ID AT132_HUMAN Reviewed; 1180 AA. AC Q9NQ11; O75700; Q5JXY1; Q5JXY2; Q6S9Z9; DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 2. DT 28-JAN-2026, entry version 210. DE RecName: Full=Polyamine-transporting ATPase 13A2 {ECO:0000305|PubMed:31996848}; DE EC=7.6.2.- {ECO:0000269|PubMed:31996848}; GN Name=ATP13A2 {ECO:0000312|HGNC:HGNC:30213}; GN Synonyms=PARK9 {ECO:0000303|PubMed:21542062}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RA Rhodes S., Huckle E.; RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RA Liu J.-P., Li H.; RT "Homo sapiens putative ATPase (N-ATPase) mRNA."; RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). RC TISSUE=Brain, and Fetus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 705-1180 (ISOFORM A). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 855-1180 (ISOFORM B). RA Casciano I., Volpi E.V., De Ambrosis A., Marchi J.M., Romani M.; RT "YAC analysis and genes identification at a site of viral integration in RT the 1p36.1-36.2 chromosomal site."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [9] RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=22186024; DOI=10.1093/hmg/ddr606; RA Ramonet D., Podhajska A., Stafa K., Sonnay S., Trancikova A., Tsika E., RA Pletnikova O., Troncoso J.C., Glauser L., Moore D.J.; RT "PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and RT regulates cation homeostasis and neuronal integrity."; RL Hum. Mol. Genet. 21:1725-1743(2012). RN [10] RP INVOLVEMENT IN KRS. RX PubMed=16964263; DOI=10.1038/ng1884; RA Ramirez A., Heimbach A., Gruendemann J., Stiller B., Hampshire D., RA Cid L.P., Goebel I., Mubaidin A.F., Wriekat A.-L., Roeper J., Al-Din A., RA Hillmer A.M., Karsak M., Liss B., Woods C.G., Behrens M.I., Kubisch C.; RT "Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, RT encoding a lysosomal type 5 P-type ATPase."; RL Nat. Genet. 38:1184-1191(2006). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-151, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24603074; DOI=10.1093/hmg/ddu099; RA Kong S.M., Chan B.K., Park J.S., Hill K.J., Aitken J.B., Cottle L., RA Farghaian H., Cole A.R., Lay P.A., Sue C.M., Cooper A.A.; RT "Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis RT and promotes alpha-Synuclein externalization via exosomes."; RL Hum. Mol. Genet. 23:2816-2833(2014). RN [13] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25392495; DOI=10.1523/jneurosci.1629-14.2014; RA Tsunemi T., Hamada K., Krainc D.; RT "ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein."; RL J. Neurosci. 34:15281-15287(2014). RN [14] RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, TOPOLOGY, RP AUTOPHOSPHORYLATION, ACTIVE SITE, GLYCOSYLATION AT ASN-1033, AND RP MUTAGENESIS OF GLY-59; 66-ARG--LYS-68; 74-ARG--ARG-78; 160-LYS--ARG-164 AND RP ASN-1033. RX PubMed=26134396; DOI=10.1073/pnas.1508220112; RA Holemans T., Soerensen D.M., van Veen S., Martin S., Hermans D., RA Kemmer G.C., Van den Haute C., Baekelandt V., Guenther Pomorski T., RA Agostinis P., Wuytack F., Palmgren M., Eggermont J., Vangheluwe P.; RT "A lipid switch unlocks Parkinson's disease-associated ATP13A2."; RL Proc. Natl. Acad. Sci. U.S.A. 112:9040-9045(2015). RN [15] RP FUNCTION. RX PubMed=31132336; DOI=10.1016/j.bbamem.2019.05.015; RA Marcos A.L., Corradi G.R., Mazzitelli L.R., Casali C.I., RA Fernandez Tome M.D.C., Adamo H.P., de Tezanos Pinto F.; RT "The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid RT homeostasis."; RL Biochim. Biophys. Acta 1861:182993-182993(2019). RN [16] RP FUNCTION, INTERACTION WITH HDAC6, AND CHARACTERIZATION OF VARIANTS KRS RP LEU-182 AND ARG-504. RX PubMed=30538141; DOI=10.1083/jcb.201804165; RA Wang R., Tan J., Chen T., Han H., Tian R., Tan Y., Wu Y., Cui J., Chen F., RA Li J., Lv L., Guan X., Shang S., Lu J., Zhang Z.; RT "ATP13A2 facilitates HDAC6 recruitment to lysosome to promote RT autophagosome-lysosome fusion."; RL J. Cell Biol. 218:267-284(2019). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL RP PROPERTIES, CHARACTERIZATION OF VARIANTS KRS MET-12; ARG-533; THR-746 AND RP ARG-877, CHARACTERIZATION OF VARIANT SPG8 ILE-517, AND MUTAGENESIS OF RP GLU-348; ALA-472; ASP-513; ASP-967 AND LYS-1067. RX PubMed=31996848; DOI=10.1038/s41586-020-1968-7; RA van Veen S., Martin S., Van den Haute C., Benoy V., Lyons J., Vanhoutte R., RA Kahler J.P., Decuypere J.P., Gelders G., Lambie E., Zielich J., RA Swinnen J.V., Annaert W., Agostinis P., Ghesquiere B., Verhelst S., RA Baekelandt V., Eggermont J., Vangheluwe P.; RT "ATP13A2 deficiency disrupts lysosomal polyamine export."; RL Nature 578:419-424(2020). RN [18] RP VARIANTS KRS MET-12; ARG-504 AND ARG-533. RX PubMed=17485642; DOI=10.1212/01.wnl.0000260963.08711.08; RA Di Fonzo A., Chien H.F., Socal M., Giraudo S., Tassorelli C., Iliceto G., RA Fabbrini G., Marconi R., Fincati E., Abbruzzese G., Marini P., RA Squitieri F., Horstink M.W., Montagna P., Libera A.D., Stocchi F., RA Goldwurm S., Ferreira J.J., Meco G., Martignoni E., Lopiano L., RA Jardim L.B., Oostra B.A., Barbosa E.R., Bonifati V.; RT "ATP13A2 missense mutations in juvenile parkinsonism and young onset RT Parkinson disease."; RL Neurology 68:1557-1562(2007). RN [19] RP VARIANT KRS LEU-182. RX PubMed=18413573; DOI=10.1212/01.wnl.0000310427.72236.68; RA Ning Y.P., Kanai K., Tomiyama H., Li Y., Funayama M., Yoshino H., Sato S., RA Asahina M., Kuwabara S., Takeda A., Hattori T., Mizuno Y., Hattori N.; RT "PARK9-linked parkinsonism in eastern Asia: mutation detection in ATP13A2 RT and clinical phenotype."; RL Neurology 70:1491-1493(2008). RN [20] RP VARIANT THR-746. RX PubMed=19015489; DOI=10.1212/01.wnl.0000335167.72412.68; RA Lin C.H., Tan E.K., Chen M.L., Tan L.C., Lim H.Q., Chen G.S., Wu R.M.; RT "Novel ATP13A2 variant associated with Parkinson disease in Taiwan and RT Singapore."; RL Neurology 71:1727-1732(2008). RN [21] RP VARIANTS SER-49; GLN-294; LEU-389; GLY-578; TRP-762; ILE-776 AND PHE-946. RX PubMed=19085912; DOI=10.1002/humu.20877; RA Vilarino-Guell C., Soto A.I., Lincoln S.J., Ben Yahmed S., Kefi M., RA Heckman M.G., Hulihan M.M., Chai H., Diehl N.N., Amouri R., Rajput A., RA Mash D.C., Dickson D.W., Middleton L.T., Gibson R.A., Hentati F., RA Farrer M.J.; RT "ATP13A2 variability in Parkinson disease."; RL Hum. Mutat. 30:406-410(2009). RN [22] RP INVOLVEMENT IN KRS. RX PubMed=20683840; DOI=10.1002/mds.22996; RA Behrens M.I., Bruggemann N., Chana P., Venegas P., Kagi M., Parrao T., RA Orellana P., Garrido C., Rojas C.V., Hauke J., Hahnen E., Gonzalez R., RA Seleme N., Fernandez V., Schmidt A., Binkofski F., Kompf D., Kubisch C., RA Hagenah J., Klein C., Ramirez A.; RT "Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with RT ATP13A2 mutations."; RL Mov. Disord. 25:1929-1937(2010). RN [23] RP VARIANT KRS ARG-1059, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT RP KRS ARG-1059. RX PubMed=21542062; DOI=10.1002/humu.21527; RA Park J.S., Mehta P., Cooper A.A., Veivers D., Heimbach A., Stiller B., RA Kubisch C., Fung V.S., Krainc D., Mackay-Sim A., Sue C.M.; RT "Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) RT causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism."; RL Hum. Mutat. 32:956-964(2011). RN [24] RP VARIANT KRS ARG-877. RX PubMed=20853184; DOI=10.1007/s10048-010-0259-0; RA Santoro L., Breedveld G.J., Manganelli F., Iodice R., Pisciotta C., RA Nolano M., Punzo F., Quarantelli M., Pappata S., Di Fonzo A., Oostra B.A., RA Bonifati V.; RT "Novel ATP13A2 (PARK9) homozygous mutation in a family with marked RT phenotype variability."; RL Neurogenetics 12:33-39(2011). RN [25] RP VARIANT KRS ARG-854. RX PubMed=22388936; DOI=10.1093/hmg/dds089; RA Bras J., Verloes A., Schneider S.A., Mole S.E., Guerreiro R.J.; RT "Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid- RT lipofuscinosis."; RL Hum. Mol. Genet. 21:2646-2650(2012). RN [26] RP VARIANT KRS VAL-522, AND FUNCTION. RX PubMed=22296644; DOI=10.1016/j.neurobiolaging.2011.12.035; RA Gruenewald A., Arns B., Seibler P., Rakovic A., Muenchau A., Ramirez A., RA Sue C.M., Klein C.; RT "ATP13A2 mutations impair mitochondrial function in fibroblasts from RT patients with Kufor-Rakeb syndrome."; RL Neurobiol. Aging 33:1843.E1-1843.E7(2012). RN [27] RP FUNCTION, CHARACTERIZATION OF VARIANTS KRS MET-12; LEU-182; ARG-504; RP ARG-533; THR-746 AND ARG-877, AND SUBCELLULAR LOCATION. RX PubMed=22768177; DOI=10.1371/journal.pone.0039942; RA Podhajska A., Musso A., Trancikova A., Stafa K., Moser R., Sonnay S., RA Glauser L., Moore D.J.; RT "Common pathogenic effects of missense mutations in the P-type ATPase RT ATP13A2 (PARK9) associated with early-onset parkinsonism."; RL PLoS ONE 7:E39942-E39942(2012). RN [28] RP FUNCTION, AND INTERACTION WITH MYCBP2. RX PubMed=27278822; DOI=10.1038/ncomms11803; RA Bento C.F., Ashkenazi A., Jimenez-Sanchez M., Rubinsztein D.C.; RT "The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate RT autophagy via a common pathway."; RL Nat. Commun. 7:11803-11803(2016). RN [29] RP INVOLVEMENT IN SPG78. RX PubMed=27217339; DOI=10.1093/brain/aww111; RA Kara E., Tucci A., Manzoni C., Lynch D.S., Elpidorou M., Bettencourt C., RA Chelban V., Manole A., Hamed S.A., Haridy N.A., Federoff M., Preza E., RA Hughes D., Pittman A., Jaunmuktane Z., Brandner S., Xiromerisiou G., RA Wiethoff S., Schottlaender L., Proukakis C., Morris H., Warner T., RA Bhatia K.P., Korlipara L.V., Singleton A.B., Hardy J., Wood N.W., RA Lewis P.A., Houlden H.; RT "Genetic and phenotypic characterization of complex hereditary spastic RT paraplegia."; RL Brain 139:1904-1918(2016). RN [30] RP INVOLVEMENT IN SPG78, VARIANT SPG78 ILE-517, CHARACTERIZATION OF VARIANTS RP KRS LEU-182 AND ARG-533, CHARACTERIZATION OF VARIANT SPG78 ILE-517, RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF ASP-513. RX PubMed=28137957; DOI=10.1093/brain/aww307; RA Estrada-Cuzcano A., Martin S., Chamova T., Synofzik M., Timmann D., RA Holemans T., Andreeva A., Reichbauer J., De Rycke R., Chang D.I., RA van Veen S., Samuel J., Schoels L., Poeppel T., Mollerup Soerensen D., RA Asselbergh B., Klein C., Zuchner S., Jordanova A., Vangheluwe P., RA Tournev I., Schuele R.; RT "Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated RT hereditary spastic paraplegia (SPG78)."; RL Brain 140:287-305(2017). RN [31] RP VARIANTS KRS PHE-441 AND THR-1069. RX PubMed=29903538; DOI=10.1016/j.braindev.2018.05.017; RA Suleiman J., Hamwi N., El-Hattab A.W.; RT "ATP13A2 novel mutations causing a rare form of juvenile-onset Parkinson RT disease."; RL Brain Dev. 40:824-826(2018). RN [32] RP VARIANT SPG78 PRO-927, AND CHARACTERIZATION OF VARIANT SPG78 PRO-927. RX PubMed=38252374; DOI=10.1007/s10072-024-07334-w; RA Zhang F., Liu P., Li J., Cen Z., Luo W.; RT "A novel ATP13A2 variant causing complicated hereditary spastic RT paraplegia."; RL Neurol. Sci. 45:1749-1753(2024). CC -!- FUNCTION: ATPase which acts as a lysosomal polyamine exporter with high CC affinity for spermine (PubMed:31996848). Also stimulates cellular CC uptake of polyamines and protects against polyamine toxicity CC (PubMed:31996848). Plays a role in intracellular cation homeostasis and CC the maintenance of neuronal integrity (PubMed:22186024). Contributes to CC cellular zinc homeostasis (PubMed:24603074). Confers cellular CC protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress CC (PubMed:26134396). Required for proper lysosomal and mitochondrial CC maintenance (PubMed:22296644, PubMed:28137957). Regulates the CC autophagy-lysosome pathway through the control of SYT11 expression at CC both transcriptional and post-translational levels (PubMed:27278822). CC Facilitates recruitment of deacetylase HDAC6 to lysosomes to CC deacetylate CTTN, leading to actin polymerization, promotion of CC autophagosome-lysosome fusion and completion of autophagy CC (PubMed:30538141). Promotes secretion of exosomes as well as secretion CC of SCNA via exosomes (PubMed:24603074, PubMed:25392495). Plays a role CC in lipid homeostasis (PubMed:31132336). {ECO:0000269|PubMed:22186024, CC ECO:0000269|PubMed:22296644, ECO:0000269|PubMed:24603074, CC ECO:0000269|PubMed:25392495, ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:28137957, CC ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:31132336, CC ECO:0000269|PubMed:31996848}. CC -!- CATALYTIC ACTIVITY: CC Reaction=spermidine(out) + ATP + H2O = spermidine(in) + ADP + phosphate CC + H(+); Xref=Rhea:RHEA:29999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57834, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:31996848}; CC -!- CATALYTIC ACTIVITY: CC Reaction=spermine(out) + ATP + H2O = spermine(in) + ADP + phosphate + CC H(+); Xref=Rhea:RHEA:63368, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:45725, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:31996848}; CC -!- ACTIVITY REGULATION: Accumulates in an inactive autophosphorylated CC state (PubMed:26134396). The presence of spermine results in a dose- CC dependent reduction in autophosphorylation (PubMed:31996848). CC {ECO:0000269|PubMed:26134396, ECO:0000269|PubMed:31996848}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=76 uM for spermine {ECO:0000269|PubMed:31996848}; CC Vmax=159 nmol/min/mg enzyme {ECO:0000269|PubMed:31996848}; CC -!- SUBUNIT: Interacts with MYCBP2; the interaction inhibits the CC ubiquitination of TSC2 by MYCBP2 (PubMed:27278822). Interacts with CC HDAC6; the interaction results in recruitment of HDAC6 to lysosomes to CC promote CTTN deacetylation (PubMed:30538141). CC {ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30538141}. CC -!- INTERACTION: CC Q9NQ11; Q2M2I8: AAK1; NbExp=2; IntAct=EBI-6308763, EBI-1383433; CC Q9NQ11; O60238: BNIP3L; NbExp=2; IntAct=EBI-6308763, EBI-849893; CC Q9NQ11; O14976: GAK; NbExp=2; IntAct=EBI-6308763, EBI-714707; CC Q9NQ11; Q9UBN7: HDAC6; NbExp=2; IntAct=EBI-6308763, EBI-301697; CC Q9NQ11; P11142: HSPA8; NbExp=2; IntAct=EBI-6308763, EBI-351896; CC Q9NQ11; Q9BT88: SYT11; NbExp=2; IntAct=EBI-6308763, EBI-751770; CC Q9NQ11; O95070: YIF1A; NbExp=2; IntAct=EBI-6308763, EBI-2799703; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:21542062, CC ECO:0000269|PubMed:22186024, ECO:0000269|PubMed:22768177, CC ECO:0000269|PubMed:24603074, ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:28137957}; Multi-pass membrane protein CC {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:24603074, CC ECO:0000269|PubMed:25392495, ECO:0000269|PubMed:26134396}; Multi-pass CC membrane protein {ECO:0000255}. Endosome, multivesicular body membrane CC {ECO:0000269|PubMed:24603074, ECO:0000269|PubMed:25392495}; Multi-pass CC membrane protein {ECO:0000255}. Cytoplasmic vesicle, autophagosome CC membrane {ECO:0000269|PubMed:24603074}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=A; CC IsoId=Q9NQ11-1; Sequence=Displayed; CC Name=B; CC IsoId=Q9NQ11-2; Sequence=VSP_007310, VSP_007311, VSP_007312; CC Name=3; CC IsoId=Q9NQ11-3; Sequence=VSP_007310; CC -!- TISSUE SPECIFICITY: Expressed in brain; protein levels are markedly CC increased in brain from subjects with Parkinson disease and subjects CC with dementia with Lewy bodies. Detected in pyramidal neurons located CC throughout the cingulate cortex (at protein level). In the substantia CC nigra, it is found in neuromelanin-positive dopaminergic neurons (at CC protein level). {ECO:0000269|PubMed:22186024}. CC -!- DOMAIN: The N-terminal region is required for targeting to late CC endosomes/lysosomes. It does not traverse the membrane but contains a CC membrane-embedded intramembrane domain and interacts with the lipids CC phosphatidic acid (PA) and phosphatidylinositol 3,5-bisphosphate CC (PI(3,5)P2) (PubMed:26134396). PA and PI(3,5)P2 are required for the CC protective effect against mitochondrial stress (PubMed:26134396). CC {ECO:0000269|PubMed:26134396}. CC -!- PTM: Autophosphorylated (PubMed:26134396, PubMed:28137957). Accumulates CC in an inactive autophosphorylated state and autophosphorylation is CC stimulated by phosphatidic acid and phosphatidylinositol 3,5- CC bisphosphate but not by Mn(2+) or Zn(2+) (PubMed:26134396). The CC presence of spermine results in a dose-dependent reduction in CC autophosphorylation (PubMed:31996848). {ECO:0000269|PubMed:26134396, CC ECO:0000269|PubMed:31996848, ECO:0000305|PubMed:28137957}. CC -!- DISEASE: Kufor-Rakeb syndrome (KRS) [MIM:606693]: A rare form of CC autosomal recessive juvenile or early-onset, levodopa-responsive CC parkinsonism. In addition to typical parkinsonian signs, clinical CC manifestations of Kufor-Rakeb syndrome include behavioral problems, CC facial tremor, pyramidal tract dysfunction, supranuclear gaze palsy, CC and dementia. {ECO:0000269|PubMed:16964263, CC ECO:0000269|PubMed:17485642, ECO:0000269|PubMed:18413573, CC ECO:0000269|PubMed:20683840, ECO:0000269|PubMed:20853184, CC ECO:0000269|PubMed:21542062, ECO:0000269|PubMed:22296644, CC ECO:0000269|PubMed:22388936, ECO:0000269|PubMed:22768177, CC ECO:0000269|PubMed:28137957, ECO:0000269|PubMed:29903538, CC ECO:0000269|PubMed:30538141, ECO:0000269|PubMed:31996848}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. KRS has also been referred to as neuronal ceroid lipofuscinosis CC 12 (CLN12), due to neuronal and glial lipofuscin deposits detected in CC the cortex, basal nuclei and cerebellum of some patients. CC {ECO:0000269|PubMed:22388936}. CC -!- DISEASE: Spastic paraplegia 78, autosomal recessive (SPG78) CC [MIM:617225]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. CC {ECO:0000269|PubMed:27217339, ECO:0000269|PubMed:28137957, CC ECO:0000269|PubMed:38252374}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type) (TC 3.A.3) CC family. Type V subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA08912.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL354615; CAB89728.1; -; mRNA. DR EMBL; AY461712; AAR23423.1; -; mRNA. DR EMBL; AK290210; BAF82899.1; -; mRNA. DR EMBL; AL049569; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471134; EAW94825.1; -; Genomic_DNA. DR EMBL; CH471134; EAW94827.1; -; Genomic_DNA. DR EMBL; BC030267; AAH30267.1; -; mRNA. DR EMBL; AL833966; CAD38813.2; -; mRNA. DR EMBL; AJ009947; CAA08912.1; ALT_FRAME; mRNA. DR CCDS; CCDS175.1; -. [Q9NQ11-1] DR CCDS; CCDS44072.1; -. [Q9NQ11-2] DR CCDS; CCDS44073.1; -. [Q9NQ11-3] DR RefSeq; NP_001135445.1; NM_001141973.3. [Q9NQ11-3] DR RefSeq; NP_001135446.1; NM_001141974.3. [Q9NQ11-2] DR RefSeq; NP_071372.1; NM_022089.4. [Q9NQ11-1] DR PDB; 7FJM; EM; 3.30 A; A=1-1180. DR PDB; 7FJP; EM; 3.00 A; B=1-1180. DR PDB; 7FJQ; EM; 3.60 A; A=1-1180. DR PDB; 7M5V; EM; 2.90 A; A=1-1180. DR PDB; 7M5X; EM; 2.70 A; A=1-1180. DR PDB; 7M5Y; EM; 3.00 A; A=1-1180. DR PDB; 7N70; EM; 2.80 A; A=1-1180. DR PDB; 7N72; EM; 2.50 A; A=1-1180. DR PDB; 7N73; EM; 2.90 A; A=1-1180. DR PDB; 7N74; EM; 2.80 A; A=1-1180. DR PDB; 7N75; EM; 2.90 A; A=1-1180. DR PDB; 7N76; EM; 2.90 A; A=1-1180. DR PDB; 7N77; EM; 3.20 A; A=1-1180. DR PDB; 7N78; EM; 3.00 A; A=1-1180. DR PDB; 7VPI; EM; 3.50 A; A=1-1180. DR PDB; 7VPJ; EM; 3.50 A; A=1-1180. DR PDB; 7VPK; EM; 3.50 A; A=1-1180. DR PDB; 7VPL; EM; 3.50 A; A=1-1180. DR PDB; 8IEK; EM; 3.20 A; P=1-1180. DR PDB; 8IEL; EM; 5.65 A; P=36-1169. DR PDB; 8IEM; EM; 3.35 A; P=36-1169. DR PDB; 8IEN; EM; 3.25 A; P=1-1180. DR PDB; 8IEO; EM; 3.78 A; P=1-1180. DR PDB; 8IER; EM; 4.87 A; P=1-1180. DR PDB; 8IES; EM; 3.73 A; P=36-1180. DR PDBsum; 7FJM; -. DR PDBsum; 7FJP; -. DR PDBsum; 7FJQ; -. DR PDBsum; 7M5V; -. DR PDBsum; 7M5X; -. DR PDBsum; 7M5Y; -. DR PDBsum; 7N70; -. DR PDBsum; 7N72; -. DR PDBsum; 7N73; -. DR PDBsum; 7N74; -. DR PDBsum; 7N75; -. DR PDBsum; 7N76; -. DR PDBsum; 7N77; -. DR PDBsum; 7N78; -. DR PDBsum; 7VPI; -. DR PDBsum; 7VPJ; -. DR PDBsum; 7VPK; -. DR PDBsum; 7VPL; -. DR PDBsum; 8IEK; -. DR PDBsum; 8IEL; -. DR PDBsum; 8IEM; -. DR PDBsum; 8IEN; -. DR PDBsum; 8IEO; -. DR PDBsum; 8IER; -. DR PDBsum; 8IES; -. DR AlphaFoldDB; Q9NQ11; -. DR EMDB; EMD-23683; -. DR EMDB; EMD-23684; -. DR EMDB; EMD-23685; -. DR EMDB; EMD-24212; -. DR EMDB; EMD-24213; -. DR EMDB; EMD-24214; -. DR EMDB; EMD-24215; -. DR EMDB; EMD-24216; -. DR EMDB; EMD-24217; -. DR EMDB; EMD-24218; -. DR EMDB; EMD-24219; -. DR EMDB; EMD-24221; -. DR EMDB; EMD-24222; -. DR EMDB; EMD-24223; -. DR EMDB; EMD-31623; -. DR EMDB; EMD-31626; -. DR EMDB; EMD-31627; -. DR EMDB; EMD-32066; -. DR EMDB; EMD-32067; -. DR EMDB; EMD-32068; -. DR EMDB; EMD-32069; -. DR EMDB; EMD-35384; -. DR EMDB; EMD-35385; -. DR EMDB; EMD-35386; -. DR EMDB; EMD-35387; -. DR EMDB; EMD-35388; -. DR EMDB; EMD-35391; -. DR EMDB; EMD-35392; -. DR SMR; Q9NQ11; -. DR BioGRID; 116973; 116. DR FunCoup; Q9NQ11; 1150. DR IntAct; Q9NQ11; 115. DR MINT; Q9NQ11; -. DR STRING; 9606.ENSP00000327214; -. DR TCDB; 3.A.3.10.7; the p-type atpase (p-atpase) superfamily. DR GlyCosmos; Q9NQ11; 2 sites, No reported glycans. DR GlyGen; Q9NQ11; 4 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q9NQ11; -. DR PhosphoSitePlus; Q9NQ11; -. DR SwissPalm; Q9NQ11; -. DR BioMuta; ATP13A2; -. DR DMDM; 14285364; -. DR jPOST; Q9NQ11; -. DR MassIVE; Q9NQ11; -. DR PaxDb; 9606-ENSP00000327214; -. DR PeptideAtlas; Q9NQ11; -. DR ProteomicsDB; 63479; -. DR ProteomicsDB; 82052; -. [Q9NQ11-1] DR ProteomicsDB; 82053; -. [Q9NQ11-2] DR ProteomicsDB; 82054; -. [Q9NQ11-3] DR Pumba; Q9NQ11; -. DR Antibodypedia; 29290; 196 antibodies from 24 providers. DR DNASU; 23400; -. DR Ensembl; ENST00000326735.13; ENSP00000327214.8; ENSG00000159363.19. [Q9NQ11-1] DR Ensembl; ENST00000341676.9; ENSP00000341115.5; ENSG00000159363.19. [Q9NQ11-2] DR Ensembl; ENST00000452699.5; ENSP00000413307.1; ENSG00000159363.19. [Q9NQ11-3] DR GeneID; 23400; -. DR KEGG; hsa:23400; -. DR MANE-Select; ENST00000326735.13; ENSP00000327214.8; NM_022089.4; NP_071372.1. DR UCSC; uc001baa.3; human. [Q9NQ11-1] DR AGR; HGNC:30213; -. DR ClinPGx; PA134897221; -. DR CTD; 23400; -. DR DisGeNET; 23400; -. DR GeneCards; ATP13A2; -. DR GeneReviews; ATP13A2; -. DR HGNC; HGNC:30213; ATP13A2. DR HPA; ENSG00000159363; Tissue enhanced (brain). DR MalaCards; ATP13A2; -. DR MIM; 606693; phenotype. DR MIM; 610513; gene. DR MIM; 617225; phenotype. DR OpenTargets; ENSG00000159363; -. DR Orphanet; 513436; Autosomal recessive spastic paraplegia type 78. DR Orphanet; 314632; CLN12 disease. DR Orphanet; 306674; Kufor-Rakeb syndrome. DR VEuPathDB; HostDB:ENSG00000159363; -. DR eggNOG; KOG0208; Eukaryota. DR GeneTree; ENSGT00940000159714; -. DR HOGENOM; CLU_001828_0_0_1; -. DR InParanoid; Q9NQ11; -. DR OMA; SGWKDPL; -. DR OrthoDB; 48943at2759; -. DR PAN-GO; Q9NQ11; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q9NQ11; -. DR PathwayCommons; Q9NQ11; -. DR Reactome; R-HSA-936837; Ion transport by P-type ATPases. DR SignaLink; Q9NQ11; -. DR Agora; ENSG00000159363; -. DR BioGRID-ORCS; 23400; 14 hits in 1156 CRISPR screens. DR ChiTaRS; ATP13A2; human. DR GeneWiki; ATP13A2; -. DR GenomeRNAi; 23400; -. DR Pharos; Q9NQ11; Tbio. DR PRO; PR:Q9NQ11; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9NQ11; protein. DR Bgee; ENSG00000159363; Expressed in right frontal lobe and 166 other cell types or tissues. DR ExpressionAtlas; Q9NQ11; baseline and differential. DR GO; GO:0005776; C:autophagosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005770; C:late endosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0005771; C:multivesicular body; IDA:ParkinsonsUK-UCL. DR GO; GO:0032585; C:multivesicular body membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0030133; C:transport vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0031982; C:vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0015417; F:ABC-type polyamine transporter activity; IEA:RHEA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; NAS:ParkinsonsUK-UCL. DR GO; GO:0019829; F:ATPase-coupled monoatomic cation transmembrane transporter activity; IBA:GO_Central. DR GO; GO:1903135; F:cupric ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0030145; F:manganese ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0015662; F:P-type ion transporter activity; IEA:InterPro. DR GO; GO:0070300; F:phosphatidic acid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0015203; F:polyamine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:ParkinsonsUK-UCL. DR GO; GO:1905037; P:autophagosome organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0061909; P:autophagosome-lysosome fusion; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0071287; P:cellular response to manganese ion; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0071294; P:cellular response to zinc ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0097734; P:extracellular exosome biogenesis; IMP:ParkinsonsUK-UCL. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IDA:ParkinsonsUK-UCL. DR GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0030003; P:intracellular monoatomic cation homeostasis; TAS:ParkinsonsUK-UCL. