLKSE DPCNWQCYID PSLTVLMVII ILSSAFPLIK ETAAILLQMV PKGVNMEELM SKLSAVPGIS SVHEVHIWEL VSGKIIATLH IKYPKDRGYQ DASTKIREIF HHAGIHNVTI QFENVDLKEP LEQKDLLLLC NSPCISKGCA KQLCCPPGAL PLAHVNGCAE HNGGPSLDTY GSDGLSRRDA REVAIEVSLD SCLSDHGQSL NKTQEDQCYV NRTHF //