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0055088; P:lipid homeostasis; IMP:UniProtKB. DR GO; GO:0007041; P:lysosomal transport; IMP:UniProtKB. DR GO; GO:0034220; P:monoatomic ion transmembrane transport; TAS:Reactome. DR GO; GO:1905166; P:negative regulation of lysosomal protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902047; P:polyamine transmembrane transport; IDA:ParkinsonsUK-UCL. DR GO; GO:1903543; P:positive regulation of exosomal secretion; IDA:ParkinsonsUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0050714; P:positive regulation of protein secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0061462; P:protein localization to lysosome; IMP:UniProtKB. DR GO; GO:0016243; P:regulation of autophagosome size; IDA:ParkinsonsUK-UCL. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:1904714; P:regulation of chaperone-mediated autophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0033157; P:regulation of intracellular protein transport; NAS:ParkinsonsUK-UCL. DR GO; GO:1905165; P:regulation of lysosomal protein catabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0016241; P:regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:ParkinsonsUK-UCL. DR GO; GO:1900180; P:regulation of protein localization to nucleus; IMP:UniProtKB. DR GO; GO:1903710; P:spermine transmembrane transport; IMP:UniProtKB. DR CDD; cd07542; P-type_ATPase_cation; 1. DR FunFam; 1.20.1110.10:FF:000023; Cation-transporting ATPase; 1. DR FunFam; 2.70.150.10:FF:000060; Cation-transporting ATPase; 1. DR FunFam; 3.40.1110.10:FF:000026; Cation-transporting ATPase; 1. DR FunFam; 3.40.50.1000:FF:000068; Cation-transporting ATPase; 1. DR Gene3D; 3.40.1110.10; Calcium-transporting ATPase, cytoplasmic domain N; 1. DR Gene3D; 2.70.150.10; Calcium-transporting ATPase, cytoplasmic transduction domain A; 1. DR Gene3D; 1.20.1110.10; Calcium-transporting ATPase, transmembrane domain; 1. DR Gene3D; 3.40.50.1000; HAD superfamily/HAD-like; 1. DR InterPro; IPR023299; ATPase_P-typ_cyto_dom_N. DR InterPro; IPR018303; ATPase_P-typ_P_site. DR InterPro; IPR023298; ATPase_P-typ_TM_dom_sf. DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A_sf. DR InterPro; IPR059000; ATPase_P-type_domA. DR InterPro; IPR036412; HAD-like_sf. DR InterPro; IPR023214; HAD_sf. DR InterPro; IPR006544; P-type_TPase_V. DR InterPro; IPR047819; P5A-ATPase_N. DR InterPro; IPR047821; P5B-type_ATPase. DR InterPro; IPR001757; P_typ_ATPase. DR InterPro; IPR044492; P_typ_ATPase_HD_dom. DR NCBIfam; TIGR01494; ATPase_P-type; 2. DR NCBIfam; TIGR01657; P-ATPase-V; 1. DR PANTHER; PTHR45630; CATION-TRANSPORTING ATPASE-RELATED; 1. DR PANTHER; PTHR45630:SF2; POLYAMINE-TRANSPORTING ATPASE 13A2; 1. DR Pfam; PF13246; Cation_ATPase; 1. DR Pfam; PF00122; E1-E2_ATPase; 1. DR Pfam; PF12409; P5-ATPase; 1. DR PRINTS; PR00119; CATATPASE. DR SFLD; SFLDG00002; C1.7:_P-type_atpase_like; 1. DR SFLD; SFLDS00003; Haloacid_Dehalogenase; 1. DR SFLD; SFLDF00027; p-type_atpase; 1. DR SUPFAM; SSF81653; Calcium ATPase, transduction domain A; 1. DR SUPFAM; SSF81665; Calcium ATPase, transmembrane domain M; 1. DR SUPFAM; SSF56784; HAD-like; 1. DR SUPFAM; SSF81660; Metal cation-transporting ATPase, ATP-binding domain N; 1. DR PROSITE; PS00154; ATPASE_E1_E2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasmic vesicle; KW Disease variant; Endosome; Glycoprotein; Hereditary spastic paraplegia; KW Lipid-binding; Lysosome; Magnesium; Membrane; Metal-binding; KW Neurodegeneration; Neuronal ceroid lipofuscinosis; Nucleotide-binding; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Translocase; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..1180 FT /note="Polyamine-transporting ATPase 13A2" FT /id="PRO_0000046423" FT TOPO_DOM 1..44 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT INTRAMEM 45..65 FT /evidence="ECO:0000255" FT TOPO_DOM 66..235 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 236..253 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 254..256 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 257..276 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 277..427 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 428..448 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 449..463 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 464..484 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 485..930 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 931..951 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 952..957 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 958..978 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 979..994 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 995..1015 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1016..1048 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1049..1069 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1070..1080 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1081..1101 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1102..1117 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:26134396" FT TRANSMEM 1118..1138 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1139..1180 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26134396" FT ACT_SITE 513 FT /note="4-aspartylphosphate intermediate" FT /evidence="ECO:0000269|PubMed:26134396" FT BINDING 878 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT BINDING 882 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250" FT MOD_RES 151 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CARBOHYD 1033 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:26134396" FT CARBOHYD 1110 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 155..159 FT /note="Missing (in isoform B and isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2, FT ECO:0000303|Ref.8" FT /id="VSP_007310" FT VAR_SEQ 805..843 FT /note="Missing (in isoform B)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.8" FT /id="VSP_007311" FT VAR_SEQ 1079..1180 FT /note="VPFLVALALLSSVLVGLVLVPGLLQGPLALRNITDTGFKLLLLGLVTLNFVG FT AFMLESVLDQCLPACLRRLRPKRASKKRFKQLERELAEQPWPPLPAGPLR -> ERARP FT VPPRLPAPPPAQAGLQEALQAAGTRAGRAALAAAARRPPEVVQAHGHPRHWNSLPLSHQ FT LDPSPATPPPPPPTSLRLATVYTPPPRPPPPWGSVDYCPLPWTIPRRGGSPQLPSVLLS FT V (in isoform B)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.8" FT /id="VSP_007312" FT VARIANT 12 FT /note="T -> M (in KRS; uncertain significance; no effect on FT stability; no effect on location; decreased ATPase FT activity; dbSNP:rs151117874)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_058451" FT VARIANT 49 FT /note="G -> S (in dbSNP:rs56379718)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058452" FT VARIANT 182 FT /note="F -> L (in KRS; decreased protein stability; loss of FT autophosphorylation; increased degradation by proteasome; FT novel location to endoplasmic reticulum; loss of lysosomal FT membrane location; impaired autophagosome-lysosome fusion; FT impaired degradation of protein aggregates)" FT /evidence="ECO:0000269|PubMed:18413573, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:30538141" FT /id="VAR_066019" FT VARIANT 294 FT /note="R -> Q (in dbSNP:rs56367069)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058453" FT VARIANT 389 FT /note="P -> L (in dbSNP:rs56275621)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058454" FT VARIANT 441 FT /note="I -> F (in KRS; uncertain significance; associated FT in cis with Thr-1069 in one individual; dbSNP:rs772446950)" FT /evidence="ECO:0000269|PubMed:29903538" FT /id="VAR_083537" FT VARIANT 504 FT /note="G -> R (in KRS; decreased protein stability; FT increased degradation by proteasome; novel location to FT endoplasmic reticulum; loss of lysosomal membrane location; FT impaired autophagosome-lysosome fusion; impaired FT degradation of protein aggregates; dbSNP:rs121918227)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:30538141" FT /id="VAR_058455" FT VARIANT 517 FT /note="T -> I (in SPG78; no effect on protein stability; FT loss of autophosphorylation; loss of lysosomal location; FT loss of ATPase activity; dbSNP:rs1057519291)" FT /evidence="ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:31996848" FT /id="VAR_078055" FT VARIANT 522 FT /note="G -> V (in KRS; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22296644" FT /id="VAR_078056" FT VARIANT 533 FT /note="G -> R (in KRS; uncertain significance; decreased FT ATPase activity; no effect on autophosphorylation; no FT effect on stability; no effect on location)" FT /evidence="ECO:0000269|PubMed:17485642, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:28137957, FT ECO:0000269|PubMed:31996848" FT /id="VAR_058456" FT VARIANT 578 FT /note="V -> G (in dbSNP:rs56186751)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058457" FT VARIANT 746 FT /note="A -> T (in KRS; decreased ATPase activity; no effect FT on stability; no effect on location; dbSNP:rs147277743)" FT /evidence="ECO:0000269|PubMed:19015489, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_058458" FT VARIANT 762 FT /note="R -> W (in dbSNP:rs55635527)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058459" FT VARIANT 776 FT /note="V -> I (in dbSNP:rs56170027)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058460" FT VARIANT 854 FT /note="M -> R (in KRS; some patients manifest FT neuropathologic findings suggestive of neuronal ceroid FT lipofuscinosis; dbSNP:rs587777053)" FT /evidence="ECO:0000269|PubMed:22388936" FT /id="VAR_070194" FT VARIANT 877 FT /note="G -> R (in KRS; found in two affected brothers also FT carrying C-481 in FBXO7; decreased protein stability; FT increased degradation by proteasome; novel location to FT endoplasmic reticulum; loss of ATPase activity; loss of FT autophosphorylation; dbSNP:rs144701072)" FT /evidence="ECO:0000269|PubMed:20853184, FT ECO:0000269|PubMed:22768177, ECO:0000269|PubMed:31996848" FT /id="VAR_066020" FT VARIANT 927 FT /note="L -> P (in SPG78; uncertain significance; contrary FT to the wild type, it does not localize to LAMP1-positive FT cytoplasmic vesicles)" FT /evidence="ECO:0000269|PubMed:38252374" FT /id="VAR_089312" FT VARIANT 946 FT /note="I -> F (in dbSNP:rs55708915)" FT /evidence="ECO:0000269|PubMed:19085912" FT /id="VAR_058461" FT VARIANT 1059 FT /note="L -> R (in KRS; the mutant protein is retained in FT the endoplasmic reticulum; dbSNP:rs137853967)" FT /evidence="ECO:0000269|PubMed:21542062" FT /id="VAR_066021" FT VARIANT 1069 FT /note="A -> T (in KRS; uncertain significance; associated FT in cis with Phe-441 in one individual; dbSNP:rs774238872)" FT /evidence="ECO:0000269|PubMed:29903538" FT /id="VAR_083538" FT MUTAGEN 59 FT /note="G->A: No effect on lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 66..68 FT /note="RWK->AWA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 74..78 FT /note="RLRLR->ALALA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 160..164 FT /note="KRVLR->AAVLA: Reduces lipid binding." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 348 FT /note="E->A: Autophosphorylated but displays limited FT spermine-induced ATPase activity and lacks spermine-induced FT dephosphorylation." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 472 FT /note="A->V: Reduced spermine-induced ATPase activity and FT lack of spermine-induced dephosphorylation." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 513 FT /note="D->N: Loss of ATPase function, autophosphorylation FT and protection against mitochondrial stress." FT /evidence="ECO:0000269|PubMed:26134396, FT ECO:0000269|PubMed:28137957, ECO:0000269|PubMed:31996848" FT MUTAGEN 967 FT /note="D->N: Reduced spermine-induced ATPase activity." FT /evidence="ECO:0000269|PubMed:31996848" FT MUTAGEN 1033 FT /note="N->A: Abolishes glycosylation." FT /evidence="ECO:0000269|PubMed:26134396" FT MUTAGEN 1067 FT /note="K->A: Reduced spermine-induced ATPase activity." FT /evidence="ECO:0000269|PubMed:31996848" FT CONFLICT 322 FT /note="Q -> R (in Ref. 6; AAH30267)" FT /evidence="ECO:0000305" FT CONFLICT 855..858 FT /note="APEQ -> IPRA (in Ref. 8; CAA08912)" FT /evidence="ECO:0000305" FT CONFLICT 861 FT /note="E -> V (in Ref. 8; CAA08912)" FT /evidence="ECO:0000305" FT STRAND 36..41 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 60..67 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 69..76 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 77..79 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 82..84 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 86..91 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 102..106 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 109..111 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 117..119 FT /evidence="ECO:0007829|PDB:7FJP" FT HELIX 120..123 FT /evidence="ECO:0007829|PDB:7FJP" FT HELIX 130..132 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 147..149 FT /evidence="ECO:0007829|PDB:7FJM" FT STRAND 159..161 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 164..168 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 171..176 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 177..180 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 181..184 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 185..187 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 188..191 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 194..199 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 200..202 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 206..216 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 228..235 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 239..253 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:7FJM" FT HELIX 257..289 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 294..299 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 300..302 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 303..308 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 309..311 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 317..320 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 329..341 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 343..346 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 350..355 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 361..363 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 366..369 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 370..372 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 379..384 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 386..397 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 399..401 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 403..412 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 422..449 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 473..491 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 493..497 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 498..505 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 508..512 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 516..518 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 524..529 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 532..534 FT /evidence="ECO:0007829|PDB:7FJP" FT STRAND 540..542 FT /evidence="ECO:0007829|PDB:7M5X" FT HELIX 543..545 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 550..557 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 562..564 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 567..570 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 572..581 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 584..586 FT /evidence="ECO:0007829|PDB:7M5X" FT STRAND 593..596 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 602..604 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 610..612 FT /evidence="ECO:0007829|PDB:7M5V" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:7M5V" FT STRAND 622..628 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 632..634 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 636..642 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 650..655 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 657..660 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 661..663 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 666..668 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 673..681 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 682..684 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 686..694 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 701..704 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 709..713 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 714..725 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 732..741 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 745..749 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 754..763 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:7N70" FT STRAND 771..779 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 783..785 FT /evidence="ECO:0007829|PDB:7M5X" FT STRAND 788..794 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 821..826 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 827..836 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 838..840 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 841..847 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 848..853 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 856..868 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 873..877 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 880..882 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 883..888 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 889..894 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 897..900 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 901..903 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 905..912 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 915..953 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 960..967 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 969..978 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 995..998 FT /evidence="ECO:0007829|PDB:7N74" FT HELIX 999..1024 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 1025..1028 FT /evidence="ECO:0007829|PDB:7M5V" FT STRAND 1034..1036 FT /evidence="ECO:0007829|PDB:7N73" FT TURN 1038..1041 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1045..1065 FT /evidence="ECO:0007829|PDB:7N72" FT TURN 1069..1071 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1075..1077 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1079..1097 FT /evidence="ECO:0007829|PDB:7N72" FT STRAND 1100..1102 FT /evidence="ECO:0007829|PDB:7M5X" FT TURN 1103..1107 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1114..1149 FT /evidence="ECO:0007829|PDB:7N72" FT HELIX 1158..1168 FT /evidence="ECO:0007829|PDB:7N72" SQ SEQUENCE 1180 AA; 128794 MW; 98D13745D3B615BE CRC64; MSADSSPLVG STPTGYGTLT IGTSIDPLSS SVSSVRLSGY CGSPWRVIGY HVVVWMMAGI PLLLFRWKPL WGVRLRLRPC NLAHAETLVI EIRDKEDSSW QLFTVQVQTE AIGEGSLEPS PQSQAEDGRS QAAVGAVPEG AWKDTAQLHK SEEAVSVGQK RVLRYYLFQG QRYIWIETQQ AFYQVSLLDH GRSCDDVHRS RHGLSLQDQM VRKAIYGPNV ISIPVKSYPQ LLVDEALNPY YGFQAFSIAL WLADHYYWYA LCIFLISSIS ICLSLYKTRK QSQTLRDMVK LSMRVCVCRP GGEEEWVDSS ELVPGDCLVL PQEGGLMPCD AALVAGECMV NESSLTGESI PVLKTALPEG LGPYCAETHR RHTLFCGTLI LQARAYVGPH VLAVVTRTGF CTAKGGLVSS ILHPRPINFK FYKHSMKFVA ALSVLALLGT IYSIFILYRN RVPLNEIVIR ALDLVTVVVP PALPAAMTVC TLYAQSRLRR QGIFCIHPLR INLGGKLQLV CFDKTGTLTE DGLDVMGVVP LKGQAFLPLV PEPRRLPVGP LLRALATCHA LSRLQDTPVG DPMDLKMVES TGWVLEEEPA ADSAFGTQVL AVMRPPLWEP QLQAMEEPPV PVSVLHRFPF SSALQRMSVV VAWPGATQPE AYVKGSPELV AGLCNPETVP TDFAQMLQSY TAAGYRVVAL ASKPLPTVPS LEAAQQLTRD TVEGDLSLLG LLVMRNLLKP QTTPVIQALR RTRIRAVMVT GDNLQTAVTV ARGCGMVAPQ EHLIIVHATH PERGQPASLE FLPMESPTAV NGVKDPDQAA SYTVEPDPRS RHLALSGPTF GIIVKHFPKL LPKVLVQGTV FARMAPEQKT ELVCELQKLQ YCVGMCGDGA NDCGALKAAD VGISLSQAEA SVVSPFTSSM ASIECVPMVI REGRCSLDTS FSVFKYMALY SLTQFISVLI LYTINTNLGD LQFLAIDLVI TTTVAVLMSR TGPALVLGRV RPPGALLSVP VLSSLLLQMV LVTGVQLGGY FLTLAQPWFV PLNRTVAAPD NLPNYENTVV FSLSSFQYLI LAAAVSKGAP FRRPLYTNVP FLVALALLSS VLVGLVLVPG LLQGPLALRN ITDTGFKLLL LGLVTLNFVG AFMLESVLDQ CLPACLRRLR PKRASKKRFK QLERELAEQP WPPLPAGPLR // ID PDE8B_HUMAN Reviewed; 885 AA. AC O95263; Q5J7V7; Q86XK8; Q8IUJ7; Q8IUJ8; Q8IUJ9; Q8IUK0; Q8N3T2; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 22-AUG-2003, sequence version 2. DT 28-JAN-2026, entry version 215. DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B; DE Short=HsPDE8B; DE EC=3.1.4.53 {ECO:0000269|PubMed:12681444}; DE AltName: Full=Cell proliferation-inducing gene 22 protein; GN Name=PDE8B; ORFNames=PIG22; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 6), AND TISSUE RP SPECIFICITY. RX PubMed=12372422; DOI=10.1016/s0006-291x(02)02371-9; RA Hayashi M., Shimada Y., Nishimura Y., Hama T., Tanaka T.; RT "Genomic organization, chromosomal localization, and alternative splicing RT of the human phosphodiesterase 8B gene."; RL Biochem. Biophys. Res. Commun. 297:1253-1258(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), CATALYTIC ACTIVITY, RP ACTIVITY REGULATION, AND TISSUE SPECIFICITY. RC TISSUE=Thyroid; RX PubMed=12681444; DOI=10.1016/s0898-6568(02)00146-8; RA Gamanuma M., Yuasa K., Sasaki T., Sakurai N., Kotera J., Omori K.; RT "Comparison of enzymatic characterization and gene organization of cyclic RT nucleotide phosphodiesterase 8 family in humans."; RL Cell. Signal. 15:565-574(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RA Kim J.W.; RT "Identification of a human proliferation-inducing gene."; RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 227-885 (ISOFORM 1). RX PubMed=9784418; DOI=10.1006/bbrc.1998.9379; RA Hayashi M., Matsushima K., Ohashi H., Tsunoda H., Murase S., Kawarada Y., RA Tanaka T.; RT "Molecular cloning and characterization of human PDE8B, a novel thyroid- RT specific isozyme of 3',5'-cyclic nucleotide phosphodiesterase."; RL Biochem. Biophys. Res. Commun. 250:751-756(1998). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-885 (ISOFORM 1). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP INVOLVEMENT IN ADSD1. RX PubMed=20085714; DOI=10.1016/j.ajhg.2009.12.003; RA Appenzeller S., Schirmacher A., Halfter H., Baumer S., Pendziwiat M., RA Timmerman V., De Jonghe P., Fekete K., Stogbauer F., Ludemann P., Hund M., RA Quabius E.S., Ringelstein E.B., Kuhlenbaumer G.; RT "Autosomal-dominant striatal degeneration is caused by a mutation in the RT phosphodiesterase 8B gene."; RL Am. J. Hum. Genet. 86:83-87(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP VARIANT PPNAD3 PRO-305, AND CHARACTERIZATION OF VARIANT PPNAD3 PRO-305. RX PubMed=18431404; DOI=10.1038/ejhg.2008.85; RA Horvath A., Giatzakis C., Tsang K., Greene E., Osorio P., Boikos S., RA Libe R., Patronas Y., Robinson-White A., Remmers E., Bertherat J., RA Nesterova M., Stratakis C.A.; RT "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal RT hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B RT isoform in human adrenal cortex."; RL Eur. J. Hum. Genet. 16:1245-1253(2008). CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key CC regulator of many important physiological processes. May be involved in CC specific signaling in the thyroid gland. CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, CC ChEBI:CHEBI:456215; EC=3.1.4.53; CC Evidence={ECO:0000269|PubMed:12681444}; CC -!- COFACTOR: CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; CC Evidence={ECO:0000250}; CC Note=Binds 2 divalent metal cations per subunit. Site 1 may CC preferentially bind zinc ions, while site 2 has a preference for CC magnesium and/or manganese ions. {ECO:0000250}; CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to CC selective PDE inhibitors including rolipram and milrinone as well as to CC the non-selective inhibitor, IBMX. Unaffected by cGMP. CC {ECO:0000269|PubMed:12681444}. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from CC 3',5'-cyclic AMP: step 1/1. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=PDE8B1; CC IsoId=O95263-1; Sequence=Displayed; CC Name=2; Synonyms=PDE8B2, PDE8B3; CC IsoId=O95263-2; Sequence=VSP_008084; CC Name=3; Synonyms=PDE8B3; CC IsoId=O95263-3; Sequence=VSP_008085; CC Name=4; Synonyms=PDE8B4; CC IsoId=O95263-4; Sequence=VSP_008082; CC Name=5; CC IsoId=O95263-5; Sequence=VSP_008081; CC Name=6; Synonyms=PDE8B2; CC IsoId=O95263-6; Sequence=VSP_008083; CC -!- TISSUE SPECIFICITY: Abundantly expressed in the thyroid. Also very CC weakly expressed in brain, spinal cord and placenta. In the thyroid CC isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. CC In the placenta isoforms 1 and 2 are expressed equally. In the brain CC isoform 2 predominates. {ECO:0000269|PubMed:12372422, CC ECO:0000269|PubMed:12681444}. CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two CC putative divalent metal sites and an N-terminal regulatory domain. CC -!- DISEASE: Striatal degeneration, autosomal dominant 1 (ADSD1) CC [MIM:609161]: A movement disorder affecting the striatal part of the CC basal ganglia and characterized by bradykinesia, dysarthria and muscle CC rigidity. These symptoms resemble idiopathic Parkinson disease, but CC tremor is not present. {ECO:0000269|PubMed:20085714}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Primary pigmented nodular adrenocortical disease 3 (PPNAD3) CC [MIM:614190]: A rare bilateral adrenal defect causing ACTH-independent CC Cushing syndrome. Macroscopic appearance of the adrenals is CC characteristic with small pigmented micronodules observed in the CC cortex. Adrenal glands show overall normal size and weight, and CC multiple small yellow-to-dark brown nodules surrounded by a cortex with CC a uniform appearance. Microscopically, there are moderate diffuse CC cortical hyperplasia with mostly nonpigmented nodules, multiple CC capsular deficits and massive circumscribed and infiltrating extra- CC adrenal cortical excrescences with micronodules. Clinical CC manifestations of Cushing syndrome include facial and truncal obesity, CC abdominal striae, muscular weakness, osteoporosis, arterial CC hypertension, diabetes. {ECO:0000269|PubMed:18431404}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC PDE8 subfamily. {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; AY129948; AAN71723.1; -; mRNA. DR EMBL; AY129949; AAN71724.1; -; mRNA. DR EMBL; AY129950; AAN71725.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71726.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71727.1; -; Genomic_DNA. DR EMBL; AB085824; BAC53762.1; -; mRNA. DR EMBL; AB085825; BAC53763.1; -; mRNA. DR EMBL; AB085826; BAC53764.1; -; mRNA. DR EMBL; AB085827; BAC53765.1; -; mRNA. DR EMBL; AY423729; AAS00492.1; -; mRNA. DR EMBL; CH471084; EAW95803.1; -; Genomic_DNA. DR EMBL; BC043209; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AF079529; AAC69564.2; -; mRNA. DR EMBL; AL831924; CAD38584.1; -; mRNA. DR CCDS; CCDS34190.1; -. [O95263-3] DR CCDS; CCDS34191.1; -. [O95263-6] DR CCDS; CCDS34192.1; -. [O95263-2] DR CCDS; CCDS34193.1; -. [O95263-4] DR CCDS; CCDS4037.1; -. [O95263-1] DR PIR; JE0293; JE0293. DR RefSeq; NP_001025022.1; NM_001029851.4. [O95263-2] DR RefSeq; NP_001025023.1; NM_001029852.4. [O95263-3] DR RefSeq; NP_001025024.1; NM_001029853.4. [O95263-4] DR RefSeq; NP_001025025.1; NM_001029854.4. [O95263-6] DR RefSeq; NP_003710.1; NM_003719.5. [O95263-1] DR AlphaFoldDB; O95263; -. DR SMR; O95263; -. DR BioGRID; 114177; 12. DR CORUM; O95263; -. DR FunCoup; O95263; 217. DR IntAct; O95263; 4. DR MINT; O95263; -. DR STRING; 9606.ENSP00000264917; -. DR BindingDB; O95263; -. DR ChEMBL; CHEMBL4408; -. DR DrugBank; DB00201; Caffeine. DR DrugBank; DB09283; Trapidil. DR DrugCentral; O95263; -. DR GuidetoPHARMACOLOGY; 1308; -. DR iPTMnet; O95263; -. DR PhosphoSitePlus; O95263; -. DR BioMuta; PDE8B; -. DR jPOST; O95263; -. DR MassIVE; O95263; -. DR PaxDb; 9606-ENSP00000264917; -. DR PeptideAtlas; O95263; -. DR ProteomicsDB; 50759; -. [O95263-1] DR ProteomicsDB; 50760; -. [O95263-2] DR ProteomicsDB; 50761; -. [O95263-3] DR ProteomicsDB; 50762; -. [O95263-4] DR ProteomicsDB; 50763; -. [O95263-5] DR ProteomicsDB; 50764; -. [O95263-6] DR Pumba; O95263; -. DR Antibodypedia; 12495; 151 antibodies from 26 providers. DR DNASU; 8622; -. DR Ensembl; ENST00000264917.10; ENSP00000264917.6; ENSG00000113231.14. [O95263-1] DR Ensembl; ENST00000333194.8; ENSP00000331336.4; ENSG00000113231.14. [O95263-3] DR Ensembl; ENST00000340978.7; ENSP00000345446.3; ENSG00000113231.14. [O95263-6] DR Ensembl; ENST00000342343.8; ENSP00000345646.4; ENSG00000113231.14. [O95263-4] DR Ensembl; ENST00000346042.7; ENSP00000330428.3; ENSG00000113231.14. [O95263-2] DR Ensembl; ENST00000505283.1; ENSP00000423461.1; ENSG00000113231.14. [O95263-5] DR GeneID; 8622; -. DR KEGG; hsa:8622; -. DR MANE-Select; ENST00000264917.10; ENSP00000264917.6; NM_003719.5; NP_003710.1. DR UCSC; uc003kfa.4; human. [O95263-1] DR AGR; HGNC:8794; -. DR ClinPGx; PA33142; -. DR CTD; 8622; -. DR DisGeNET; 8622; -. DR GeneCards; PDE8B; -. DR HGNC; HGNC:8794; PDE8B. DR HPA; ENSG00000113231; Tissue enriched (thyroid). DR MalaCards; PDE8B; -. DR MIM; 603390; gene. DR MIM; 609161; phenotype. DR MIM; 614190; phenotype. DR OpenTargets; ENSG00000113231; -. DR Orphanet; 228169; Autosomal dominant striatal neurodegeneration. DR Orphanet; 647782; Isolated micronodular adrenocortical disease. DR VEuPathDB; HostDB:ENSG00000113231; -. DR eggNOG; KOG1229; Eukaryota. DR GeneTree; ENSGT00940000157817; -. DR HOGENOM; CLU_005940_4_2_1; -. DR InParanoid; O95263; -. DR OMA; RWCCGGS; -. DR OrthoDB; 189220at2759; -. DR PAN-GO; O95263; 2 GO annotations based on evolutionary models. DR PhylomeDB; O95263; -. DR BRENDA; 3.1.4.53; 2681. DR PathwayCommons; O95263; -. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; O95263; -. DR UniPathway; UPA00762; UER00747. DR Agora; ENSG00000113231; -. DR BioGRID-ORCS; 8622; 19 hits in 1161 CRISPR screens. DR ChiTaRS; PDE8B; human. DR GeneWiki; PDE8B; -. DR GenomeRNAi; 8622; -. DR Pharos; O95263; Tclin. DR PRO; PR:O95263; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; O95263; protein. DR Bgee; ENSG00000113231; Expressed in left lobe of thyroid gland and 104 other cell types or tissues. DR ExpressionAtlas; O95263; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IMP:UniProtKB. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0141162; P:negative regulation of cAMP/PKA signal transduction; IBA:GO_Central. DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090032; P:negative regulation of steroid hormone biosynthetic process; IEA:Ensembl. DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl. DR GO; GO:0035106; P:operant conditioning; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; IEA:InterPro. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd00077; HDc; 1. DR CDD; cd00130; PAS; 1. DR FunFam; 1.10.1300.10:FF:000002; Phosphodiesterase; 1. DR FunFam; 3.30.450.20:FF:000023; Phosphodiesterase; 1. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 1. DR InterPro; IPR003607; HD/PDEase_dom. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR057304; PDE8-like_REC_N. DR InterPro; IPR023088; PDEase. DR InterPro; IPR002073; PDEase_catalytic_dom. DR InterPro; IPR036971; PDEase_catalytic_dom_sf. DR InterPro; IPR023174; PDEase_CS. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR Pfam; PF13426; PAS_9; 1. DR Pfam; PF08629; PDE8; 1. DR Pfam; PF23198; PDE8A_N; 1. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00471; HDc; 1. DR SMART; SM00091; PAS; 1. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 1. DR PROSITE; PS50112; PAS; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; cAMP; Cushing syndrome; Disease variant; Hydrolase; KW Metal-binding; Phosphoprotein; Proteomics identification; KW Reference proteome. FT CHAIN 1..885 FT /note="High affinity cAMP-specific and IBMX-insensitive FT 3',5'-cyclic phosphodiesterase 8B" FT /id="PRO_0000198840" FT DOMAIN 267..338 FT /note="PAS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 539..875 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 18..41 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 72..95 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 393..436 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 23..34 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 75..90 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 422..436 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 615 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 619 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 655 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 781 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT MOD_RES 517 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q4S1" FT VAR_SEQ 1..535 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.3" FT /id="VSP_008081" FT VAR_SEQ 114..133 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008082" FT VAR_SEQ 293..389 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12372422, FT ECO:0000303|PubMed:12681444" FT /id="VSP_008084" FT VAR_SEQ 293..339 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:12372422" FT /id="VSP_008083" FT VAR_SEQ 456..510 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008085" FT VARIANT 305 FT /note="H -> P (in PPNAD3; shows significantly higher cyclic FT AMP levels after transfection with the mutant protein than FT after transfection with the wild-type, indicating an FT impaired ability of the mutant protein to degrade cAMP; FT dbSNP:rs121918360)" FT /evidence="ECO:0000269|PubMed:18431404" FT /id="VAR_066503" FT CONFLICT 147 FT /note="G -> R (in Ref. 7; CAD38584)" FT /evidence="ECO:0000305" SQ SEQUENCE 885 AA; 98979 MW; DB4F763E51F745A3 CRC64; MGCAPSIHVS QSGVIYCRDS DESSSPRQTT SVSQGPAAPL PGLFVQTDAA DAIPPSRASG PPSVARVRRA RTELGSGSSA GSAAPAATTS RGRRRHCCSS AEAETQTCYT SVKQVSSAEV RIGPMRLTQD PIQVLLIFAK EDSQSDGFWW ACDRAGYRCN IARTPESALE CFLDKHHEII VIDHRQTQNF DAEAVCRSIR ATNPSEHTVI LAVVSRVSDD HEEASVLPLL HAGFNRRFME NSSIIACYNE LIQIEHGEVR SQFKLRACNS VFTALDHCHE AIEITSDDHV IQYVNPAFER MMGYHKGELL GKELADLPKS DKNRADLLDT INTCIKKGKE WQGVYYARRK SGDSIQQHVK ITPVIGQGGK IRHFVSLKKL CCTTDNNKQI HKIHRDSGDN SQTEPHSFRY KNRRKESIDV KSISSRGSDA PSLQNRRYPS MARIHSMTIE APITKVINII NAAQENSPVT VAEALDRVLE ILRTTELYSP QLGTKDEDPH TSDLVGGLMT DGLRRLSGNE YVFTKNVHQS HSHLAMPITI NDVPPCISQL LDNEESWDFN IFELEAITHK RPLVYLGLKV FSRFGVCEFL NCSETTLRAW FQVIEANYHS SNAYHNSTHA ADVLHATAFF LGKERVKGSL DQLDEVAALI AATVHDVDHP GRTNSFLCNA GSELAVLYND TAVLESHHTA LAFQLTVKDT KCNIFKNIDR NHYRTLRQAI IDMVLATEMT KHFEHVNKFV NSINKPMAAE IEGSDCECNP AGKNFPENQI LIKRMMIKCA DVANPCRPLD LCIEWAGRIS EEYFAQTDEE KRQGLPVVMP VFDRNTCSIP KSQISFIDYF ITDMFDAWDA FAHLPALMQH LADNYKHWKT LDDLKCKSLR LPSDS // ID PEO1_HUMAN Reviewed; 684 AA. AC Q96RR1; B2CQL2; Q6MZX2; Q6PJP5; Q96RR0; DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Twinkle mtDNA helicase {ECO:0000312|HGNC:HGNC:1160}; DE EC=5.6.2.3 {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550}; DE AltName: Full=Progressive external ophthalmoplegia 1 protein; DE AltName: Full=T7 gp4-like protein with intramitochondrial nucleoid localization; DE AltName: Full=T7-like mitochondrial DNA helicase; DE AltName: Full=Twinkle protein, mitochondrial {ECO:0000305}; DE Flags: Precursor; GN Name=TWNK {ECO:0000312|HGNC:HGNC:1160}; Synonyms=C10orf2, PEO1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, VARIANT ILE-368, AND VARIANTS PEOA3 LEU-315; PRO-354; RP THR-359; THR-367; PRO-369; GLN-374; PRO-381; CYS-474 AND PRO-475. RX PubMed=11431692; DOI=10.1038/90058; RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RT "Human mitochondrial DNA deletions associated with mutations in the gene RT for Twinkle, a phage T7 gene 4-like protein localized in mitochondria."; RL Nat. Genet. 28:223-231(2001). RN [2] RP ERRATUM OF PUBMED:11431692. RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RL Nat. Genet. 29:100-100(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Fetal 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 [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-348; ILE-368 AND RP LYS-634. RG NIEHS SNPs program; RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 132-582 (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=12975372; DOI=10.1074/jbc.m306981200; RA Korhonen J.A., Gaspari M., Falkenberg M.; RT "TWINKLE has 5' -> 3' DNA helicase activity and is specifically stimulated RT by mitochondrial single-stranded DNA-binding protein."; RL J. Biol. Chem. 278:48627-48632(2003). RN [9] RP FUNCTION (ISOFORM 1), AND INTERACTION WITH POLG (ISOFORM 1). RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP TISSUE SPECIFICITY, AND COREGULATION WITH MRPL43. RX PubMed=15509589; DOI=10.1093/hmg/ddh342; RA Tyynismaa H., Sembongi H., Bokori-Brown M., Granycome C., Ashley N., RA Poulton J., Jalanko A., Spelbrink J.N., Holt I.J., Suomalainen A.; RT "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA RT copy number."; RL Hum. Mol. Genet. 13:3219-3227(2004). RN [11] RP INTERACTION WITH LONP1. RX PubMed=14739292; DOI=10.1074/jbc.m309642200; RA Liu T., Lu B., Lee I., Ondrovicova G., Kutejova E., Suzuki C.K.; RT "DNA and RNA binding by the mitochondrial lon protease is regulated by RT nucleotide and protein substrate."; RL J. Biol. Chem. 279:13902-13910(2004). RN [12] RP POSSIBLE MECHANISM OF DELETION FORMATION. RX PubMed=15181170; DOI=10.1093/nar/gkh634; RA Wanrooij S., Luoma P., van Goethem G., van Broeckhoven C., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle and POLG defects enhance age-dependent accumulation of mutations RT in the control region of mtDNA."; RL Nucleic Acids Res. 32:3053-3064(2004). RN [13] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=17324440; DOI=10.1016/j.jmb.2007.01.079; RA Ziebarth T.D., Farr C.L., Kaguni L.S.; RT "Modular architecture of the hexameric human mitochondrial DNA helicase."; RL J. Mol. Biol. 367:1382-1391(2007). RN [14] RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT RP (ISOFORMS 1 AND 2), AND DOMAIN. RX PubMed=18039713; DOI=10.1093/nar/gkm1025; RA Farge G., Holmlund T., Khvorostova J., Rofougaran R., Hofer A., RA Falkenberg M.; RT "The N-terminal domain of TWINKLE contributes to single-stranded DNA RT binding and DNA helicase activities."; RL Nucleic Acids Res. 36:393-403(2008). RN [15] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT (ISOFORM 1), RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LEU-315; GLU-319; RP THR-359; PRO-369; GLN-374 AND CYS-474. RX PubMed=18971204; DOI=10.1093/hmg/ddn359; RA Goffart S., Cooper H.M., Tyynismaa H., Wanrooij S., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle mutations associated with autosomal dominant progressive external RT ophthalmoplegia lead to impaired helicase function and in vivo mtDNA RT replication stalling."; RL Hum. Mol. Genet. 18:328-340(2009). RN [16] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), ACTIVITY REGULATION RP (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES (ISOFORM 1), SUBUNIT (ISOFORM RP 1), AND MUTAGENESIS OF LYS-421. RX PubMed=22383523; DOI=10.1074/jbc.m111.309468; RA Sen D., Nandakumar D., Tang G.Q., Patel S.S.; RT "Human mitochondrial DNA helicase TWINKLE is both an unwinding and RT annealing helicase."; RL J. Biol. Chem. 287:14545-14556(2012). RN [17] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=25824949; DOI=10.1093/nar/gkv189; RA Fernandez-Millan P., Lazaro M., Cansiz-Arda S., Gerhold J.M., Rajala N., RA Schmitz C.A., Silva-Espina C., Gil D., Bernado P., Valle M., RA Spelbrink J.N., Sola M.; RT "The hexameric structure of the human mitochondrial replicative helicase RT Twinkle."; RL Nucleic Acids Res. 43:4284-4295(2015). RN [18] RP FUNCTION (ISOFORM 1). RX PubMed=26887820; DOI=10.1093/nar/gkw098; RA Sen D., Patel G., Patel S.S.; RT "Homologous DNA strand exchange activity of the human mitochondrial DNA RT helicase TWINKLE."; RL Nucleic Acids Res. 44:4200-4210(2016). RN [19] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=27226550; DOI=10.1074/jbc.m115.712026; RA Khan I., Crouch J.D., Bharti S.K., Sommers J.A., Carney S.M., RA Yakubovskaya E., Garcia-Diaz M., Trakselis M.A., Brosh R.M. Jr.; RT "Biochemical Characterization of the Human Mitochondrial Replicative RT Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY RT TO OVERCOME BLOCKADES TO DNA UNWINDING."; RL J. Biol. Chem. 291:14324-14339(2016). RN [20] RP SUBUNIT (ISOFORM 1), AND CHARACTERIZATION OF PEOA3 LEU-314; GLN-334; RP LEU-335; PRO-369 AND PRO-381. RX PubMed=30496414; DOI=10.1093/hmg/ddy415; RA Peter B., Farge G., Pardo-Hernandez C., Taangefjord S., Falkenberg M.; RT "Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE RT helicase."; RL Hum. Mol. Genet. 28:1090-1099(2019). RN [21] RP SUBCELLULAR LOCATION. RX PubMed=34950192; DOI=10.3389/fgene.2021.790521; RA So M., Stiban J., Ciesielski G.L., Hovde S.L., Kaguni L.S.; RT "Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal RT Domain in the Drosophila Mitochondrial Replicative DNA Helicase."; RL Front. Genet. 12:790521-790521(2021). RN [22] {ECO:0007744|PDB:7T8B, ECO:0007744|PDB:7T8C} RP STRUCTURE BY ELECTRON MICROSCOPY (3.8 ANGSTROMS) OF 1-684 OF VARIANT RP LEU-315, CATALYTIC ACTIVITY, SUBUNIT, AND CHARACTERIZATION OF VARIANT RP LEU-315. RX PubMed=35914129; DOI=10.1073/pnas.2207459119; RA Riccio A.A., Bouvette J., Perera L., Longley M.J., Krahn J.M., RA Williams J.G., Dutcher R., Borgnia M.J., Copeland W.C.; RT "Structural insight and characterization of human Twinkle helicase in RT mitochondrial disease."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207459119-e2207459119(2022). RN [23] RP VARIANTS PEOA3 LEU-335 AND TYR-369. RX PubMed=12163192; DOI=10.1016/s0022-510x(02)00190-9; RA Lewis S., Hutchison W., Thyagarajan D., Dahl H.-H.M.; RT "Clinical and molecular features of adPEO due to mutations in the Twinkle RT gene."; RL J. Neurol. Sci. 201:39-44(2002). RN [24] RP VARIANT ILE-368. RX PubMed=12557300; DOI=10.1002/ana.10430; RA Arenas J., Briem E., Dahl H.-H.M., Hutchison W., Lewis S., Martin M.A., RA Spelbrink H., Tiranti V., Jacobs H., Zeviani M.; RT "The V368I mutation in Twinkle does not segregate with AdPEO."; RL Ann. Neurol. 53:278-278(2003). RN [25] RP VARIANT PEO GLN-334. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [26] RP VARIANTS PEO TRP-303 AND GLN-334. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [27] RP VARIANT PEOA3 THR-319. RX PubMed=12921794; DOI=10.1016/s0960-8966(03)00071-3; RA Deschauer M., Kiefer R., Blakely E.L., He L., Zierz S., Turnbull D.M., RA Taylor R.W.; RT "A novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia."; RL Neuromuscul. Disord. 13:568-572(2003). RN [28] RP VARIANT MTDPS7 CYS-508. RX PubMed=16135556; DOI=10.1093/hmg/ddi328; RA Nikali K., Suomalainen A., Saharinen J., Kuokkanen M., Spelbrink J.N., RA Loennqvist T., Peltonen L.; RT "Infantile onset spinocerebellar ataxia is caused by recessive mutations in RT mitochondrial proteins Twinkle and Twinky."; RL Hum. Mol. Genet. 14:2981-2990(2005). RN [29] RP VARIANT PEOA3 GLU-319. RX PubMed=15668446; DOI=10.1212/01.wnl.0000149767.51152.83; RA Hudson G., Deschauer M., Busse K., Zierz S., Chinnery P.F.; RT "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable RT germline mosaicism."; RL Neurology 64:371-373(2005). RN [30] RP VARIANT PEOA3 GLN-374, AND VARIANT ILE-368. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [31] RP VARIANT MTDPS7 ILE-457, AND CHARACTERIZATION OF VARIANT MTDPS7 ILE-457. RX PubMed=17722119; DOI=10.1002/ana.21207; RA Sarzi E., Goffart S., Serre V., Chretien D., Slama A., Munnich A., RA Spelbrink J.N., Roetig A.; RT "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA RT depletion."; RL Ann. Neurol. 62:579-587(2007). RN [32] RP VARIANTS MTDPS7 THR-318 AND CYS-508. RX PubMed=17921179; DOI=10.1093/brain/awm242; RA Hakonen A.H., Isohanni P., Paetau A., Herva R., Suomalainen A., RA Lonnqvist T.; RT "Recessive Twinkle mutations in early onset encephalopathy with mtDNA RT depletion."; RL Brain 130:3032-3040(2007). RN [33] RP VARIANT PEOA3 PRO-357. RX PubMed=17614277; DOI=10.1016/j.nmd.2007.05.006; RA Rivera H., Blazquez A., Carretero J., Alvarez-Cermeno J.C., Campos Y., RA Cabello A., Gonzalez-Vioque E., Borstein B., Garesse R., Arenas J., RA Martin M.A.; RT "Mild ocular myopathy associated with a novel mutation in mitochondrial RT twinkle helicase."; RL Neuromuscul. Disord. 17:677-680(2007). RN [34] RP VARIANTS PEOA3 TRP-303; SER-315; PRO-334; ASN-426; SER-474; ILE-478 AND RP LYS-479. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [35] RP VARIANT PEOA3 LEU-370. RX PubMed=18396044; DOI=10.1016/j.nmd.2007.10.007; RA Jeppesen T.D., Schwartz M., Colding-Jorgensen E., Krag T., Hauerslev S., RA Vissing J.; RT "Phenotype and clinical course in a family with a new de novo Twinkle gene RT mutation."; RL Neuromuscul. Disord. 18:306-309(2008). RN [36] RP VARIANT PEOA3 GLN-303. RX PubMed=19353676; DOI=10.1002/ajmg.a.32731; RA Van Hove J.L., Cunningham V., Rice C., Ringel S.P., Zhang Q., Chou P.C., RA Truong C.K., Wong L.J.; RT "Finding twinkle in the eyes of a 71-year-old lady: a case report and RT review of the genotypic and phenotypic spectrum of TWINKLE-related dominant RT disease."; RL Am. J. Med. Genet. A 149:861-867(2009). RN [37] RP VARIANT PEOA3 TRP-303. RX PubMed=19428252; DOI=10.1016/j.nmd.2009.04.008; RA Negro R., Zoccolella S., Dell'aglio R., Amati A., Artuso L., Bisceglia L., RA Lavolpe V., Papa S., Serlenga L., Petruzzella V.; RT "Molecular analysis in a family presenting with a mild form of late-onset RT autosomal dominant chronic progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 19:423-426(2009). RN [38] RP VARIANT MTDPS7 GLY-360. RX PubMed=19853444; DOI=10.1016/j.nmd.2009.10.002; RA Bohlega S., Van Goethem G., Al Semari A., Lofgren A., Al Hamed M., RA Van Broeckhoven C., Kambouris M.; RT "Novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia and multisystem failure."; RL Neuromuscul. Disord. 19:845-848(2009). RN [39] RP VARIANTS PEOA3 GLN-303; TRP-303; GLN-334; PRO-354; PRO-357; THR-359; RP PRO-362; LEU-363; CYS-370; GLN-374; PRO-381; HIS-458; PRO-460; ASP-475 AND RP LYS-479. RX PubMed=20479361; DOI=10.1212/wnl.0b013e3181df099f; RA Fratter C., Gorman G.S., Stewart J.D., Buddles M., Smith C., Evans J., RA Seller A., Poulton J., Roberts M., Hanna M.G., Rahman S., Omer S.E., RA Klopstock T., Schoser B., Kornblum C., Czermin B., Lecky B., Blakely E.L., RA Craig K., Chinnery P.F., Turnbull D.M., Horvath R., Taylor R.W.; RT "The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)- RT linked adPEO."; RL Neurology 74:1619-1626(2010). RN [40] RP VARIANT PEOA3 GLN-374. RX PubMed=20880070; DOI=10.1111/j.1468-1331.2010.03171.x; RA Martin-Negrier M.L., Sole G., Jardel C., Vital C., Ferrer X., Vital A.; RT "TWINKLE gene mutation: report of a French family with an autosomal RT dominant progressive external ophthalmoplegia and literature review."; RL Eur. J. Neurol. 18:436-441(2011). RN [41] RP VARIANT MTDPS7 VAL-456. RX PubMed=22353293; DOI=10.1016/j.pediatrneurol.2011.12.006; RA Dundar H., Ozgul R.K., Yalnizoglu D., Erdem S., Oguz K.K., Tuncel D., RA Temucin C.M., Dursun A.; RT "Identification of a novel Twinkle mutation in a family with infantile RT onset spinocerebellar ataxia by whole exome sequencing."; RL Pediatr. Neurol. 46:172-177(2012). RN [42] RP INVOLVEMENT IN PRLTS5, AND VARIANTS PRLTS5 HIS-391; GLY-441; ILE-507 AND RP SER-585. RX PubMed=25355836; DOI=10.1212/wnl.0000000000001036; RA Morino H., Pierce S.B., Matsuda Y., Walsh T., Ohsawa R., Newby M., RA Hiraki-Kamon K., Kuramochi M., Lee M.K., Klevit R.E., Martin A., RA Maruyama H., King M.C., Kawakami H.; RT "Mutations in Twinkle primase-helicase cause Perrault syndrome with RT neurologic features."; RL Neurology 83:2054-2061(2014). CC -!- FUNCTION: [Isoform 1]: Mitochondrial helicase involved in mtDNA CC replication and repair (PubMed:12975372, PubMed:15167897, CC PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, CC PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair CC (PubMed:27226550). Has DNA strand separation activity needed to form a CC processive replication fork for leading strand synthesis which is CC catalyzed by the formation of a replisome complex with POLG and mtSDB CC (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, CC PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA CC substrates with pre-existing 5'-and 3'- single-stranded tails but is CC also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, CC PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). CC Can dissociate the invading strand of immobile or mobile D-loop DNA CC structures irrespective of the single strand polarity of the third CC strand (PubMed:27226550). In addition to its DNA strand separation CC activity, also has DNA strand annealing, DNA strand-exchange and DNA CC branch migration activities (PubMed:22383523, PubMed:26887820, CC PubMed:27226550). {ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:26887820, ECO:0000269|PubMed:27226550}. CC -!- FUNCTION: [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities CC (PubMed:18039713). Does not bind single-stranded or double-stranded DNA CC (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3; CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the CC replication fork by translocating in the 5'-3' direction.; CC EC=5.6.2.3; Evidence={ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550, CC ECO:0000269|PubMed:35914129}; CC -!- ACTIVITY REGULATION: [Isoform 1]: Strand annealing activity is CC inhibited by 150 mM NaCl (in vitro). {ECO:0000269|PubMed:22383523}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]: CC Kinetic parameters: CC KM=1.7 mM for UTP (using ssM13mp18 as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.6 mM for UTP (using ssDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.4 mM for UTP (using forked dsDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=3.4 mM for UTP (using no DNA as substrate) CC {ECO:0000269|PubMed:22383523}; CC -!- SUBUNIT: Interacts with LONP1. {ECO:0000269|PubMed:14739292}. CC -!- SUBUNIT: [Isoform 1]: Homohexamer (via C-terminus), which assembles in CC a ring-like structure (PubMed:17324440, PubMed:18039713, CC PubMed:18971204, PubMed:22383523, PubMed:25824949, PubMed:30496414). CC Homoheptamer, which assembles in a ring-like structure CC (PubMed:25824949, PubMed:30496414, PubMed:35914129). Homooctamer, which CC assembles in a ring-like structure (PubMed:35914129). Oligomers may CC sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA CC binding (PubMed:35914129). Oligomerization is Mg(2+), nucleotide and CC DNA-independent, however, Mg(2+) and nucleotide stabilize the CC homohexameric form (PubMed:18039713). Interacts with POLG in vitro CC (PubMed:15167897). {ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:30496414, CC ECO:0000269|PubMed:35914129}. CC -!- SUBUNIT: [Isoform 2]: Monomer (PubMed:18039713). Does not form CC oligomers (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- INTERACTION: CC Q96RR1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-716458, EBI-354956; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:18971204}. CC Mitochondrion inner membrane {ECO:0000303|PubMed:34950192}; Peripheral CC membrane protein {ECO:0000269|PubMed:34950192}. Note=Colocalizes with CC mtDNA in mitochondrial nucleoids, a nucleoproteins complex consisting CC of a number of copies of proteins associated with mtDNA, probably CC involved in mtDNA maintenance and expression (PubMed:11431692). CC Associates with phospholipid membranes via electrostatic binding (By CC similarity). Preferentially associates with membranes enriched with CC cardiolipin, a lipid abundant in the mitochondrial inner membrane CC (PubMed:34950192). ATPase and helicase activity is enhanced by binding CC to lipid membranes (PubMed:34950192). {ECO:0000250|UniProtKB:Q9VL76, CC ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:34950192}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q96RR1-1; Sequence=Displayed; CC Name=2; Synonyms=Twinky; CC IsoId=Q96RR1-2; Sequence=VSP_015960, VSP_015961; CC Name=3; CC IsoId=Q96RR1-3; Sequence=VSP_015959; CC -!- TISSUE SPECIFICITY: High relative levels in skeletal muscle, testis and CC pancreas. Lower levels of expression in the heart, brain, placenta, CC lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, CC colon and leukocytes. Expression is coregulated with MRPL43. CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:15509589}. CC -!- DOMAIN: N-terminus enhances protein stability and hexamer formation, CC which is important for DNA binding, and is required for DNA helicase CC activity and, ultimately, for mtDNA replisome processivity. CC {ECO:0000269|PubMed:18039713}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 3 (PEOA3) [MIM:609286]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11431692, CC ECO:0000269|PubMed:12163192, ECO:0000269|PubMed:12921794, CC ECO:0000269|PubMed:15668446, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:17614277, ECO:0000269|PubMed:18396044, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19353676, CC ECO:0000269|PubMed:19428252, ECO:0000269|PubMed:20479361, CC ECO:0000269|PubMed:20880070}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: CC A severe disease associated with mitochondrial dysfunction. Some CC patients are affected by progressive atrophy of the cerebellum, brain CC stem, the spinal cord, and sensory axonal neuropathy. Clinical features CC include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural CC hearing deficit, sensory axonal neuropathy, epileptic encephalopathy CC and female hypogonadism. In some individuals liver dysfunction and CC multi-organ failure is present. {ECO:0000269|PubMed:16135556, CC ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, CC ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault CC syndrome, a sex-influenced disorder characterized by sensorineural CC deafness in both males and females, and ovarian dysgenesis in females. CC Affected females have primary amenorrhea, streak gonads, and CC infertility, whereas affected males show normal pubertal development CC and are fertile. PRLTS5 is an autosomal recessive form characterized by CC progressive ataxia, axonal neuropathy, hyporeflexia and abnormal eye CC movements, in addition to deafness and ovarian dysgenesis. CC {ECO:0000269|PubMed:25355836}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- CAUTION: The N-terminus contains a putative primase-like domain; CC however the absence of the zinc binding domain and other motifs CC important for catalysis suggests that TWNK lacks primase activity. CC {ECO:0000305|PubMed:25824949}. CC -!- CAUTION: In vitro, can catalyze the hydrolysis of different nucleotide CC triphosphate (NTP) substrates with different efficiency. CC {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949}. 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; AF292004; AAK69558.1; -; mRNA. DR EMBL; AF292005; AAK69559.1; -; mRNA. DR EMBL; BX640829; CAE45905.1; -; mRNA. DR EMBL; AL133215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; EU543650; ACB21043.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49794.1; -; Genomic_DNA. DR EMBL; BC013349; AAH13349.1; -; mRNA. DR CCDS; CCDS53570.1; -. [Q96RR1-2] DR CCDS; CCDS7506.1; -. [Q96RR1-1] DR RefSeq; NP_001157284.1; NM_001163812.2. [Q96RR1-2] DR RefSeq; NP_068602.2; NM_021830.4. [Q96RR1-1] DR PDB; 7T8B; EM; 3.80 A; A/B/C/D/E/F/G/H=1-684. DR PDB; 7T8C; EM; 4.50 A; A/B/C/D/E/F/G=1-684. DR PDBsum; 7T8B; -. DR PDBsum; 7T8C; -. DR AlphaFoldDB; Q96RR1; -. DR EMDB; EMD-25743; -. DR EMDB; EMD-25744; -. DR SMR; Q96RR1; -. DR BioGRID; 121166; 148. DR FunCoup; Q96RR1; 1571. DR IntAct; Q96RR1; 83. DR MINT; Q96RR1; -. DR STRING; 9606.ENSP00000309595; -. DR GlyGen; Q96RR1; 1 site. DR iPTMnet; Q96RR1; -. DR PhosphoSitePlus; Q96RR1; -. DR BioMuta; TWNK; -. DR DMDM; 74752111; -. DR jPOST; Q96RR1; -. DR MassIVE; Q96RR1; -. DR PaxDb; 9606-ENSP00000309595; -. DR PeptideAtlas; Q96RR1; -. DR ProteomicsDB; 78006; -. [Q96RR1-1] DR ProteomicsDB; 78007; -. [Q96RR1-2] DR ProteomicsDB; 78008; -. [Q96RR1-3] DR Pumba; Q96RR1; -. DR Antibodypedia; 1261; 217 antibodies from 25 providers. DR DNASU; 56652; -. DR Ensembl; ENST00000311916.8; ENSP00000309595.2; ENSG00000107815.10. [Q96RR1-1] DR Ensembl; ENST00000370228.2; ENSP00000359248.1; ENSG00000107815.10. [Q96RR1-2] DR Ensembl; ENST00000643860.1; ENSP00000494389.1; ENSG00000107815.10. [Q96RR1-3] DR GeneID; 56652; -. DR KEGG; hsa:56652; -. DR MANE-Select; ENST00000311916.8; ENSP00000309595.2; NM_021830.5; NP_068602.2. DR UCSC; uc001ksf.3; human. [Q96RR1-1] DR AGR; HGNC:1160; -. DR ClinPGx; PA162377675; -. DR CTD; 56652; -. DR DisGeNET; 56652; -. DR GeneCards; TWNK; -. DR HGNC; HGNC:1160; TWNK. DR HPA; ENSG00000107815; Low tissue specificity. DR MalaCards; TWNK; -. DR MIM; 271245; phenotype. DR MIM; 606075; gene. DR MIM; 609286; phenotype. DR MIM; 616138; phenotype. DR OpenTargets; ENSG00000107815; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1186; Infantile-onset spinocerebellar ataxia. DR Orphanet; 363534; Mitochondrial DNA depletion syndrome, hepatocerebrorenal form. DR Orphanet; 642945; Perrault syndrome type 1. DR Orphanet; 642976; Perrault syndrome type 2. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR VEuPathDB; HostDB:ENSG00000107815; -. DR eggNOG; KOG2373; Eukaryota. DR GeneTree; ENSGT00390000004495; -. DR HOGENOM; CLU_012336_1_0_1; -. DR InParanoid; Q96RR1; -. DR OMA; GIRWSRF; -. DR OrthoDB; 275278at2759; -. DR PAN-GO; Q96RR1; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96RR1; -. DR BRENDA; 3.6.4.12; 2681. DR PathwayCommons; Q96RR1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q96RR1; -. DR Agora; ENSG00000107815; -. DR BioGRID-ORCS; 56652; 354 hits in 1149 CRISPR screens. DR ChiTaRS; TWNK; human. DR GeneWiki; PEO1; -. DR GenomeRNAi; 56652; -. DR Pharos; Q96RR1; Tbio. DR PRO; PR:Q96RR1; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q96RR1; protein. DR Bgee; ENSG00000107815; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 139 other cell types or tissues. DR ExpressionAtlas; Q96RR1; baseline and differential. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase. DR GO; GO:0003678; F:DNA helicase activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:FlyBase. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:FlyBase. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB. DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB. DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB. DR CDD; cd01029; TOPRIM_primases; 1. DR CDD; cd01122; Twinkle_C; 1. DR FunFam; 3.40.1360.10:FF:000008; Mitochondrial helicase twinkle; 1. DR FunFam; 3.40.50.300:FF:000845; Mitochondrial helicase twinkle; 1. DR Gene3D; 3.40.1360.10; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR007694; DNA_helicase_DnaB-like_C. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR034154; TOPRIM_DnaG/twinkle. DR InterPro; IPR027032; Twinkle-like. DR PANTHER; PTHR12873; T7-LIKE MITOCHONDRIAL DNA HELICASE; 1. DR PANTHER; PTHR12873:SF0; TWINKLE MTDNA HELICASE; 1. DR Pfam; PF13481; AAA_25; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51199; SF4_HELICASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Deafness; Disease variant; KW DNA replication; Helicase; Hydrolase; Isomerase; Lipid-binding; Membrane; KW Mitochondrion; Mitochondrion inner membrane; Mitochondrion nucleoid; KW Neurodegeneration; Neuropathy; Nucleotide-binding; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..31 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 32..684 FT /note="Twinkle mtDNA helicase" FT /id="PRO_0000042640" FT DOMAIN 384..635 FT /note="SF4 helicase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT REGION 1..121 FT /note="Contributes to single strand DNA binding activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 54..214 FT /note="N-terminal region (NTR)" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 121..372 FT /note="Required for hexamers formation and DNA helicase FT activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 215..335 FT /note="Primase-like domain" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 405..590 FT /note="Maybe required for stable oligomeric structure" FT /evidence="ECO:0000269|PubMed:17324440" FT REGION 637..684 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 640..684 FT /note="Might negatively regulate ATPase activity" FT /evidence="ECO:0000269|PubMed:17324440" FT COMPBIAS 659..677 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 415..422 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT VAR_SEQ 532..684 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_015959" FT VAR_SEQ 579..582 FT /note="ASQE -> VSGL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015960" FT VAR_SEQ 583..684 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015961" FT VARIANT 303 FT /note="R -> Q (in PEOA3; dbSNP:rs137852956)" FT /evidence="ECO:0000269|PubMed:19353676, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065102" FT VARIANT 303 FT /note="R -> W (in PEOA3; also detected in a case showing FT digenic inheritance; dbSNP:rs1159929268)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19428252, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023647" FT VARIANT 315 FT /note="W -> L (in PEOA3; reduced single-strand DNA binding; FT increased heptamer oligomerization; increased stability of FT the closed or 'compacted' conformation; dbSNP:rs111033575)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:30496414, ECO:0000269|PubMed:35914129" FT /id="VAR_023648" FT VARIANT 315 FT /note="W -> S (in PEOA3; reduces helicase activity; reduced FT single-strand DNA binding)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:18971204" FT /id="VAR_065103" FT VARIANT 318 FT /note="A -> T (in MTDPS7; dbSNP:rs80356542)" FT /evidence="ECO:0000269|PubMed:17921179" FT /id="VAR_065104" FT VARIANT 319 FT /note="K -> E (in PEOA3; the phenotype highly overlaps with FT sensory ataxic neuropathy dysarthria and ophthalmoparesis; FT reduces helicase activity and single-strand DNA binding; FT dbSNP:rs80356543)" FT /evidence="ECO:0000269|PubMed:15668446, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023649" FT VARIANT 319 FT /note="K -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:12921794" FT /id="VAR_023650" FT VARIANT 334 FT /note="R -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065105" FT VARIANT 334 FT /note="R -> Q (in PEO; sporadic case; the patient also FT carries the S-848 mutation in the POLG gene suggesting FT digenic inheritance; retains hexamer and heptamer FT formation; dbSNP:rs28937887)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:20479361, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023651" FT VARIANT 335 FT /note="P -> L (in PEOA3; displays unusual oligomeric FT forms)" FT /evidence="ECO:0000269|PubMed:12163192, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023652" FT VARIANT 348 FT /note="G -> R (in dbSNP:rs62626271)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062268" FT VARIANT 354 FT /note="R -> P (in PEOA3; dbSNP:rs111033576)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023653" FT VARIANT 357 FT /note="R -> P (in PEOA3; dbSNP:rs758026634)" FT /evidence="ECO:0000269|PubMed:17614277, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065106" FT VARIANT 359 FT /note="A -> T (in PEOA3; reduces helicase activity; FT dbSNP:rs111033573)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:20479361" FT /id="VAR_023654" FT VARIANT 360 FT /note="L -> G (in MTDPS7; patients manifest multi-organ FT failure; requires 2 nucleotide substitutions)" FT /evidence="ECO:0000269|PubMed:19853444" FT /id="VAR_065107" FT VARIANT 362 FT /note="A -> P (in PEOA3; dbSNP:rs1554887075)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065108" FT VARIANT 363 FT /note="W -> L (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065109" FT VARIANT 367 FT /note="I -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023655" FT VARIANT 368 FT /note="V -> I (in dbSNP:rs17113613)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:12557300, ECO:0000269|PubMed:16639411, FT ECO:0000269|Ref.4" FT /id="VAR_023656" FT VARIANT 369 FT /note="S -> P (in PEOA3; reduces helicase activity; FT increases single strand DNA affinity; reduces closed-ring FT quaternary structure formation)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:30496414" FT /id="VAR_023657" FT VARIANT 369 FT /note="S -> Y (in PEOA3; dbSNP:rs111033579)" FT /evidence="ECO:0000269|PubMed:12163192" FT /id="VAR_023658" FT VARIANT 370 FT /note="F -> C (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065110" FT VARIANT 370 FT /note="F -> L (in PEOA3; dbSNP:rs863223920)" FT /evidence="ECO:0000269|PubMed:18396044" FT /id="VAR_065111" FT VARIANT 374 FT /note="R -> Q (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs1554887097)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18971204, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:20880070" FT /id="VAR_023659" FT VARIANT 381 FT /note="L -> P (in PEOA3; reduces closed-ring quaternary FT structure formation; dbSNP:rs111033577)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:30496414" FT /id="VAR_023660" FT VARIANT 391 FT /note="R -> H (in PRLTS5; dbSNP:rs556445621)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072657" FT VARIANT 426 FT /note="S -> N (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065112" FT VARIANT 427 FT /note="E -> G (in dbSNP:rs11542126)" FT /id="VAR_051267" FT VARIANT 441 FT /note="W -> G (in PRLTS5; dbSNP:rs672601361)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072658" FT VARIANT 456 FT /note="L -> V (in MTDPS7; infantile spinocerebellar ataxia FT phenotype; dbSNP:rs386834145)" FT /evidence="ECO:0000269|PubMed:22353293" FT /id="VAR_067722" FT VARIANT 457 FT /note="T -> I (in MTDPS7; affects helicase activity; FT dbSNP:rs80356544)" FT /evidence="ECO:0000269|PubMed:17722119" FT /id="VAR_039045" FT VARIANT 458 FT /note="Q -> H (in PEOA3; dbSNP:rs1554887213)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065113" FT VARIANT 460 FT /note="A -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065114" FT VARIANT 474 FT /note="W -> C (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs111033574)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023661" FT VARIANT 474 FT /note="W -> S (in PEOA3; dbSNP:rs11542127)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065115" FT VARIANT 475 FT /note="A -> D (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065116" FT VARIANT 475 FT /note="A -> P (in PEOA3; dbSNP:rs111033572)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023662" FT VARIANT 478 FT /note="F -> I (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065117" FT VARIANT 479 FT /note="E -> K (in PEOA3; dbSNP:rs1085307937)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065118" FT VARIANT 507 FT /note="V -> I (in PRLTS5; dbSNP:rs369588002)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072659" FT VARIANT 508 FT /note="Y -> C (in MTDPS7; dbSNP:rs80356540)" FT /evidence="ECO:0000269|PubMed:16135556, FT ECO:0000269|PubMed:17921179" FT /id="VAR_043797" FT VARIANT 585 FT /note="N -> S (in PRLTS5; dbSNP:rs672601360)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072660" FT VARIANT 634 FT /note="N -> K (in dbSNP:rs62626293)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062269" FT MUTAGEN 421 FT /note="K->A: Loss of helicase activity on 5'-tailed FT substrate." FT /evidence="ECO:0000269|PubMed:22383523" FT CONFLICT 351 FT /note="N -> D (in Ref. 3; CAE45905)" FT /evidence="ECO:0000305" SQ SEQUENCE 684 AA; 77154 MW; 58186043888234DA CRC64; MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATEI RQYLRGHGIP FQDGHSCLRA LSPFAESSQL KGQTGVTTSF SLFIDKTTGH FLCMTSLAEG SWEDFQASVE GRGDGAREGF LLSKAPEFED SEEVRRIWNR AIPLWELPDQ EEVQLADTMF GLTKVTDDTL KRFSVRYLRP ARSLVFPWFS PGGSGLRGLK LLEAKCQGDG VSYEETTIPR PSAYHNLFGL PLISRRDAEV VLTSRELDSL ALNQSTGLPT LTLPRGTTCL PPALLPYLEQ FRRIVFWLGD DLRSWEAAKL FARKLNPKRC FLVRPGDQQP RPLEALNGGF NLSRILRTAL PAWHKSIVSF RQLREEVLGE LSNVEQAAGL RWSRFPDLNR ILKGHRKGEL TVFTGPTGSG KTTFISEYAL DLCSQGVNTL WGSFEISNVR LARVMLTQFA EGRLEDQLDK YDHWADRFED LPLYFMTFHG QQSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG VFRKFATDNN CHVTLVIHPR KEDDDKELQT ASIFGSAKAS QEADNVLILQ DRKLVTGPGK RYLQVSKNRF DGDVGVFPLE FNKNSLTFSI PPKNKARLKK IKDDTGPVAK KPSSGKKGAT TQNSEICSGQ APTPDQPDTS KRSK // ID PRKN_HUMAN Reviewed; 465 AA. AC O60260; A3FG77; A8K975; D3JZW7; D3K2X0; Q5TFV8; Q5VVX4; Q6Q2I6; Q8NI41; AC Q8NI43; Q8NI44; Q8WW07; DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 28-JAN-2026, entry version 236. DE RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000305}; DE Short=Parkin; DE EC=2.3.2.31 {ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:32047033}; DE AltName: Full=Parkin RBR E3 ubiquitin-protein ligase {ECO:0000312|HGNC:HGNC:8607}; DE AltName: Full=Parkinson juvenile disease protein 2; DE Short=Parkinson disease protein 2; GN Name=PRKN {ECO:0000312|HGNC:HGNC:8607}; Synonyms=PARK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INVOLVEMENT IN PARK2, AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain, and Skeletal muscle; RX PubMed=9560156; DOI=10.1038/33416; RA Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., RA Yokochi M., Mizuno Y., Shimizu N.; RT "Mutations in the parkin gene cause autosomal recessive juvenile RT parkinsonism."; RL Nature 392:605-608(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP VARIANTS ARG-311 AND THR-371, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19501131; DOI=10.1016/j.neulet.2009.05.079; RA Kasap M., Akpinar G., Sazci A., Idrisoglu H.A., Vahaboglu H.; RT "Evidence for the presence of full-length PARK2 mRNA and Parkin protein in RT human blood."; RL Neurosci. Lett. 460:196-200(2009). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4). RA D'Agata V., Scapagnini G., Cavallaro S.; RT "Functional and molecular diversity of parkin."; RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 7 AND 8). RC TISSUE=Retina; RA Campello L., Esteve-Rudd J., Cuenca N., Martin-Nieto J.; RT "Homo sapiens PARK2 transcript variants."; RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 312-361. RA Zou H.Q., Chan P.; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP SUBCELLULAR LOCATION. RX PubMed=10319893; RX DOI=10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z; RA Shimura H., Hattori N., Kubo S., Yoshikawa M., Kitada T., Matsumine H., RA Asakawa S., Minoshima S., Yamamura Y., Shimizu N., Mizuno Y.; RT "Immunohistochemical and subcellular localization of Parkin protein: RT absence of protein in autosomal recessive juvenile parkinsonism patients."; RL Ann. Neurol. 45:668-672(1999). RN [11] RP FUNCTION IN UBIQUITINATION. RX PubMed=10973942; DOI=10.1074/jbc.c000447200; RA Imai Y., Soda M., Takahashi R.; RT "Parkin suppresses unfolded protein stress-induced cell death through its RT E3 ubiquitin-protein ligase activity."; RL J. Biol. Chem. 275:35661-35664(2000). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240. RX PubMed=10888878; DOI=10.1038/77060; RA Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., RA Shimizu N., Iwai K., Chiba T., Tanaka K., Suzuki T.; RT "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein RT ligase."; RL Nat. Genet. 25:302-305(2000). RN [13] RP INTERACTION WITH UBE2L6 AND SEPTIN5, AND UBIQUITINATION OF SEPTIN5. RX PubMed=11078524; DOI=10.1073/pnas.240347797; RA Zhang Y., Gao J., Chung K.K.K., Huang H., Dawson V.L., Dawson T.M.; RT "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes RT the degradation of the synaptic vesicle-associated protein, CDCrel-1."; RL Proc. Natl. Acad. Sci. U.S.A. 97:13354-13359(2000). RN [14] RP UBIQUITINATION OF GPR37. RX PubMed=11439185; DOI=10.1016/s0092-8674(01)00407-x; RA Imai Y., Soda M., Inoue H., Hattori N., Mizuno Y., Takahashi R.; RT "An unfolded putative transmembrane polypeptide, which can lead to RT endoplasmic reticulum stress, is a substrate of Parkin."; RL Cell 105:891-902(2001). RN [15] RP FUNCTION, INTERACTION WITH SNCAIP, CHARACTERIZATION OF VARIANTS PARK2 RP ARG-240; CYS-256; TRP-275 AND ASN-415, AND MUTAGENESIS OF CYS-337; CYS-421 RP AND CYS-431. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK2 RP PRO-42 AND ARG-240. RX PubMed=11431533; DOI=10.1126/science.1060627; RA Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P., Trockenbacher A., RA Schneider R., Mizuno Y., Kosik K.S., Selkoe D.J.; RT "Ubiquitination of a new form of alpha-synuclein by parkin from human RT brain: implications for Parkinson's disease."; RL Science 293:263-269(2001). RN [17] RP PRESENCE OF ATYPICAL RING FINGER DOMAINS. RX PubMed=12446796; DOI=10.1093/oxfordjournals.molbev.a004029; RA Marin I., Ferrus A.; RT "Comparative genomics of the RBR family, including the Parkinson's disease- RT related gene parkin and the genes of the ariadne subfamily."; RL Mol. Biol. Evol. 19:2039-2050(2002). RN [18] RP FUNCTION, INTERACTION WITH STUB1; HSP70 AND GPR37, AND UBIQUITINATION OF RP STUB1. RX PubMed=12150907; DOI=10.1016/s1097-2765(02)00583-x; RA Imai Y., Soda M., Hatakeyama S., Akagi T., Hashikawa T., Nakayama K., RA Takahashi R.; RT "CHIP is associated with Parkin, a gene responsible for familial RT Parkinson's disease, and enhances its ubiquitin ligase activity."; RL Mol. Cell 10:55-67(2002). RN [19] RP INTERACTION WITH SYT11, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF RP VARIANTS PARK2 GLY-289 AND ARG-418. RX PubMed=12925569; DOI=10.1093/hmg/ddg269; RA Huynh D.P., Scoles D.R., Nguyen D., Pulst S.M.; RT "The autosomal recessive juvenile Parkinson disease gene product, parkin, RT interacts with and ubiquitinates synaptotagmin XI."; RL Hum. Mol. Genet. 12:2587-2597(2003). RN [20] RP INTERACTION WITH PACRG. RX PubMed=14532270; DOI=10.1074/jbc.m309655200; RA Imai Y., Soda M., Murakami T., Shoji M., Abe K., Takahashi R.; RT "A product of the human gene adjacent to parkin is a component of Lewy RT bodies and suppresses Pael receptor-induced cell death."; RL J. Biol. Chem. 278:51901-51910(2003). RN [21] RP FUNCTION, INTERACTION WITH FBXW7 AND CUL1, TISSUE SPECIFICITY, AND RP UBIQUITINATION OF CYCLIN E. RX PubMed=12628165; DOI=10.1016/s0896-6273(03)00084-9; RA Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E., RA Abeliovich A.; RT "Parkin is a component of an SCF-like ubiquitin ligase complex and protects RT postmitotic neurons from kainate excitotoxicity."; RL Neuron 37:735-749(2003). RN [22] RP INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=14614460; DOI=10.1038/sj.onc.1207072; RA Denison S.R., Wang F., Becker N.A., Schuele B., Kock N., Phillips L.A., RA Klein C., Smith D.I.; RT "Alterations in the common fragile site gene Parkin in ovarian and other RT cancers."; RL Oncogene 22:8370-8378(2003). RN [23] RP FUNCTION, INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=12719539; DOI=10.1073/pnas.0931262100; RA Cesari R., Martin E.S., Calin G.A., Pentimalli F., Bichi R., McAdams H., RA Trapasso F., Drusco A., Shimizu M., Masciullo V., D'Andrilli G., RA Scambia G., Picchio M.C., Alder H., Godwin A.K., Croce C.M.; RT "Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is RT a candidate tumor suppressor gene on chromosome 6q25-q27."; RL Proc. Natl. Acad. Sci. U.S.A. 100:5956-5961(2003). RN [24] RP REVIEW. RX PubMed=15229644; DOI=10.1038/sj.embor.7400188; RA Kahle P.J., Haass C.; RT "How does parkin ligate ubiquitin to Parkinson's disease?"; RL EMBO Rep. 5:681-685(2004). RN [25] RP FUNCTION, UBIQUITINATION, AND S-NITROSYLATION. RX PubMed=15105460; DOI=10.1126/science.1093891; RA Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., RA Dawson V.L., Dawson T.M.; RT "S-nitrosylation of parkin regulates ubiquitination and compromises RT parkin's protective function."; RL Science 304:1328-1331(2004). RN [26] RP INTERACTION WITH PSMA7. RX PubMed=15987638; DOI=10.1016/j.febslet.2005.06.003; RA Dachsel J.C., Lucking C.B., Deeg S., Schultz E., Lalowski M., RA Casademunt E., Corti O., Hampe C., Patenge N., Vaupel K., Yamamoto A., RA Dichgans M., Brice A., Wanker E.E., Kahle P.J., Gasser T.; RT "Parkin interacts with the proteasome subunit alpha4."; RL FEBS Lett. 579:3913-3919(2005). RN [27] RP FUNCTION, AND INTERACTION WITH SNCAIP. RX PubMed=15728840; DOI=10.1523/jneurosci.4474-04.2005; RA Lim K.L., Chew K.C., Tan J.M., Wang C., Chung K.K., Zhang Y., Tanaka Y., RA Smith W., Engelender S., Ross C.A., Dawson V.L., Dawson T.M.; RT "Parkin mediates nonclassical, proteasomal-independent ubiquitination of RT synphilin-1: implications for Lewy body formation."; RL J. Neurosci. 25:2002-2009(2005). RN [28] RP FUNCTION, AND INTERACTION WITH AIMP2. RX PubMed=16135753; DOI=10.1523/jneurosci.2172-05.2005; RA Ko H.S., von Coelln R., Sriram S.R., Kim S.W., Chung K.K.K., Pletnikova O., RA Troncoso J., Johnson B., Saffary R., Goh E.L., Song H., Park B.-J., RA Kim M.J., Kim S., Dawson V.L., Dawson T.M.; RT "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase RT cofactor, p38/JTV-1, leads to catecholaminergic cell death."; RL J. Neurosci. 25:7968-7978(2005). RN [29] RP INTERACTION WITH LRRK2. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., RA Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [30] RP INTERACTION WITH RANBP2. RX PubMed=16332688; DOI=10.1074/jbc.m504994200; RA Um J.W., Min D.S., Rhim H., Kim J., Paik S.R., Chung K.C.; RT "Parkin ubiquitinates and promotes the degradation of RanBP2."; RL J. Biol. Chem. 281:3595-3603(2006). RN [31] RP INTERACTION WITH SUMO1, AND SUBCELLULAR LOCATION. RX PubMed=16955485; DOI=10.1002/jnr.21041; RA Um J.W., Chung K.C.; RT "Functional modulation of parkin through physical interaction with SUMO- RT 1."; RL J. Neurosci. Res. 84:1543-1554(2006). RN [32] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17846173; DOI=10.1083/jcb.200611128; RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D., RA Chin L.S.; RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to RT aggresomes via binding to HDAC6."; RL J. Cell Biol. 178:1025-1038(2007). RN [33] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-175 AND THR-217, AND RP MUTAGENESIS OF THR-175; THR-217 AND CYS-238. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [34] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND SUBCELLULAR LOCATION. RX PubMed=19029340; DOI=10.1083/jcb.200809125; RA Narendra D., Tanaka A., Suen D.F., Youle R.J.; RT "Parkin is recruited selectively to impaired mitochondria and promotes RT their autophagy."; RL J. Cell Biol. 183:795-803(2008). RN [35] RP INTERACTION WITH RNF41, UBIQUITINATION, MUTAGENESIS OF CYS-421, AND RP FUNCTION. RX PubMed=18541373; DOI=10.1016/j.neulet.2008.05.052; RA Yu F., Zhou J.; RT "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative RT stress."; RL Neurosci. Lett. 440:4-8(2008). RN [36] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PARK2 RP PRO-42. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [37] RP FUNCTION IN PROTECTION OF APOPTOSIS, CHARACTERIZATION OF VARIANTS PARK2 RP ASN-161; CYS-256; TRP-275; ARG-418 AND ARG-441, AND DOMAIN. RX PubMed=19801972; DOI=10.1038/ncb1981; RA da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A., Safe S., RA Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S., Shen J., RA Checler F.; RT "Transcriptional repression of p53 by parkin and impairment by mutations RT associated with autosomal recessive juvenile Parkinson's disease."; RL Nat. Cell Biol. 11:1370-1375(2009). RN [38] RP INTERACTION WITH PINK1. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [39] RP FUNCTION, INTERACTION WITH BCL2, SUBCELLULAR LOCATION, AND CHARACTERIZATION RP OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND LEU-437. RX PubMed=20889974; DOI=10.1074/jbc.m110.101469; RA Chen D., Gao F., Li B., Wang H., Xu Y., Zhu C., Wang G.; RT "Parkin mono-ubiquitinates Bcl-2 and regulates autophagy."; RL J. Biol. Chem. 285:38214-38223(2010). RN [40] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PINK1, AND CHARACTERIZATION OF VARIANTS PARK ASN-415 AND ASP-430. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [41] RP FUNCTION, INTERACTION WITH ZNF746, AND CHARACTERIZATION OF VARIANTS PARK2 RP TRP-275; ASP-430 AND PHE-431. RX PubMed=21376232; DOI=10.1016/j.cell.2011.02.010; RA Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., RA Troconso J.C., Dawson V.L., Dawson T.M.; RT "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration RT in Parkinson's disease."; RL Cell 144:689-702(2011). RN [42] RP CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289. RX PubMed=20889486; DOI=10.1093/hmg/ddq428; RA Rose J.M., Novoselov S.S., Robinson P.A., Cheetham M.E.; RT "Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain RT mutant."; RL Hum. Mol. Genet. 20:16-27(2011). RN [43] RP FUNCTION. RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011; RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K., RA De Strooper B., Vandenberghe W.; RT "Parkin interacts with Ambra1 to induce mitophagy."; RL J. Neurosci. 31:10249-10261(2011). RN [44] RP FUNCTION, REACTION MECHANISM, AND INTERACTION WITH UBE2L3. RX PubMed=21532592; DOI=10.1038/nature09966; RA Wenzel D.M., Lissounov A., Brzovic P.S., Klevit R.E.; RT "UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT RT hybrids."; RL Nature 474:105-108(2011). RN [45] RP FUNCTION, INTERACTION WITH CHPF, AND SUBCELLULAR LOCATION. RX PubMed=22082830; DOI=10.1093/hmg/ddr530; RA Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y., Takahashi T., RA Kagawa N., Matsumoto M., Matsumoto M., Takahashi R., Kaji R., Mitsui T.; RT "Parkin interacts with Klokin1 for mitochondrial import and maintenance of RT membrane potential."; RL Hum. Mol. Genet. 21:991-1003(2012). RN [46] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 ASN-211 AND ASN-415. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [47] RP PHOSPHORYLATION AT SER-65, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [48] RP FUNCTION. RX PubMed=23685073; DOI=10.1016/j.molcel.2013.04.012; RA Haddad D.M., Vilain S., Vos M., Esposito G., Matta S., Kalscheuer V.M., RA Craessaerts K., Leyssen M., Nascimento R.M., Vianna-Morgante A.M., RA De Strooper B., Van Esch H., Morais V.A., Verstreken P.; RT "Mutations in the intellectual disability gene Ube2a cause neuronal RT dysfunction and impair parkin-dependent mitophagy."; RL Mol. Cell 50:831-843(2013). RN [49] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [50] RP INTERACTION WITH BAG4; BAG5; HSPA1L; HSPA1A AND HSPA8. RX PubMed=24270810; DOI=10.1038/nature12748; RA Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A., Buehler E., RA Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E., Youle R.J.; RT "High-content genome-wide RNAi screens identify regulators of parkin RT upstream of mitophagy."; RL Nature 504:291-295(2013). RN [51] RP UBIQUITINATION, MUTAGENESIS OF GLY-429, AND CHARACTERIZATION OF VARIANTS RP PARK2 ASN-415 AND ASP-430. RX PubMed=23770917; DOI=10.1038/ncomms2983; RA Spratt D.E., Martinez-Torres R.J., Noh Y.J., Mercier P., Manczyk N., RA Barber K.R., Aguirre J.D., Burchell L., Purkiss A., Walden H., Shaw G.S.; RT "A molecular explanation for the recessive nature of parkin-linked RT Parkinson's disease."; RL Nat. Commun. 4:1983-1983(2013). RN [52] RP FUNCTION IN MITOPHAGY, INTERACTION WITH MFN2, AND SUBCELLULAR LOCATION. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [53] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [54] RP SUBCELLULAR LOCATION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [55] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND CYS-431. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [56] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [57] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND TRP-403. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [58] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [59] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [60] RP FUNCTION. RX PubMed=25621951; DOI=10.1038/ncb3097; RA Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M., RA Kirkpatrick D.S., Bingol B., Corn J.E.; RT "USP30 and parkin homeostatically regulate atypical ubiquitin chains on RT mitochondria."; RL Nat. Cell Biol. 17:160-169(2015). RN [61] RP FUNCTION, ISGYLATION OF LYS-349 AND LYS-369, AND ACTIVITY REGULATION. RX PubMed=27534820; DOI=10.1098/rsob.160193; RA Im E., Yoo L., Hyun M., Shin W.H., Chung K.C.; RT "Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase RT activity of parkin."; RL Open Biol. 6:0-0(2016). RN [62] RP FUNCTION, MUTAGENESIS OF CYS-431, AND CHARACTERIZATION OF VARIANT PARK2 RP ASN-415. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [63] RP FUNCTION. RX PubMed=33499712; DOI=10.1080/15548627.2021.1874133; RA Kojima W., Yamano K., Kosako H., Imai K., Kikuchi R., Tanaka K., RA Matsuda N.; RT "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site RT in response to selective and non-selective autophagy."; RL Autophagy 1:1-26(2021). RN [64] RP STRUCTURE BY NMR OF 1-76, AND INTERACTION WITH PSMD4. RX PubMed=12634850; DOI=10.1038/sj.embor.embor764; RA Sakata E., Yamaguchi Y., Kurimoto E., Kikuchi J., Yokoyama S., Yamada S., RA Kawahara H., Yokosawa H., Hattori N., Mizuno Y., Tanaka K., Kato K.; RT "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin- RT like domain."; RL EMBO Rep. 4:301-306(2003). RN [65] RP STRUCTURE BY NMR OF 307-384 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF RP VARIANT PARK2 PRO-351, MUTAGENESIS OF CYS-332 AND CYS-365, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17360614; DOI=10.1073/pnas.0610548104; RA Beasley S.A., Hristova V.A., Shaw G.S.; RT "Structure of the Parkin in-between-ring domain provides insights for E3- RT ligase dysfunction in autosomal recessive Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 104:3095-3100(2007). RN [66] RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 137-465, ACTIVITY REGULATION, AND RP MUTAGENESIS OF CYS-431; HIS-433 AND GLU-444. RX PubMed=23727886; DOI=10.1038/emboj.2013.125; RA Wauer T., Komander D.; RT "Structure of the human Parkin ligase domain in an autoinhibited state."; RL EMBO J. 32:2099-2112(2013). RN [67] RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 137-465, ACTIVE SITE, CATALYTIC RP ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-431; HIS-433 AND RP GLU-444. RX PubMed=23770887; DOI=10.1038/ncomms2982; RA Riley B.E., Lougheed J.C., Callaway K., Velasquez M., Brecht E., Nguyen L., RA Shaler T., Walker D., Yang Y., Regnstrom K., Diep L., Zhang Z., Chiou S., RA Bova M., Artis D.R., Yao N., Baker J., Yednock T., Johnston J.A.; RT "Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RT RING and HECT ligases."; RL Nat. Commun. 4:1982-1982(2013). RN [68] RP REVIEW ON VARIANTS. RX PubMed=14976155; DOI=10.1093/hmg/ddh089; RA Mata I.F., Lockhart P.J., Farrer M.J.; RT "Parkin genetics: one model for Parkinson's disease."; RL Hum. Mol. Genet. 13:R127-R133(2004). RN [69] RP VARIANT PARK2 ARG-240. RX PubMed=9731209; DOI=10.1006/bbrc.1998.9134; RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RT "Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene."; RL Biochem. Biophys. Res. Commun. 249:754-758(1998). RN [70] RP ERRATUM OF PUBMED:9731209. RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RL Biochem. Biophys. Res. Commun. 251:666-666(1998). RN [71] RP VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415, AND VARIANTS ASN-167; RP LEU-380 AND ASN-394. RX PubMed=10072423; DOI=10.1093/hmg/8.4.567; RA Abbas N., Luecking C.B., Ricard S., Duerr A., Bonifati V., De Michele G., RA Bouley S., Vaughan J.R., Gasser T., Marconi R., Broussolle E., RA Brefel-Courbon C., Harhangi B.S., Oostra B.A., Fabrizio E., Bohme G.A., RA Pradier L., Wood N.W., Filla A., Meco G., Denefle P., Agid Y., Brice A.; RT "A wide variety of mutations in the parkin gene are responsible for RT autosomal recessive parkinsonism in Europe."; RL Hum. Mol. Genet. 8:567-574(1999). RN [72] RP VARIANT ASN-167. RX PubMed=10511432; DOI=10.1097/00001756-199909090-00008; RA Satoh J., Kuroda Y.; RT "Association of codon 167 Ser/Asn heterozygosity in the parkin gene with RT sporadic Parkinson's disease."; RL NeuroReport 10:2735-2739(1999). RN [73] RP VARIANT PARK2 PHE-431. RX PubMed=10939576; RX DOI=10.1002/1531-8249(200008)48:2<245::aid-ana15>3.3.co;2-u; RA Maruyama M., Ikeuchi T., Saito M., Ishikawa A., Yuasa T., Tanaka H., RA Hayashi S., Wakabayashi K., Takahashi H., Tsuji S.; RT "Novel mutations, pseudo-dominant inheritance, and possible familial RT affects in patients with autosomal recessive juvenile parkinsonism."; RL Ann. Neurol. 48:245-250(2000). RN [74] RP VARIANTS ASN-167; TRP-366 AND LEU-380. RX PubMed=10965160; DOI=10.1159/000008203; RA Hu C.-J., Sung S.-M., Liu H.-C., Lee C.-C., Tsai C.-H., Chang J.-G.; RT "Polymorphisms of the parkin gene in sporadic Parkinson's disease among RT Chinese in Taiwan."; RL Eur. Neurol. 44:90-93(2000). RN [75] RP VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; RP GLU-328; ASN-415 AND ASP-430, AND VARIANT CYS-334. RX PubMed=10824074; DOI=10.1056/nejm200005253422103; RA Luecking C.B., Duerr A., Bonifati V., Vaughan J.R., De Michele G., RA Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y., RA Brice A.; RT "Association between early-onset Parkinson's disease and mutations in the RT parkin gene."; RL N. Engl. J. Med. 342:1560-1567(2000). RN [76] RP VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430. RX PubMed=11179010; DOI=10.1086/318791; RA Periquet M., Luecking C.B., Vaughan J.R., Bonifati V., Duerr A., RA De Michele G., Horstink M., Farrer M., Illarioshkin S.N., Pollak P., RA Borg M., Brefel-Courbon C., Denefle P., Meco G., Gasser T., Breteler M.M., RA Wood N.W., Agid Y., Brice A.; RT "Origin of the mutations in the parkin gene in Europe: exon rearrangements RT are independent recurrent events, whereas point mutations may result from RT founder effects."; RL Am. J. Hum. Genet. 68:617-626(2001). RN [77] RP VARIANT PARK2 GLU-82. RX PubMed=11487568; DOI=10.1093/hmg/10.16.1649; RA Hedrich K., Kann M., Lanthaler A.J., Dalski A., Eskelson C., Landt O., RA Schwinger E., Vieregge P., Lang A.E., Breakefield X.O., Ozelius L.J., RA Pramstaller P.P., Klein C.; RT "The importance of gene dosage studies: mutational analysis of the parkin RT gene in early-onset parkinsonism."; RL Hum. Mol. Genet. 10:1649-1656(2001). RN [78] RP VARIANT PARK2 TYR-212. RX PubMed=11163284; DOI=10.1016/s0304-3940(00)01733-x; RA Pineda-Trujillo N., Carvajal-Carmona L.G., Buritica O., Moreno S., RA Uribe C., Pineda D., Toro M., Garcia F., Arias W., Bedoya G., Lopera F., RA Ruiz-Linares A.; RT "A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of RT juvenile parkinsonism in a population from North West Colombia."; RL Neurosci. Lett. 298:87-90(2001). RN [79] RP VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441. RX PubMed=12116199; DOI=10.1002/ajmg.10525; RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.; RT "Complex relationship between parkin mutations and Parkinson disease."; RL Am. J. Med. Genet. 114:584-591(2002). RN [80] RP ERRATUM OF PUBMED:12116199. RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.J.; RL Am. J. Med. Genet. 114:992-992(2002). RN [81] RP VARIANTS PARK2 LEU-37 AND PRO-351. RX PubMed=12112109; DOI=10.1002/ana.10179; RA Kann M., Jacobs H., Mohrmann K., Schumacher K., Hedrich K., Garrels J., RA Wiegers K., Schwinger E., Pramstaller P.P., Breakefield X.O., Ozelius L.J., RA Vieregge P., Klein C.; RT "Role of parkin mutations in 111 community-based patients with early-onset RT parkinsonism."; RL Ann. Neurol. 51:621-625(2002). RN [82] RP VARIANTS PARK2 GLU-56 AND TYR-212. RX PubMed=12056932; DOI=10.1001/archneur.59.6.966; RA Hoenicka J., Vidal L., Morales B., Ampuero I., Jimenez-Jimenez F.J., RA Berciano J., del Ser T., Jimenez A., Ruiz P.G., de Yebenes J.G.; RT "Molecular findings in familial Parkinson disease in Spain."; RL Arch. Neurol. 59:966-970(2002). RN [83] RP VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437. RX PubMed=12114481; DOI=10.1136/jmg.39.7.489; RA Nichols W.C., Pankratz N., Uniacke S.K., Pauciulo M.W., Halter C., RA Rudolph A., Conneally P.M., Foroud T.; RT "Linkage stratification and mutation analysis at the parkin locus RT identifies mutation positive Parkinson's disease families."; RL J. Med. Genet. 39:489-492(2002). RN [84] RP VARIANT PARK2 MET-15, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12397156; DOI=10.1136/jnnp.73.5.582; RA Munoz E., Tolosa E., Pastor P., Marti M.J., Valldeoriola F., RA Campdelacreu J., Oliva R.; RT "Relative high frequency of the c.255delA parkin gene mutation in Spanish RT patients with autosomal recessive parkinsonism."; RL J. Neurol. Neurosurg. Psych. 73:582-584(2002). RN [85] RP VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437. RX PubMed=11971093; DOI=10.1212/wnl.58.8.1239; RA Hedrich K., Marder K., Harris J., Kann M., Lynch T., Meija-Santana H., RA Pramstaller P.P., Schwinger E., Bressman S.B., Fahn S., Klein C.; RT "Evaluation of 50 probands with early-onset Parkinson's disease for parkin RT mutations."; RL Neurology 58:1239-1246(2002). RN [86] RP VARIANT PARK2 PRO-46. RX PubMed=12362318; RA Xu Y., Liu Z., Wang Y., Tao E., Chen G., Chen B.; RT "A new point mutation on exon 2 of parkin gene in Parkinson's disease."; RL Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:409-411(2002). RN [87] RP VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437, VARIANTS PARK TYR-253; RP CYS-256; TRP-275 AND ASN-280, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12730996; DOI=10.1002/ana.10524; RA Oliveira S.A., Scott W.K., Martin E.R., Nance M.A., Watts R.L., RA Hubble J.P., Koller W.C., Pahwa R., Stern M.B., Hiner B.C., Ondo W.G., RA Allen F.H. Jr., Scott B.L., Goetz C.G., Small G.W., Mastaglia F., RA Stajich J.M., Zhang F., Booze M.W., Winn M.P., Middleton L.T., Haines J.L., RA Pericak-Vance M.A., Vance J.M.; RT "Parkin mutations and susceptibility alleles in late-onset Parkinson's RT disease."; RL Ann. Neurol. 53:624-629(2003). RN [88] RP VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437, VARIANT ASN-167, AND RP INVOLVEMENT IN LATE-ONSET PARK. RX PubMed=12629236; DOI=10.1212/01.wnl.0000049470.00180.07; RA Foroud T., Uniacke S.K., Liu L., Pankratz N., Rudolph A., Halter C., RA Shults C., Marder K., Conneally P.M., Nichols W.C.; RT "Heterozygosity for a mutation in the parkin gene leads to later onset RT Parkinson disease."; RL Neurology 60:796-801(2003). RN [89] RP VARIANTS HIS-100; SER-271 AND SER-339. RX PubMed=12781599; DOI=10.1016/s1353-8020(03)00018-x; RA Chen R., Gosavi N.S., Langston J.W., Chan P.; RT "Parkin mutations are rare in patients with young-onset parkinsonism in a RT US population."; RL Parkinsonism Relat. Disord. 9:309-312(2003). RN [90] RP VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418. RX PubMed=15584030; DOI=10.1002/mds.20343; RG Italian Parkinson Genetics Network; RA Bertoli-Avella A.M., Giroud-Benitez J.L., Akyol A., Barbosa E., Schaap O., RA van der Linde H.C., Martignoni E., Lopiano L., Lamberti P., Fincati E., RA Antonini A., Stocchi F., Montagna P., Squitieri F., Marini P., RA Abbruzzese G., Fabbrini G., Marconi R., Dalla Libera A., Trianni G., RA Guidi M., De Gaetano A., Boff Maegawa G., De Leo A., Gallai V., de Rosa G., RA Vanacore N., Meco G., van Duijn C.M., Oostra B.A., Heutink P., Bonifati V.; RT "Novel parkin mutations detected in patients with early-onset Parkinson's RT disease."; RL Mov. Disord. 20:424-431(2005). RN [91] RP CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ASN-211; ARG-240; ASN-280 AND RP GLU-328. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [92] RP VARIANT PARK2 TRP-275. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). RN [93] RP VARIANT CYS-334. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [94] RP CHARACTERIZATION OF VARIANTS PARK PRO-42 AND TRP-275, AND FUNCTION. RX PubMed=29311685; DOI=10.1038/s41467-017-02593-y; RA Wang C., Kang X., Zhou L., Chai Z., Wu Q., Huang R., Xu H., Hu M., Sun X., RA Sun S., Li J., Jiao R., Zuo P., Zheng L., Yue Z., Zhou Z.; RT "Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and RT Parkinson's disease-like pathology."; RL Nat. Commun. 9:81-81(2018). CC -!- FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, CC catalyzing the covalent attachment of ubiquitin moieties onto substrate CC proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:29311685, CC PubMed:32047033). Substrates include SYT11 and VDAC1 (PubMed:29311685, CC PubMed:32047033). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, CC MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and CC AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536). Mediates CC monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and CC 'Lys-63'-linked polyubiquitination of substrates depending on the CC context (PubMed:19229105, PubMed:20889974, PubMed:25474007, CC PubMed:25621951, PubMed:32047033). Participates in the removal and/or CC detoxification of abnormally folded or damaged protein by mediating CC 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: CC 'Lys-63'-linked polyubiquitinated misfolded proteins are then CC recognized by HDAC6, leading to their recruitment to aggresomes, CC followed by degradation (PubMed:17846173, PubMed:19229105). Mediates CC 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated CC isoform of SNCAIP, possibly playing a role in Lewy-body formation CC (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:15728840, CC PubMed:19229105). Mediates monoubiquitination of BCL2, thereby acting CC as a positive regulator of autophagy (PubMed:20889974). Protects CC against mitochondrial dysfunction during cellular stress, by acting CC downstream of PINK1 to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:11439185, PubMed:18957282, PubMed:19029340, CC PubMed:19966284, PubMed:21376232, PubMed:22082830, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24660806, PubMed:24784582, CC PubMed:24896179, PubMed:25474007, PubMed:25527291, PubMed:32047033). CC Depending on the severity of mitochondrial damage and/or dysfunction, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to regulating mitochondrial dynamics and eliminating CC severely damaged mitochondria via mitophagy (PubMed:11439185, CC PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:21376232, CC PubMed:22082830, PubMed:22396657, PubMed:23620051, PubMed:23685073, CC PubMed:23933751, PubMed:24896179, PubMed:25527291, PubMed:32047033, CC PubMed:33499712). Activation and recruitment onto the outer membrane of CC damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated CC phosphorylation of both PRKN and ubiquitin (PubMed:24660806, CC PubMed:24784582, PubMed:25474007, PubMed:25527291). After mitochondrial CC damage, functions with PINK1 to mediate the decision between mitophagy CC or preventing apoptosis by inducing either the poly- or CC monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 CC promotes mitophagy, while monoubiquitination of VDAC1 decreases CC mitochondrial calcium influx which ultimately inhibits apoptosis CC (PubMed:27534820, PubMed:32047033). When cellular stress results in CC irreversible mitochondrial damage, promotes the autophagic degradation CC of dysfunctional depolarized mitochondria (mitophagy) by promoting the CC ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, CC MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, CC PubMed:22396657, PubMed:23620051, PubMed:23685073, PubMed:23933751, CC PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, CC 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to CC mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway CC also promotes fission of damaged mitochondria by PINK1-mediated CC phosphorylation which promotes the PRKN-dependent degradation of CC mitochondrial proteins involved in fission such as MFN2 CC (PubMed:23620051). This prevents the refusion of unhealthy mitochondria CC with the mitochondrial network or initiates mitochondrial fragmentation CC facilitating their later engulfment by autophagosomes CC (PubMed:23620051). Regulates motility of damaged mitochondria via the CC ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor CC neurons, this likely inhibits mitochondrial intracellular anterograde CC transport along the axons which probably increases the chance of the CC mitochondria undergoing mitophagy in the soma (PubMed:22396657). CC Involved in mitochondrial biogenesis via the 'Lys-48'-linked CC polyubiquitination of transcriptional repressor ZNF746/PARIS which CC leads to its subsequent proteasomal degradation and allows activation CC of the transcription factor PPARGC1A (PubMed:21376232). Limits the CC production of reactive oxygen species (ROS) (PubMed:18541373). CC Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In CC collaboration with CHPF isoform 2, may enhance cell viability and CC protect cells from oxidative stress (PubMed:22082830). Independently of CC its ubiquitin ligase activity, protects from apoptosis by the CC transcriptional repression of p53/TP53 (PubMed:19801972). May protect CC neurons against alpha synuclein toxicity, proteasomal dysfunction, CC GPR37 accumulation, and kainate-induced excitotoxicity CC (PubMed:11439185). May play a role in controlling neurotransmitter CC trafficking at the presynaptic terminal and in calcium-dependent CC exocytosis. May represent a tumor suppressor gene (PubMed:12719539). CC {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11439185, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12150907, CC ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:21753002, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23685073, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:25621951, ECO:0000269|PubMed:27534820, CC ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:33499712}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; CC EC=2.3.2.31; Evidence={ECO:0000269|PubMed:23770887}; CC -!- ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe- CC 463 inserts into a hydrophobic groove in RING-0, occluding the CC ubiquitin acceptor site Cys-431, whereas the REP repressor element CC binds RING-1 and blocks its E2-binding site (PubMed:23727886, CC PubMed:23770887). Activation of PRKN requires 2 steps: (1) CC phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated CC ubiquitin, leading to unlock repression of the catalytic Cys-431 by the CC RING-0 region via an allosteric mechanism and converting PRKN to its CC fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25474007, CC PubMed:25527291). According to another report, phosphorylation at Ser- CC 65 by PINK1 is not essential for activation and only binding to CC phosphorylated ubiquitin is essential to unlock repression CC (PubMed:24751536). In addition, ISG15 conjugation positively regulates CC its ubiquitin E3 ligase activity by suppressing the intramolecular CC interaction that maintains its autoinhibited conformation CC (PubMed:27534820). {ECO:0000269|PubMed:23727886, CC ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:27534820}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 CC (PubMed:11078524, PubMed:21532592). Mediates 'Lys-63'-linked CC polyubiquitination by associating with UBE2V1. Part of a SCF-like CC complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). CC Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the CC C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates CC the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including CC STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the CC complex increases during ER stress (PubMed:12150907). STUB1 promotes CC the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN- CC mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently CC associates with unfolded GPR37 and inhibits the E3 activity of PRKN, CC whereas, STUB1 enhances the E3 activity of PRKN through promotion of CC dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). CC Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). CC Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 CC (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes CC nuclear localization and autoubiquitination (PubMed:16955485). CC Interacts (via first RING-type domain) with AIMP2 (via N-terminus) CC (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, CC PubMed:18541373). Interacts with PINK1 (PubMed:19966284, CC PubMed:20798600). Forms a complex with PINK1 and PARK7 CC (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 CC may facilitate PRKN transport into the mitochondria (PubMed:22082830). CC Interacts with MFN2 (phosphorylated), promotes PRKN localization in CC dysfunctional depolarized mitochondria (PubMed:23620051). Interacts CC with FBXO7; this promotes translocation to dysfunctional depolarized CC mitochondria (PubMed:23933751). Interacts with ZNF746 CC (PubMed:21376232). Interacts with heat shock protein 70 family members, CC including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes CC translocation to damaged mitochondria (PubMed:24270810). Interacts with CC BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits CC translocation to damaged mitochondria (PubMed:24270810). Forms a CC complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 CC (By similarity). {ECO:0000250|UniProtKB:Q9WVS6, CC ECO:0000269|PubMed:11078524, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165, CC ECO:0000269|PubMed:12634850, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:14532270, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:15987638, ECO:0000269|PubMed:16135753, CC ECO:0000269|PubMed:16332688, ECO:0000269|PubMed:16352719, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:18541373, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24270810}. CC -!- INTERACTION: CC O60260; P54252-2: ATXN3; NbExp=5; IntAct=EBI-716346, EBI-9684323; CC O60260; Q8IZ52-2: CHPF; NbExp=5; IntAct=EBI-716346, EBI-9029620; CC O60260; Q9Y3I1: FBXO7; NbExp=10; IntAct=EBI-716346, EBI-1161222; CC O60260; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-716346, EBI-9102965; CC O60260; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-716346, EBI-301697; CC O60260; P08238: HSP90AB1; NbExp=2; IntAct=EBI-716346, EBI-352572; CC O60260; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-716346, EBI-739832; CC O60260; Q5S007: LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863; CC O60260; Q86UL8: MAGI2; NbExp=2; IntAct=EBI-716346, EBI-311035; CC O60260; O95140: MFN2; NbExp=4; IntAct=EBI-716346, EBI-3324756; CC O60260; Q16342: PDCD2; NbExp=5; IntAct=EBI-716346, EBI-359462; CC O60260; Q9BXM7: PINK1; NbExp=7; IntAct=EBI-716346, EBI-2846068; CC O60260; Q9BXM7-1: PINK1; NbExp=2; IntAct=EBI-716346, EBI-15643376; CC O60260; O60260: PRKN; NbExp=5; IntAct=EBI-716346, EBI-716346; CC O60260; O14818-1: PSMA7; NbExp=5; IntAct=EBI-716346, EBI-7679034; CC O60260; P49792: RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138; CC O60260; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430; CC O60260; Q15645: TRIP13; NbExp=4; IntAct=EBI-716346, EBI-358993; CC O60260; Q6NUN9: ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525; CC O60260; Q9Z2Q6: Septin5; Xeno; NbExp=2; IntAct=EBI-716346, EBI-772125; CC O60260; P68510: Ywhah; Xeno; NbExp=6; IntAct=EBI-716346, EBI-444641; CC O60260; PRO_0000045592 [Q99IB8]; Xeno; NbExp=3; IntAct=EBI-716346, EBI-6858513; CC O60260-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-21251460, EBI-25840993; CC O60260-5; Q86WR3: ANUBL1; NbExp=3; IntAct=EBI-21251460, EBI-25880850; CC O60260-5; P63010-2: AP2B1; NbExp=6; IntAct=EBI-21251460, EBI-11529439; CC O60260-5; P05067: APP; NbExp=5; IntAct=EBI-21251460, EBI-77613; CC O60260-5; Q0P5N6: ARL16; NbExp=6; IntAct=EBI-21251460, EBI-10186132; CC O60260-5; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-21251460, EBI-25844820; CC O60260-5; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-707573; CC O60260-5; Q8WXK3-2: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-12015080; CC O60260-5; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-21251460, EBI-14199987; CC O60260-5; Q9H672-2: ASB7; NbExp=3; IntAct=EBI-21251460, EBI-12104328; CC O60260-5; Q96DX5: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-745641; CC O60260-5; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-25843552; CC O60260-5; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-21251460, EBI-1048913; CC O60260-5; P54253: ATXN1; NbExp=6; IntAct=EBI-21251460, EBI-930964; CC O60260-5; O14867: BACH1; NbExp=3; IntAct=EBI-21251460, EBI-1263541; CC O60260-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-21251460, EBI-10988864; CC O60260-5; A8KA13: BCL6B; NbExp=3; IntAct=EBI-21251460, EBI-10174813; CC O60260-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-21251460, EBI-2837444; CC O60260-5; P29466-3: CASP1; NbExp=6; IntAct=EBI-21251460, EBI-12248206; CC O60260-5; Q13939: CCIN; NbExp=3; IntAct=EBI-21251460, EBI-25879469; CC O60260-5; P78396-2: CCNA1; NbExp=3; IntAct=EBI-21251460, EBI-21770675; CC O60260-5; Q00535: CDK5; NbExp=3; IntAct=EBI-21251460, EBI-1041567; CC O60260-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-21251460, EBI-350590; CC O60260-5; Q9UBU7: DBF4; NbExp=3; IntAct=EBI-21251460, EBI-372690; CC O60260-5; Q5QP82-2: DCAF10; NbExp=3; IntAct=EBI-21251460, EBI-10983996; CC O60260-5; P61962: DCAF7; NbExp=3; IntAct=EBI-21251460, EBI-359808; CC O60260-5; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-21251460, EBI-25842815; CC O60260-5; Q9BW61: DDA1; NbExp=3; IntAct=EBI-21251460, EBI-2510241; CC O60260-5; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-21251460, EBI-25842538; CC O60260-5; P78352-2: DLG4; NbExp=6; IntAct=EBI-21251460, EBI-631152; CC O60260-5; P31689: DNAJA1; NbExp=6; IntAct=EBI-21251460, EBI-347834; CC O60260-5; O77932: DXO; NbExp=3; IntAct=EBI-21251460, EBI-372173; CC O60260-5; O75530-2: EED; NbExp=3; IntAct=EBI-21251460, EBI-11132357; CC O60260-5; Q8TC29: ENKUR; NbExp=6; IntAct=EBI-21251460, EBI-9246952; CC O60260-5; Q6P1L5: FAM117B; NbExp=3; IntAct=EBI-21251460, EBI-3893327; CC O60260-5; O00757: FBP2; NbExp=3; IntAct=EBI-21251460, EBI-719781; CC O60260-5; P57775: FBXW4; NbExp=3; IntAct=EBI-21251460, EBI-2372268; CC O60260-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-21251460, EBI-396453; CC O60260-5; P22607: FGFR3; NbExp=3; IntAct=EBI-21251460, EBI-348399; CC O60260-5; Q9H2C0: GAN; NbExp=3; IntAct=EBI-21251460, EBI-764342; CC O60260-5; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-21251460, EBI-8799578; CC O60260-5; Q96IK5: GMCL1; NbExp=3; IntAct=EBI-21251460, EBI-2548508; CC O60260-5; P62879: GNB2; NbExp=3; IntAct=EBI-21251460, EBI-356942; CC O60260-5; Q7Z602: GPR141; NbExp=3; IntAct=EBI-21251460, EBI-21649723; CC O60260-5; P06396: GSN; NbExp=3; IntAct=EBI-21251460, EBI-351506; CC O60260-5; P68431: H3C12; NbExp=3; IntAct=EBI-21251460, EBI-79722; CC O60260-5; Q86YM7: HOMER1; NbExp=6; IntAct=EBI-21251460, EBI-746815; CC O60260-5; P0DMV8: HSPA1A; NbExp=6; IntAct=EBI-21251460, EBI-11052499; CC O60260-5; P11142: HSPA8; NbExp=9; IntAct=EBI-21251460, EBI-351896; CC O60260-5; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-21251460, EBI-21911304; CC O60260-5; Q8NA54: IQUB; NbExp=3; IntAct=EBI-21251460, EBI-10220600; CC O60260-5; P05161: ISG15; NbExp=3; IntAct=EBI-21251460, EBI-746466; CC O60260-5; Q9UKP3-2: ITGB1BP2; NbExp=3; IntAct=EBI-21251460, EBI-25856470; CC O60260-5; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-21251460, EBI-25871195; CC O60260-5; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-21251460, EBI-2796400; CC O60260-5; Q6TDP4: KLHL17; NbExp=3; IntAct=EBI-21251460, EBI-21328926; CC O60260-5; O94889: KLHL18; NbExp=3; IntAct=EBI-21251460, EBI-2510096; CC O60260-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-21251460, EBI-714379; CC O60260-5; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-21251460, EBI-6426464; CC O60260-5; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-21251460, EBI-10241252; CC O60260-5; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-21251460, EBI-1044640; CC O60260-5; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-21251460, EBI-1108377; CC O60260-5; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-21251460, EBI-739832; CC O60260-5; O95777: LSM8; NbExp=6; IntAct=EBI-21251460, EBI-347779; CC O60260-5; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-21251460, EBI-373144; CC O60260-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-21251460, EBI-7796455; CC O60260-5; P61244-4: MAX; NbExp=3; IntAct=EBI-21251460, EBI-25848049; CC O60260-5; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-21251460, EBI-4397720; CC O60260-5; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-21251460, EBI-21250407; CC O60260-5; P51948: MNAT1; NbExp=3; IntAct=EBI-21251460, EBI-716139; CC O60260-5; Q8N594: MPND; NbExp=3; IntAct=EBI-21251460, EBI-2512452; CC O60260-5; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-21251460, EBI-10698053; CC O60260-5; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-21251460, EBI-3446748; CC O60260-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-21251460, EBI-1058491; CC O60260-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-21251460, EBI-25830200; CC O60260-5; P68402: PAFAH1B2; NbExp=3; IntAct=EBI-21251460, EBI-713724; CC O60260-5; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-21251460, EBI-17159452; CC O60260-5; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-21251460, EBI-11022007; CC O60260-5; Q96MG8: PCMTD1; NbExp=3; IntAct=EBI-21251460, EBI-2561395; CC O60260-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-21251460, EBI-6309018; CC O60260-5; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-21251460, EBI-716063; CC O60260-5; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-21251460, EBI-12339509; CC O60260-5; Q6ZR37: PLEKHG7; NbExp=6; IntAct=EBI-21251460, EBI-12891828; CC O60260-5; P25786: PSMA1; NbExp=6; IntAct=EBI-21251460, EBI-359352; CC O60260-5; P40306: PSMB10; NbExp=3; IntAct=EBI-21251460, EBI-603329; CC O60260-5; P28070: PSMB4; NbExp=3; IntAct=EBI-21251460, EBI-603350; CC O60260-5; O60671: RAD1; NbExp=6; IntAct=EBI-21251460, EBI-721835; CC O60260-5; Q8NDN9-2: RCBTB1; NbExp=3; IntAct=EBI-21251460, EBI-25880533; CC O60260-5; P41220: RGS2; NbExp=6; IntAct=EBI-21251460, EBI-712388; CC O60260-5; A0A087WUY2: RGS3; NbExp=6; IntAct=EBI-21251460, EBI-25879714; CC O60260-5; O94844: RHOBTB1; NbExp=3; IntAct=EBI-21251460, EBI-6426999; CC O60260-5; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-21251460, EBI-714023; CC O60260-5; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-21251460, EBI-396669; CC O60260-5; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-21251460, EBI-21535400; CC O60260-5; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-21251460, EBI-25829984; CC O60260-5; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-21251460, EBI-749039; CC O60260-5; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-21251460, EBI-2130308; CC O60260-5; Q96A37: RNF166; NbExp=3; IntAct=EBI-21251460, EBI-2130320; CC O60260-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-21251460, EBI-743938; CC O60260-5; Q96BH1: RNF25; NbExp=3; IntAct=EBI-21251460, EBI-2129220; CC O60260-5; P08865: RPSA; NbExp=3; IntAct=EBI-21251460, EBI-354112; CC O60260-5; Q8N488: RYBP; NbExp=6; IntAct=EBI-21251460, EBI-752324; CC O60260-5; Q15393: SF3B3; NbExp=3; IntAct=EBI-21251460, EBI-346977; CC O60260-5; Q2NKQ1-4: SGSM1; NbExp=6; IntAct=EBI-21251460, EBI-10182463; CC O60260-5; Q14190-2: SIM2; NbExp=3; IntAct=EBI-21251460, EBI-21623725; CC O60260-5; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-21251460, EBI-358545; CC O60260-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-21251460, EBI-9845742; CC O60260-5; P37840: SNCA; NbExp=8; IntAct=EBI-21251460, EBI-985879; CC O60260-5; Q9Y6H5-5: SNCAIP; NbExp=6; IntAct=EBI-21251460, EBI-25880040; CC O60260-5; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-21251460, EBI-538492; CC O60260-5; O14544: SOCS6; NbExp=3; IntAct=EBI-21251460, EBI-3929549; CC O60260-5; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-21251460, EBI-11959123; CC O60260-5; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-21251460, EBI-2510414; CC O60260-5; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-21251460, EBI-8345366; CC O60260-5; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-21251460, EBI-5235340; CC O60260-5; Q9C004: SPRY4; NbExp=3; IntAct=EBI-21251460, EBI-354861; CC O60260-5; Q96BD6: SPSB1; NbExp=3; IntAct=EBI-21251460, EBI-2659201; CC O60260-5; Q99619: SPSB2; NbExp=3; IntAct=EBI-21251460, EBI-2323209; CC O60260-5; O75886: STAM2; NbExp=3; IntAct=EBI-21251460, EBI-373258; CC O60260-5; O95630: STAMBP; NbExp=3; IntAct=EBI-21251460, EBI-396676; CC O60260-5; Q9UNE7: STUB1; NbExp=6; IntAct=EBI-21251460, EBI-357085; CC O60260-5; Q9BT88: SYT11; NbExp=6; IntAct=EBI-21251460, EBI-751770; CC O60260-5; Q13148: TARDBP; NbExp=3; IntAct=EBI-21251460, EBI-372899; CC O60260-5; Q16650: TBR1; NbExp=6; IntAct=EBI-21251460, EBI-1047158; CC O60260-5; Q15554-4: TERF2; NbExp=6; IntAct=EBI-21251460, EBI-25840535; CC O60260-5; Q04724: TLE1; NbExp=3; IntAct=EBI-21251460, EBI-711424; CC O60260-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-21251460, EBI-25831574; CC O60260-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-21251460, EBI-74615; CC O60260-5; P19474: TRIM21; NbExp=3; IntAct=EBI-21251460, EBI-81290; CC O60260-5; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-21251460, EBI-17716262; CC O60260-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-21251460, EBI-25840976; CC O60260-5; P57075-2: UBASH3A; NbExp=6; IntAct=EBI-21251460, EBI-7353612; CC O60260-5; P0CG47: UBB; NbExp=6; IntAct=EBI-21251460, EBI-413034; CC O60260-5; O15205: UBD; NbExp=3; IntAct=EBI-21251460, EBI-6657186; CC O60260-5; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-21251460, EBI-988826; CC O60260-5; P68036: UBE2L3; NbExp=3; IntAct=EBI-21251460, EBI-711173; CC O60260-5; P61081: UBE2M; NbExp=3; IntAct=EBI-21251460, EBI-1041660; CC O60260-5; Q9C0C9: UBE2O; NbExp=3; IntAct=EBI-21251460, EBI-2339946; CC O60260-5; Q13404: UBE2V1; NbExp=3; IntAct=EBI-21251460, EBI-1050671; CC O60260-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-21251460, EBI-11530712; CC O60260-5; Q9Y3C8: UFC1; NbExp=3; IntAct=EBI-21251460, EBI-1045733; CC O60260-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-21251460, EBI-17761788; CC O60260-5; O75604-3: USP2; NbExp=3; IntAct=EBI-21251460, EBI-10696113; CC O60260-5; P18206-2: VCL; NbExp=6; IntAct=EBI-21251460, EBI-11027067; CC O60260-5; P45880: VDAC2; NbExp=6; IntAct=EBI-21251460, EBI-354022; CC O60260-5; P40337-2: VHL; NbExp=3; IntAct=EBI-21251460, EBI-12157263; CC O60260-5; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-21251460, EBI-11141397; CC O60260-5; O00308: WWP2; NbExp=3; IntAct=EBI-21251460, EBI-743923; CC O60260-5; Q04917: YWHAH; NbExp=6; IntAct=EBI-21251460, EBI-306940; CC O60260-5; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-21251460, EBI-25842419; CC O60260-5; Q15916: ZBTB6; NbExp=3; IntAct=EBI-21251460, EBI-7227791; CC O60260-5; Q9Y649; NbExp=3; IntAct=EBI-21251460, EBI-25900580; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24898855}. Nucleus CC {ECO:0000269|PubMed:16955485}. Endoplasmic reticulum CC {ECO:0000269|PubMed:19501131}. Mitochondrion CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24898855}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:Q9WVS6}. Cell projection, neuron projection CC {ECO:0000269|PubMed:12925569}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9WVS6}. Presynapse CC {ECO:0000250|UniProtKB:Q9WVS6}. Note=Mainly localizes in the cytosol CC (PubMed:19029340, PubMed:19229105). Co-localizes with SYT11 in CC neutrites (PubMed:12925569). Co-localizes with SNCAIP in brainstem Lewy CC bodies (PubMed:10319893, PubMed:11431533). Translocates to CC dysfunctional mitochondria that have lost the mitochondrial membrane CC potential; recruitment to mitochondria is PINK1-dependent CC (PubMed:18957282, PubMed:19966284, PubMed:23620051, PubMed:24898855). CC Mitochondrial localization also gradually increases with cellular CC growth (PubMed:22082830). {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:24898855}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=1; CC IsoId=O60260-1; Sequence=Displayed; CC Name=2; Synonyms=SV5DEL; CC IsoId=O60260-2; Sequence=VSP_011707; CC Name=3; CC IsoId=O60260-3; Sequence=VSP_011706, VSP_011709, VSP_011710; CC Name=4; CC IsoId=O60260-4; Sequence=VSP_011705; CC Name=5; CC IsoId=O60260-5; Sequence=VSP_011708, VSP_011711, VSP_011712; CC Name=6; CC IsoId=O60260-6; Sequence=VSP_041563; CC Name=7; Synonyms=SV5,9DEL; CC IsoId=O60260-7; Sequence=VSP_011707, VSP_053651; CC Name=8; Synonyms=SV9DEL; CC IsoId=O60260-8; Sequence=VSP_053651; CC -!- TISSUE SPECIFICITY: Highly expressed in the brain including the CC substantia nigra (PubMed:19501131, PubMed:9560156). Expressed in heart, CC testis and skeletal muscle (PubMed:9560156). Expression is down- CC regulated or absent in tumor biopsies, and absent in the brain of PARK2 CC patients (PubMed:12719539, PubMed:14614460). Overexpression protects CC dopamine neurons from kainate-mediated apoptosis (PubMed:12628165). CC Found in serum (at protein level) (PubMed:19501131). CC {ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:14614460, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:9560156}. CC -!- DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S CC proteasomes. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: The RING-type 1 zinc finger domain is required to repress CC p53/TP53 transcription. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: Members of the RBR family are atypical E3 ligases. They CC interact with the E2 conjugating enzyme UBE2L3 and function like HECT- CC type E3 enzymes: they bind E2s via the first RING domain, but require CC an obligate trans-thiolation step during the ubiquitin transfer, CC requiring a conserved cysteine residue in the second RING domain. CC {ECO:0000269|PubMed:23770917, ECO:0000305|PubMed:21532592}. CC -!- PTM: ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN- CC beta stimulation. ISGylation positively regulates its E3 ligase CC activity. {ECO:0000269|PubMed:27534820}. CC -!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own CC degradation (PubMed:19229105, PubMed:23770917, PubMed:25474007). Also CC polyubiquitinated by RNF41 for proteasomal degradation CC (PubMed:19229105). {ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:25474007}. CC -!- PTM: S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase CC activity by S-nitrosylation could contribute to the degenerative CC process in PD by impairing the ubiquitination of PRKN substrates. CC {ECO:0000269|PubMed:15105460}. CC -!- PTM: Phosphorylated (PubMed:18957282, PubMed:23754282, PubMed:24660806, CC PubMed:24784582, PubMed:25474007). Activation requires phosphorylation CC at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin CC (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, CC PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is CC important for mitochondrial localization (PubMed:18957282). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12629236, CC ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:29311685}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC Heterozygous mutations act as susceptibility alleles for late-onset CC Parkinson disease (PubMed:12629236, PubMed:12730996). CC -!- DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: An autosomal CC recessive form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability. PARK2 differs from classic forms of CC Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation CC of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia CC is absent. Pathologically, patients show loss of dopaminergic neurons CC in the substantia nigra, similar to that seen in classic Parkinson CC disease; however, Lewy bodies (intraneuronal accumulations of CC aggregated proteins) are absent. Disease onset is usually before age 40 CC years. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, CC ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, CC ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, CC ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, CC ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, CC ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, CC ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, CC ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, CC ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:9560156, CC ECO:0000269|PubMed:9731209}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PRKN may be involved in the development and/or CC progression of ovarian cancer. CC -!- MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q telomere is CC hyper-recombinable and lies within FRA6E, the third most common fragile CC site in tumor tissue. CC -!- SIMILARITY: Belongs to the RBR family. Parkin subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue 131 CC of September 2011; CC URL="https://www.proteinspotlight.org/back_issues/131"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB009973; BAA25751.1; -; mRNA. DR EMBL; EF375726; ABN46990.1; -; mRNA. DR EMBL; AF381282; AAM21457.1; -; mRNA. DR EMBL; AF381283; AAM21458.1; -; mRNA. DR EMBL; AF381286; AAM21461.1; -; mRNA. DR EMBL; GU345839; ADB90270.1; -; mRNA. DR EMBL; GU345840; ADB90271.1; -; mRNA. DR EMBL; GU361467; ADB91979.1; -; mRNA. DR EMBL; AK292590; BAF85279.1; -; mRNA. DR EMBL; AL035697; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL132982; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000886; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001576; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001577; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001578; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP003699; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47573.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47574.1; -; Genomic_DNA. DR EMBL; BC022014; AAH22014.1; -; mRNA. DR EMBL; AY564225; AAS88422.1; -; Genomic_DNA. DR CCDS; CCDS5281.1; -. [O60260-1] DR CCDS; CCDS5282.1; -. [O60260-2] DR CCDS; CCDS5283.1; -. [O60260-6] DR RefSeq; NP_004553.2; NM_004562.3. [O60260-1] DR RefSeq; NP_054642.2; NM_013987.3. [O60260-2] DR RefSeq; NP_054643.2; NM_013988.3. [O60260-6] DR PDB; 1IYF; NMR; -; A=1-76. DR PDB; 2JMO; NMR; -; A=308-384. DR PDB; 4BM9; X-ray; 2.25 A; A=137-465. DR PDB; 4I1F; X-ray; 1.58 A; A=141-465. DR PDB; 4I1H; X-ray; 2.00 A; A=141-465. DR PDB; 5C1Z; X-ray; 1.79 A; A/B=1-465. DR PDB; 5C23; X-ray; 2.37 A; A/B=1-465. DR PDB; 5C9V; X-ray; 2.35 A; A=137-465. DR PDB; 5N2W; X-ray; 2.68 A; A=1-465. DR PDB; 5N38; X-ray; 2.60 A; A=1-465. DR PDB; 5TR5; NMR; -; A=1-76. DR PDB; 6GLC; X-ray; 1.80 A; A=1-382. DR PDB; 6HUE; X-ray; 2.85 A; A/B=1-465. DR PDB; 6N13; NMR; -; B=144-465. DR PDB; 8IK6; X-ray; 3.30 A; A/C=139-465. DR PDB; 8IKM; X-ray; 1.92 A; A=141-382, C=1-140. DR PDB; 8IKT; X-ray; 2.60 A; A=77-382, C=1-76. DR PDB; 8IKV; X-ray; 2.35 A; A/C=139-465. DR PDB; 8JWV; X-ray; 2.90 A; A=141-465. DR PDB; 8WZN; X-ray; 1.80 A; A=141-465. DR PDB; 8WZO; X-ray; 2.25 A; A=141-465. DR PDBsum; 1IYF; -. DR PDBsum; 2JMO; -. DR PDBsum; 4BM9; -. DR PDBsum; 4I1F; -. DR PDBsum; 4I1H; -. DR PDBsum; 5C1Z; -. DR PDBsum; 5C23; -. DR PDBsum; 5C9V; -. DR PDBsum; 5N2W; -. DR PDBsum; 5N38; -. DR PDBsum; 5TR5; -. DR PDBsum; 6GLC; -. DR PDBsum; 6HUE; -. DR PDBsum; 6N13; -. DR PDBsum; 8IK6; -. DR PDBsum; 8IKM; -. DR PDBsum; 8IKT; -. DR PDBsum; 8IKV; -. DR PDBsum; 8JWV; -. DR PDBsum; 8WZN; -. DR PDBsum; 8WZO; -. DR AlphaFoldDB; O60260; -. DR BMRB; O60260; -. DR SMR; O60260; -. DR BioGRID; 111105; 3437. DR CORUM; O60260; -. DR DIP; DIP-37655N; -. DR FunCoup; O60260; 952. DR IntAct; O60260; 311. DR MINT; O60260; -. DR STRING; 9606.ENSP00000355865; -. DR BindingDB; O60260; -. DR TCDB; 8.A.52.2.1; the ubiquitin-related protein degradation (upd) family. DR GlyGen; O60260; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O60260; -. DR PhosphoSitePlus; O60260; -. DR BioMuta; PRKN; -. DR MassIVE; O60260; -. DR PaxDb; 9606-ENSP00000355865; -. DR PeptideAtlas; O60260; -. DR ProteomicsDB; 49290; -. [O60260-1] DR ProteomicsDB; 49291; -. [O60260-2] DR ProteomicsDB; 49292; -. [O60260-3] DR ProteomicsDB; 49293; -. [O60260-4] DR ProteomicsDB; 49294; -. [O60260-5] DR ProteomicsDB; 49295; -. [O60260-6] DR Antibodypedia; 4264; 797 antibodies from 52 providers. DR DNASU; 5071; -. DR Ensembl; ENST00000366896.5; ENSP00000355862.1; ENSG00000185345.25. [O60260-6] DR Ensembl; ENST00000366897.5; ENSP00000355863.1; ENSG00000185345.25. [O60260-2] DR Ensembl; ENST00000366898.6; ENSP00000355865.1; ENSG00000185345.25. [O60260-1] DR Ensembl; ENST00000479615.5; ENSP00000434414.1; ENSG00000185345.25. [O60260-3] DR GeneID; 5071; -. DR KEGG; hsa:5071; -. DR MANE-Select; ENST00000366898.6; ENSP00000355865.1; NM_004562.3; NP_004553.2. DR UCSC; uc003qty.5; human. [O60260-1] DR AGR; HGNC:8607; -. DR CIViC; 5071; 2 evidence items across 2 molecular profiles. DR ClinPGx; PA32942; -. DR CTD; 5071; -. DR DisGeNET; 5071; -. DR GeneCards; PRKN; -. DR GeneReviews; PRKN; -. DR HGNC; HGNC:8607; PRKN. DR HPA; ENSG00000185345; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PRKN; -. DR MIM; 168600; phenotype. DR MIM; 600116; phenotype. DR MIM; 602544; gene. DR OpenTargets; ENSG00000185345; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000185345; -. DR eggNOG; KOG0006; Eukaryota. DR GeneTree; ENSGT00390000011034; -. DR HOGENOM; CLU_050804_0_0_1; -. DR InParanoid; O60260; -. DR OMA; DPKWDIK; -. DR OrthoDB; 1431934at2759; -. DR PAN-GO; O60260; 15 GO annotations based on evolutionary models. DR PhylomeDB; O60260; -. DR BRENDA; 2.3.2.27; 2681. DR BRENDA; 2.3.2.31; 2681. DR PathwayCommons; O60260; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; O60260; -. DR SIGNOR; O60260; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000185345; -. DR BioGRID-ORCS; 5071; 13 hits in 1187 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PARK2; human. DR EvolutionaryTrace; O60260; -. DR GeneWiki; Parkin_(ligase); -. DR GenomeRNAi; 5071; -. DR Pharos; O60260; Tbio. DR PRO; PR:O60260; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O60260; protein. DR Bgee; ENSG00000185345; Expressed in sural nerve and 107 other cell types or tissues. DR ExpressionAtlas; O60260; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:1990452; C:Parkin-FBXW7-Cul1 ubiquitin ligase complex; IPI:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0097602; F:cullin family protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990444; F:F-box domain binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0031072; F:heat shock protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042826; F:histone deacetylase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0043274; F:phospholipase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0017124; F:SH3 domain binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0003714; F:transcription corepressor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0015631; F:tubulin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IMP:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008270; F:zinc ion binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IMP:BHF-UCL. DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome. DR GO; GO:0000422; P:autophagy of mitochondrion; IDA:UniProtKB. DR GO; GO:1903351; P:cellular response to dopamine; TAS:ParkinsonsUK-UCL. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:1905232; P:cellular response to L-glutamate; IEA:Ensembl. DR GO; GO:1904845; P:cellular response to L-glutamine; IEA:Ensembl. DR GO; GO:0071287; P:cellular response to manganese ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; TAS:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; IMP:ParkinsonsUK-UCL. DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL. DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc. DR GO; GO:0042417; P:dopamine metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl. DR GO; GO:0036503; P:ERAD pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0010994; P:free ubiquitin chain polymerization; IMP:ParkinsonsUK-UCL. DR GO; GO:0044828; P:host-mediated suppression of viral genome replication; IDA:AgBase. DR GO; GO:0007612; P:learning; IEA:Ensembl. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0000266; P:mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IEA:Ensembl. DR GO; GO:0051646; P:mitochondrion localization; IEA:Ensembl. DR GO; GO:0007005; P:mitochondrion organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IDA:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProtKB. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0032232; P:negative regulation of actin filament bundle assembly; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903382; P:negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:1903542; P:negative regulation of exosomal secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0033132; P:negative regulation of glucokinase activity; IDA:MGI. DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:MGI. DR GO; GO:1905366; P:negative regulation of intralumenal vesicle formation; IMP:ParkinsonsUK-UCL. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IEA:Ensembl. DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IEA:Ensembl. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:BHF-UCL. DR GO; GO:1904049; P:negative regulation of spontaneous neurotransmitter secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0051967; P:negative regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:ParkinsonsUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:ParkinsonsUK-UCL. DR GO; GO:0042415; P:norepinephrine metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0010636; P:positive regulation of mitochondrial fusion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IEA:Ensembl. DR GO; GO:1901526; P:positive regulation of mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0051582; P:positive regulation of neurotransmitter uptake; IMP:ParkinsonsUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; IGI:ParkinsonsUK-UCL. DR GO; GO:1905477; P:positive regulation of protein localization to membrane; IMP:ParkinsonsUK-UCL. DR GO; GO:1905281; P:positive regulation of retrograde transport, endosome to Golgi; NAS:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:BHF-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0016579; P:protein deubiquitination; TAS:Reactome. DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0044314; P:protein K27-linked ubiquitination; IDA:UniProt. DR GO; GO:0035519; P:protein K29-linked ubiquitination; TAS:ParkinsonsUK-UCL. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0085020; P:protein K6-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; IEA:Ensembl. DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:ParkinsonsUK-UCL. DR GO; GO:0010906; P:regulation of glucose metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0032368; P:regulation of lipid transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome. DR GO; GO:0099072; P:regulation of postsynaptic membrane neurotransmitter receptor levels; IEA:Ensembl. DR GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IMP:ParkinsonsUK-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; NAS:ParkinsonsUK-UCL. DR GO; GO:0140251; P:regulation protein catabolic process at presynapse; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:1904643; P:response to curcumin; IEA:Ensembl. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:ParkinsonsUK-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0001964; P:startle response; IEA:Ensembl. DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0061734; P:type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd20340; BRcat_RBR_parkin; 1. DR CDD; cd20357; Rcat_RBR_parkin; 1. DR CDD; cd16627; RING-HC_RBR_parkin; 1. DR CDD; cd21382; RING0_parkin; 1. DR CDD; cd01798; Ubl_parkin; 1. DR DisProt; DP01849; -. DR FunFam; 1.20.120.1750:FF:000009; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 2.20.25.20:FF:000008; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 3.10.20.90:FF:000142; E3 ubiquitin-protein ligase parkin; 1. DR Gene3D; 1.20.120.1750; -; 1. DR Gene3D; 2.20.25.20; -; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00008; -. DR InterPro; IPR047534; BRcat_RBR_parkin. DR InterPro; IPR002867; IBR_dom. DR InterPro; IPR003977; Parkin. DR InterPro; IPR054694; Parkin-like_IBR. DR InterPro; IPR041565; Parkin_Znf-RING. DR InterPro; IPR047536; Rcat_RBR_parkin. DR InterPro; IPR047535; RING-HC_RBR_parkin. DR InterPro; IPR044066; TRIAD_supradom. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR041170; Znf-RING_14. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR PANTHER; PTHR10677:SF40; UBIQUITIN-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF22605; IBR_2; 1. DR Pfam; PF00240; ubiquitin; 1. DR Pfam; PF17976; zf-RING_12; 1. DR Pfam; PF17978; zf-RING_14; 1. DR PIRSF; PIRSF037880; Parkin; 1. DR PRINTS; PR01475; PARKIN. DR SMART; SM00647; IBR; 2. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cell projection; Cytoplasm; KW Disease variant; Endoplasmic reticulum; Isopeptide bond; Membrane; KW Metal-binding; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW S-nitrosylation; Synapse; Transcription; Transcription regulation; KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..465 FT /note="E3 ubiquitin-protein ligase parkin" FT /id="PRO_0000058576" FT DOMAIN 1..76 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT ZN_FING 141..225 FT /note="RING-type 0; atypical" FT ZN_FING 238..293 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 313..377 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 418..449 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 77..237 FT /note="Necessary for PINK1-dependent localization to FT mitochondria" FT /evidence="ECO:0000269|PubMed:18957282" FT REGION 77..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 204..238 FT /note="SYT11 binding 1" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 234..465 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 257..293 FT /note="SYT11 binding 2" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 378..410 FT /note="REP" FT /evidence="ECO:0000250|UniProtKB:Q9JK66" FT ACT_SITE 431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 238 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 241 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 253 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 257 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 260 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 263 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 289 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 293 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 332 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 337 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 352 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 360 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 365 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 368 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 373 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 418 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 421 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 436 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 441 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 446 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 449 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 457 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 461 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT MOD_RES 65 FT /note="Phosphoserine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MOD_RES 175 FT /note="Phosphothreonine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282" FT MOD_RES 217 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:18957282" FT CROSSLNK 349 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT CROSSLNK 369 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT VAR_SEQ 1..191 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011705" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011706" FT VAR_SEQ 58..206 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_041563" FT VAR_SEQ 179..206 FT /note="Missing (in isoform 2 and isoform 7)" FT /evidence="ECO:0000303|PubMed:9560156, ECO:0000303|Ref.4" FT /id="VSP_011707" FT VAR_SEQ 290 FT /note="V -> VGTGDTVVLRGALGGFRRGV (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011708" FT VAR_SEQ 291..297 FT /note="AGCPNSL -> VCLLPGM (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011709" FT VAR_SEQ 298..465 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011710" FT VAR_SEQ 312..361 FT /note="Missing (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_053651" FT VAR_SEQ 362..368 FT /note="FAFCREC -> YGQRRTK (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011711" FT VAR_SEQ 369..465 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011712" FT VARIANT 15 FT /note="V -> M (in PARK2; dbSNP:rs532703934)" FT /evidence="ECO:0000269|PubMed:12397156" FT /id="VAR_019733" FT VARIANT 33 FT /note="R -> Q (in PARK2; dbSNP:rs147757966)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019734" FT VARIANT 37 FT /note="P -> L (in PARK2; dbSNP:rs148990138)" FT /evidence="ECO:0000269|PubMed:12112109" FT /id="VAR_019735" FT VARIANT 42 FT /note="R -> P (in PARK2 and PARK; induces a conformational FT change in the PSMD4-binding site of Ubl resulting in FT impaired proteasomal binding; decreases ubiquitination and FT degradation; increased aggregation; impairs the ability to FT ubiquitinate and degrade SYT11; dbSNP:rs368134308)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:29311685" FT /id="VAR_019736" FT VARIANT 46 FT /note="A -> P (in PARK2)" FT /evidence="ECO:0000269|PubMed:12362318" FT /id="VAR_019737" FT VARIANT 56 FT /note="V -> E (in PARK2; dbSNP:rs137853059)" FT /evidence="ECO:0000269|PubMed:12056932" FT /id="VAR_070078" FT VARIANT 82 FT /note="A -> E (in PARK2; dbSNP:rs55774500)" FT /evidence="ECO:0000269|PubMed:11487568, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12730996" FT /id="VAR_019738" FT VARIANT 92 FT /note="A -> V (in PARK2; dbSNP:rs566229879)" FT /id="VAR_019739" FT VARIANT 100 FT /note="Q -> H (in dbSNP:rs1256316516)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019740" FT VARIANT 161 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs137853057)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974" FT /id="VAR_019741" FT VARIANT 167 FT /note="S -> N (in dbSNP:rs1801474)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10511432, ECO:0000269|PubMed:10965160, FT ECO:0000269|PubMed:12629236" FT /id="VAR_019742" FT VARIANT 192 FT /note="M -> L (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:11971093" FT /id="VAR_054107" FT VARIANT 192 FT /note="M -> V (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019743" FT VARIANT 211 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; loss FT of activity towards MIRO1; dbSNP:rs137853060)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:12114481, FT ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:20404107, FT ECO:0000269|PubMed:22396657" FT /id="VAR_019744" FT VARIANT 212 FT /note="C -> Y (in PARK2; dbSNP:rs137853058)" FT /evidence="ECO:0000269|PubMed:11163284, FT ECO:0000269|PubMed:12056932" FT /id="VAR_019746" FT VARIANT 240 FT /note="T -> M (in PARK2; dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019747" FT VARIANT 240 FT /note="T -> R (in PARK2; impairs the ability to FT ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; FT severely compromises the mitochondrial localization; FT dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974, FT ECO:0000269|PubMed:9731209" FT /id="VAR_019748" FT VARIANT 253 FT /note="C -> Y (in PARK; late onset; dbSNP:rs747427602)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019749" FT VARIANT 256 FT /note="R -> C (in PARK2 and PARK; uncertain significance; FT impairs the ability to ubiquitinate SNCAIP and ZNF746; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs150562946)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972" FT /id="VAR_019750" FT VARIANT 271 FT /note="R -> S (in dbSNP:rs772622421)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019751" FT VARIANT 275 FT /note="R -> W (in PARK2 and PARK; impairs the ability to FT ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional FT repression; impairs the ability to ubiquitinate and degrade FT SYT11; dbSNP:rs34424986)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11179010, FT ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:29311685" FT /id="VAR_019752" FT VARIANT 280 FT /note="D -> N (in PARK; does not affect PINK-1 dependent FT localization to depolarized mitochondria; FT dbSNP:rs72480422)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20404107" FT /id="VAR_019753" FT VARIANT 284 FT /note="G -> R (in PARK2; dbSNP:rs751037529)" FT /id="VAR_019754" FT VARIANT 289 FT /note="C -> G (in PARK2; increased aggregation; fails to FT ubiquitinate SYT11; loses ability to bind SYT11; impaired FT relocalization to damaged mitochondria; loss of function in FT mitophagy; dbSNP:rs55961220)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:20889486" FT /id="VAR_019755" FT VARIANT 311 FT /note="Q -> R (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062672" FT VARIANT 328 FT /note="G -> E (in PARK2; does not affect PINK-1 dependent FT localization to depolarized mitochondria)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:20404107" FT /id="VAR_019756" FT VARIANT 334 FT /note="R -> C (in dbSNP:rs199657839)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:27535533" FT /id="VAR_019757" FT VARIANT 339 FT /note="A -> S (in dbSNP:rs1554274880)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019758" FT VARIANT 351 FT /note="T -> P (in PARK2; impairs folding of IBR domain; FT dbSNP:rs1554274861)" FT /evidence="ECO:0000269|PubMed:12112109, FT ECO:0000269|PubMed:17360614" FT /id="VAR_019759" FT VARIANT 366 FT /note="R -> W (in dbSNP:rs56092260)" FT /evidence="ECO:0000269|PubMed:10965160" FT /id="VAR_019760" FT VARIANT 371 FT /note="A -> T (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062673" FT VARIANT 380 FT /note="V -> L (in dbSNP:rs1801582)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10965160, ECO:0000269|PubMed:12397156, FT ECO:0000269|PubMed:12730996" FT /id="VAR_019761" FT VARIANT 394 FT /note="D -> N (in dbSNP:rs1801334)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12730996" FT /id="VAR_019762" FT VARIANT 402 FT /note="R -> C (in PARK2; dbSNP:rs55830907)" FT /evidence="ECO:0000269|PubMed:15584030" FT /id="VAR_070079" FT VARIANT 415 FT /note="T -> N (in PARK2; loss of activity and self- FT ubiquitination; impairs the ability to ubiquitinate SNCAIP; FT no effect on polyubiquitination or mitophagy; does not FT affect turnover of CDCRE1; impairs PINK1-dependent FT localization to dysfunctional depolarized mitochondria; FT dbSNP:rs778125254)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19966284, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23770917, FT ECO:0000269|PubMed:32047033" FT /id="VAR_019763" FT VARIANT 418 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; fails FT to ubiquitinate SYT11 but does not loose ability to bind FT SYT11; dbSNP:rs1554252200)" FT /evidence="ECO:0000269|PubMed:12925569, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19801972" FT /id="VAR_070080" FT VARIANT 430 FT /note="G -> D (in PARK2; loss of self-ubiquitination; FT impairs PINK1-dependent localization to dysfunctional FT depolarized mitochondria; impaired E3 ubiquitin-protein FT ligase toward ZNF746; dbSNP:rs191486604)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12730996, FT ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:21376232, FT ECO:0000269|PubMed:23770917" FT /id="VAR_019764" FT VARIANT 431 FT /note="C -> F (in PARK2; impaired E3 ubiquitin-protein FT ligase toward ZNF746 and BCL2; dbSNP:rs397514694)" FT /evidence="ECO:0000269|PubMed:10939576, FT ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232" FT /id="VAR_019765" FT VARIANT 437 FT /note="P -> L (in PARK2; impaired E3 ubiquitin-protein FT ligase toward BCL2; dbSNP:rs149953814)" FT /evidence="ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12629236, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20889974" FT /id="VAR_019766" FT VARIANT 441 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; FT dbSNP:rs778305273)" FT /evidence="ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:19801972" FT /id="VAR_019767" FT MUTAGEN 65 FT /note="S->A: Loss of phosphorylation. Undergoes FT autoubiquitination in the presence of phosphorylated FT ubiquitin." FT /evidence="ECO:0000269|PubMed:25474007" FT MUTAGEN 65 FT /note="S->E: Phosphomimetic mutant; still requires PINK1 FT for activation. PRKN is activated in presence of FT phosphorylated ubiquitin." FT /evidence="ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MUTAGEN 175 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 175 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 238 FT /note="C->S: Loss of mitochondrial localization." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 332 FT /note="C->S: Impairs folding of IBR domain." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 337 FT /note="C->A: Impairs the ability to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439" FT MUTAGEN 365 FT /note="C->S: Impairs protein folding." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 403 FT /note="W->A: Decreased autoinhibition and increased E3 FT activity." FT /evidence="ECO:0000269|PubMed:24784582" FT MUTAGEN 421 FT /note="C->A: Impairs the ability of self-ubiquitination and FT to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:18541373" FT MUTAGEN 429 FT /note="G->E: Reduced self-ubiquitination." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->S: Impairs the ability to ubiquitinate target FT proteins. No effect on translocation to mitochondria." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:23727886, ECO:0000269|PubMed:23770887, FT ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:32047033" FT MUTAGEN 433 FT /note="H->N,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT MUTAGEN 444 FT /note="E->Q,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT CONFLICT 223 FT /note="S -> P (in Ref. 1; BAA25751 and 3; AAM21458/ FT AAM21457)" FT /evidence="ECO:0000305" FT CONFLICT 289..290 FT /note="CV -> MI (in Ref. 2; AAM21461)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="A -> V (in Ref. 9; AAS88422)" FT /evidence="ECO:0000305" FT STRAND 2..11 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 13..16 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 19..21 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 23..34 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 38..40 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 41..45 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 48..50 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 52..55 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 62..64 FT /evidence="ECO:0007829|PDB:5N2W" FT STRAND 66..71 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 147..150 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 156..166 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 174..178 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 183..187 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 188..190 FT /evidence="ECO:0007829|PDB:8WZO" FT STRAND 192..196 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5N38" FT STRAND 205..212 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:4I1H" FT TURN 239..241 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 257..260 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 261..273 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 281..283 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 290..292 FT /evidence="ECO:0007829|PDB:6N13" FT HELIX 301..307 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 309..326 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 348..351 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 355..358 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 366..368 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 374..376 FT /evidence="ECO:0007829|PDB:6GLC" FT HELIX 379..381 FT /evidence="ECO:0007829|PDB:4BM9" FT HELIX 395..400 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 403..406 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 414..417 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 419..421 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 424..426 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 429..431 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 433..435 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 439..441 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 447..449 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 455..461 FT /evidence="ECO:0007829|PDB:4I1F" SQ SEQUENCE 465 AA; 51641 MW; 9A8BB802A3FC84C3 CRC64; MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG CEWNRVCMGD HWFDV // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID S39AE_HUMAN Reviewed; 492 AA. AC Q15043; A6NH98; B4DIW3; B6EU88; D3DSR4; Q6ZME8; Q96BB3; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 28-JAN-2026, entry version 178. DE RecName: Full=Metal cation symporter ZIP14 {ECO:0000305|PubMed:18270315}; DE AltName: Full=LIV-1 subfamily of ZIP zinc transporter 4 {ECO:0000303|PubMed:12659941}; DE Short=LZT-Hs4 {ECO:0000303|PubMed:12659941}; DE AltName: Full=Solute carrier family 39 member 14 {ECO:0000312|HGNC:HGNC:20858}; DE AltName: Full=Zrt- and Irt-like protein 14 {ECO:0000303|PubMed:15642354}; DE Short=ZIP-14 {ECO:0000303|PubMed:15642354}; DE Flags: Precursor; GN Name=SLC39A14 {ECO:0000312|HGNC:HGNC:20858}; GN Synonyms=KIAA0062 {ECO:0000312|EMBL:BAA06685.1}, GN ZIP14 {ECO:0000303|PubMed:15642354}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Bone marrow; RX PubMed=7584044; DOI=10.1093/dnares/1.5.223; RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N., RA Kawarabayasi Y., Ishikawa K., Tabata S.; RT "Prediction of the coding sequences of unidentified human genes. II. The RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of RT cDNA clones from human cell line KG-1."; RL DNA Res. 1:223-229(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT PRO-33. RC TISSUE=Colon; 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 SUBUNIT, AND MOTIF. RX PubMed=12659941; DOI=10.1016/s0005-2736(03)00048-8; RA Taylor K.M., Nicholson R.I.; RT "The LZT proteins; the LIV-1 subfamily of zinc transporters."; RL Biochim. Biophys. Acta 1611:16-30(2003). RN [7] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=15642354; DOI=10.1016/j.febslet.2004.12.006; RA Taylor K.M., Morgan H.E., Johnson A., Nicholson R.I.; RT "Structure-function analysis of a novel member of the LIV-1 subfamily of RT zinc transporters, ZIP14."; RL FEBS Lett. 579:427-432(2005). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 2). RX PubMed=18270315; DOI=10.1124/mol.107.043588; RA Girijashanker K., He L., Soleimani M., Reed J.M., Li H., Liu Z., Wang B., RA Dalton T.P., Nebert D.W.; RT "Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities RT to the ZIP8 transporter."; RL Mol. Pharmacol. 73:1413-1423(2008). RN [9] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [10] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77 AND ASN-102. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=20682781; DOI=10.1074/jbc.m110.143248; RA Zhao N., Gao J., Enns C.A., Knutson M.D.; RT "ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron RT from transferrin."; RL J. Biol. Chem. 285:32141-32150(2010). RN [12] 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 [13] RP FUNCTION, INDUCTION, AND TISSUE SPECIFICITY. RX PubMed=23052185; DOI=10.1007/s00011-012-0559-y; RA Sayadi A., Nguyen A.T., Bard F.A., Bard-Chapeau E.A.; RT "Zip14 expression induced by lipopolysaccharides in macrophages attenuates RT inflammatory response."; RL Inflamm. Res. 62:133-143(2013). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [15] RP INDUCTION BY IRON, UBIQUITINATION, MUTAGENESIS OF ASN-77; ASN-87 AND RP ASN-102, AND GLYCOSYLATION AT ASN-77; ASN-87 AND ASN-102. RX PubMed=24927598; DOI=10.1073/pnas.1405355111; RA Zhao N., Zhang A.S., Worthen C., Knutson M.D., Enns C.A.; RT "An iron-regulated and glycosylation-dependent proteasomal degradation RT pathway for the plasma membrane metal transporter ZIP14."; RL Proc. Natl. Acad. Sci. U.S.A. 111:9175-9180(2014). RN [16] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27703010; DOI=10.1074/jbc.m116.748632; RA Aydemir T.B., Troche C., Kim M.H., Cousins R.J.; RT "Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin RT Receptor Trafficking and Glucose Metabolism."; RL J. Biol. Chem. 291:23939-23951(2016). RN [17] RP INDUCTION. RX PubMed=28673968; DOI=10.1073/pnas.1704012114; RA Kim M.H., Aydemir T.B., Kim J., Cousins R.J.; RT "Hepatic ZIP14-mediated zinc transport is required for adaptation to RT endoplasmic reticulum stress."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E5805-E5814(2017). RN [18] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=31028174; DOI=10.1074/jbc.ra119.008762; RA Scheiber I.F., Wu Y., Morgan S.E., Zhao N.; RT "The intestinal metal transporter ZIP14 maintains systemic manganese RT homeostasis."; RL J. Biol. Chem. 294:9147-9160(2019). RN [19] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=31699897; DOI=10.1074/jbc.ra119.009371; RA Steimle B.L., Smith F.M., Kosman D.J.; RT "The solute carriers ZIP8 and ZIP14 regulate manganese accumulation in RT brain microvascular endothelial cells and control brain manganese levels."; RL J. Biol. Chem. 294:19197-19208(2019). RN [20] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY (ISOFORM 2), INVOLVEMENT RP IN HMNDYT2, MOTIF, VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469, AND RP CHARACTERIZATION OF VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469. RX PubMed=27231142; DOI=10.1038/ncomms11601; RA Tuschl K., Meyer E., Valdivia L.E., Zhao N., Dadswell C., Abdul-Sada A., RA Hung C.Y., Simpson M.A., Chong W.K., Jacques T.S., Woltjer R.L., Eaton S., RA Gregory A., Sanford L., Kara E., Houlden H., Cuno S.M., Prokisch H., RA Valletta L., Tiranti V., Younis R., Maher E.R., Spencer J., RA Straatman-Iwanowska A., Gissen P., Selim L.A., Pintos-Morell G., RA Coroleu-Lletget W., Mohammad S.S., Yoganathan S., Dale R.C., Thomas M., RA Rihel J., Bodamer O.A., Enns C.A., Hayflick S.J., Clayton P.T., Mills P.B., RA Kurian M.A., Wilson S.W.; RT "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood- RT onset parkinsonism-dystonia."; RL Nat. Commun. 7:11601-11601(2016). RN [21] RP INVOLVEMENT IN HCIN, VARIANT HCIN ARG-441, CHARACTERIZATION OF VARIANT HCIN RP ARG-441, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=29621230; DOI=10.1371/journal.pgen.1007321; RA Hendrickx G., Borra V.M., Steenackers E., Yorgan T.A., Hermans C., RA Boudin E., Waterval J.J., Jansen I.D.C., Aydemir T.B., Kamerling N., RA Behets G.J., Plumeyer C., D'Haese P.C., Busse B., Everts V., Lammens M., RA Mortier G., Cousins R.J., Schinke T., Stokroos R.J., Manni J.J., RA Van Hul W.; RT "Conditional mouse models support the role of SLC39A14 (ZIP14) in RT Hyperostosis Cranialis Interna and in bone homeostasis."; RL PLoS Genet. 14:E1007321-E1007321(2018). CC -!- FUNCTION: Electroneutral transporter of the plasma membrane mediating CC the cellular uptake of the divalent metal cations zinc, manganese and CC iron that are important for tissue homeostasis, metabolism, development CC and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230). CC Functions as an energy-dependent symporter, transporting through the CC membranes an electroneutral complex composed of a divalent metal cation CC and two bicarbonate anions (By similarity). Beside these endogenous CC cellular substrates, can also import cadmium a non-essential metal CC which is cytotoxic and carcinogenic (By similarity). Controls the CC cellular uptake by the intestinal epithelium of systemic zinc, which is CC in turn required to maintain tight junctions and the intestinal CC permeability (By similarity). Modifies the activity of zinc-dependent CC phosphodiesterases, thereby indirectly regulating G protein-coupled CC receptor signaling pathways important for gluconeogenesis and CC chondrocyte differentiation (By similarity). Regulates insulin receptor CC signaling, glucose uptake, glycogen synthesis and gluconeogenesis in CC hepatocytes through the zinc-dependent intracellular catabolism of CC insulin (PubMed:27703010). Through zinc cellular uptake also plays a CC role in the adaptation of cells to endoplasmic reticulum stress (By CC similarity). Major manganese transporter of the basolateral membrane of CC intestinal epithelial cells, it plays a central role in manganese CC systemic homeostasis through intestinal manganese uptake CC (PubMed:31028174). Also involved in manganese extracellular uptake by CC cells of the blood-brain barrier (PubMed:31699897). May also play a CC role in manganese and zinc homeostasis participating in their CC elimination from the blood through the hepatobiliary excretion (By CC similarity). Also functions in the extracellular uptake of free iron. CC May also function intracellularly and mediate the transport from CC endosomes to cytosol of iron endocytosed by transferrin CC (PubMed:20682781). Plays a role in innate immunity by regulating the CC expression of cytokines by activated macrophages (PubMed:23052185). CC {ECO:0000250|UniProtKB:Q75N73, ECO:0000269|PubMed:15642354, CC ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:23052185, CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:29621230, ECO:0000269|PubMed:31028174, CC ECO:0000269|PubMed:31699897}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(out) + 2 hydrogencarbonate(out) = Zn(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62252, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29105; Evidence={ECO:0000305|PubMed:15642354}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253; CC Evidence={ECO:0000269|PubMed:15642354}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + 2 hydrogencarbonate(out) = Mn(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62260, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29035; Evidence={ECO:0000305|PubMed:31699897}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261; CC Evidence={ECO:0000269|PubMed:31699897}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Fe(2+)(out) + 2 hydrogencarbonate(out) = Fe(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62368, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29033; Evidence={ECO:0000250|UniProtKB:Q75N73}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62369; CC Evidence={ECO:0000250|UniProtKB:Q75N73}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62256, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:48775; Evidence={ECO:0000250|UniProtKB:Q75N73}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257; CC Evidence={ECO:0000250|UniProtKB:Q75N73}; CC -!- SUBUNIT: Homotrimer. {ECO:0000269|PubMed:12659941}. CC -!- INTERACTION: CC Q15043-2; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-12176399, EBI-741037; CC Q15043-2; Q9UH03: SEPTIN3; NbExp=3; IntAct=EBI-12176399, EBI-727037; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15642354, CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:29621230}; Multi-pass membrane protein CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:31699897}; CC Multi-pass membrane protein {ECO:0000255}. Basolateral cell membrane CC {ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}; Multi-pass CC membrane protein {ECO:0000255}. Early endosome membrane CC {ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:27703010}; Multi-pass CC membrane protein {ECO:0000255}. Late endosome membrane CC {ECO:0000269|PubMed:27703010}; Multi-pass membrane protein CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:20682781}; Multi- CC pass membrane protein {ECO:0000255}. Note=Localized and functional at CC both apical and basolateral membranes of microvascular capillary CC endothelial cells that constitute the blood-brain barrier CC (PubMed:31699897). Localized at the basolateral membrane of enterocytes CC (PubMed:31028174). Enriched at the plasma membrane upon glucose uptake CC (PubMed:27703010). {ECO:0000269|PubMed:27703010, CC ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14B CC {ECO:0000303|PubMed:18270315}; CC IsoId=Q15043-1; Sequence=Displayed; CC Name=3; CC IsoId=Q15043-2; Sequence=VSP_029728; CC Name=2 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14A CC {ECO:0000303|PubMed:18270315}; CC IsoId=Q15043-3; Sequence=VSP_040139; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with higher expression in CC liver, pancreas, fetal liver, thyroid gland, left and right ventricle, CC right atrium and fetal heart (PubMed:15642354, PubMed:20682781, CC PubMed:7584044). Weakly expressed in spleen, thymus, and peripheral CC blood leukocytes (PubMed:7584044). Expressed in liver and in brain by CC large neurons in the globus pallidus, the insular cortex and the CC dentate nucleus and to a lower extent in the putamen and the caudate CC nucleus (at protein level) (PubMed:27231142). Expressed in osteoblasts CC and giant osteoclast-like cells, but not in osteocytes found CC osteoblastoma and giant cell tumors (at protein level) CC (PubMed:29621230). Expressed by microvascular capillary endothelial CC cells that constitute the blood-brain barrier (at protein level) CC (PubMed:31699897). Expressed by macrophages (PubMed:23052185). CC {ECO:0000269|PubMed:15642354, ECO:0000269|PubMed:20682781, CC ECO:0000269|PubMed:23052185, ECO:0000269|PubMed:31699897, CC ECO:0000269|PubMed:7584044}. CC -!- TISSUE SPECIFICITY: [Isoform 2]: Widely expressed but not detected in CC brain, heart, skeletal muscle, placenta and fetal skin. CC {ECO:0000269|PubMed:27231142}. CC -!- INDUCTION: Up-regulated by iron (at protein level) (PubMed:24927598). CC Down-regulation upon iron depletion occurs through proteasomal CC degradation of the intracellular pool (PubMed:24927598). Up-regulated CC by tunicamycin, a drug inducing endoplasmic reticulum stress (at CC protein level) (PubMed:28673968). Up-regulated by CC lipopolysaccharide/LPS (PubMed:23052185). {ECO:0000269|PubMed:23052185, CC ECO:0000269|PubMed:24927598, ECO:0000269|PubMed:28673968}. CC -!- PTM: Ubiquitinated. Ubiquitination occurs upon iron depletion. The CC ubiquitinated form undergoes proteasomal degradation. CC {ECO:0000269|PubMed:24927598}. CC -!- PTM: N-glycosylated. N-glycosylation at Asn-102 is required for iron- CC regulated extraction of the transporter from membranes and subsequent CC proteasomal degradation. {ECO:0000269|PubMed:24927598}. CC -!- DISEASE: Hypermanganesemia with dystonia 2 (HMNDYT2) [MIM:617013]: A CC metabolic autosomal recessive disorder characterized by increased blood CC manganese levels, neurodegeneration, and rapidly progressive CC parkinsonism and dystonia. Affected individuals present with loss of CC developmental milestones, progressive dystonia and bulbar dysfunction CC in infancy or early childhood. Towards the end of the first decade, CC they manifest severe generalized pharmacoresistant dystonia, CC spasticity, limb contractures and scoliosis, and loss of independent CC ambulation. Cognition may be impaired, but is better preserved than CC motor function. {ECO:0000269|PubMed:27231142}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Hyperostosis cranialis interna (HCIN) [MIM:144755]: An CC autosomal dominant bone disorder characterized by endosteal CC hyperostosis and osteosclerosis of the calvaria and the skull base. The CC progressive bone overgrowth causes entrapment and dysfunction of CC cranial nerves I, II, V, VII, and VIII, its first symptoms often CC presenting during the second decade of life. CC {ECO:0000269|PubMed:29621230}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Conditional knockin mice CC overexpressing Arg-438 variant, which is the mouse equivalent of human CC variant Leu-441, in osteoblasts have a severe skeletal phenotype marked CC by a drastic increase in cortical thickness due to an enhanced CC endosteal bone formation, resembling the underlying pathology in HCI CC patients. {ECO:0000269|PubMed:29621230}. CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA06685.1; 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; D31887; BAA06685.1; ALT_INIT; mRNA. DR EMBL; AK172810; BAD18780.1; -; mRNA. DR EMBL; AK295807; BAG58625.1; -; mRNA. DR EMBL; AC087854; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC105910; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471080; EAW63681.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63682.1; -; Genomic_DNA. DR EMBL; CH471080; EAW63683.1; -; Genomic_DNA. DR EMBL; BC015770; AAH15770.1; -; mRNA. DR CCDS; CCDS47822.1; -. [Q15043-2] DR CCDS; CCDS47823.1; -. [Q15043-1] DR CCDS; CCDS6030.1; -. [Q15043-3] DR RefSeq; NP_001121903.1; NM_001128431.4. [Q15043-1] DR RefSeq; NP_001128625.1; NM_001135153.3. [Q15043-1] DR RefSeq; NP_001128626.1; NM_001135154.3. [Q15043-2] DR RefSeq; NP_001338584.1; NM_001351655.2. [Q15043-1] DR RefSeq; NP_001338585.1; NM_001351656.2. [Q15043-1] DR RefSeq; NP_001338589.1; NM_001351660.2. [Q15043-1] DR RefSeq; NP_056174.2; NM_015359.6. [Q15043-3] DR RefSeq; XP_006716387.1; XM_006716324.4. [Q15043-1] DR RefSeq; XP_047277610.1; XM_047421654.1. [Q15043-1] DR RefSeq; XP_047277611.1; XM_047421655.1. [Q15043-1] DR AlphaFoldDB; Q15043; -. DR SMR; Q15043; -. DR BioGRID; 117063; 343. DR FunCoup; Q15043; 631. DR IntAct; Q15043; 255. DR MINT; Q15043; -. DR STRING; 9606.ENSP00000370635; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.5.4.5; the zinc (zn(2+))-iron (fe(2+)) permease (zip) family. DR GlyCosmos; Q15043; 3 sites, No reported glycans. DR GlyGen; Q15043; 4 sites, 21 N-linked glycans (3 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q15043; -. DR PhosphoSitePlus; Q15043; -. DR SwissPalm; Q15043; -. DR BioMuta; SLC39A14; -. DR DMDM; 313104191; -. DR jPOST; Q15043; -. DR MassIVE; Q15043; -. DR PaxDb; 9606-ENSP00000352779; -. DR PeptideAtlas; Q15043; -. DR ProteomicsDB; 60392; -. [Q15043-1] DR ProteomicsDB; 60393; -. [Q15043-2] DR ProteomicsDB; 60394; -. [Q15043-3] DR Pumba; Q15043; -. DR Antibodypedia; 9517; 193 antibodies from 27 providers. DR DNASU; 23516; -. DR Ensembl; ENST00000240095.10; ENSP00000240095.6; ENSG00000104635.16. [Q15043-2] DR Ensembl; ENST00000289952.9; ENSP00000289952.5; ENSG00000104635.16. [Q15043-1] DR Ensembl; ENST00000359741.10; ENSP00000352779.5; ENSG00000104635.16. [Q15043-3] DR Ensembl; ENST00000381237.6; ENSP00000370635.1; ENSG00000104635.16. [Q15043-1] DR GeneID; 23516; -. DR KEGG; hsa:23516; -. DR MANE-Select; ENST00000381237.6; ENSP00000370635.1; NM_001128431.4; NP_001121903.1. DR UCSC; uc003xbp.5; human. [Q15043-1] DR AGR; HGNC:20858; -. DR ClinPGx; PA134863701; -. DR CTD; 23516; -. DR DisGeNET; 23516; -. DR GeneCards; SLC39A14; -. DR GeneReviews; SLC39A14; -. DR HGNC; HGNC:20858; SLC39A14. DR HPA; ENSG00000104635; Tissue enhanced (liver, pancreas). DR MalaCards; SLC39A14; -. DR MIM; 144755; phenotype. DR MIM; 608736; gene. DR MIM; 617013; phenotype. DR OpenTargets; ENSG00000104635; -. DR Orphanet; 521406; Dystonia-parkinsonism-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000104635; -. DR eggNOG; KOG2693; Eukaryota. DR GeneTree; ENSGT00940000157986; -. DR InParanoid; Q15043; -. DR OMA; ADHYSTP; -. DR OrthoDB; 200954at2759; -. DR PAN-GO; Q15043; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q15043; -. DR PathwayCommons; Q15043; -. DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family. DR SignaLink; Q15043; -. DR Agora; ENSG00000104635; -. DR BioGRID-ORCS; 23516; 16 hits in 1166 CRISPR screens. DR ChiTaRS; SLC39A14; human. DR GenomeRNAi; 23516; -. DR Pharos; Q15043; Tbio. DR PRO; PR:Q15043; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q15043; protein. DR Bgee; ENSG00000104635; Expressed in cartilage tissue and 199 other cell types or tissues. DR ExpressionAtlas; Q15043; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; ISS:UniProtKB. DR GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IEA:Ensembl. DR GO; GO:0005381; F:iron ion transmembrane transporter activity; ISS:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0015296; F:monoatomic anion:monoatomic cation symporter activity; ISS:UniProtKB. DR GO; GO:0140410; F:monoatomic cation:bicarbonate symporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB. DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB. DR GO; GO:0002062; P:chondrocyte differentiation; ISS:UniProtKB. DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB. DR GO; GO:0098739; P:import across plasma membrane; IMP:UniProtKB. DR GO; GO:0098662; P:inorganic cation transmembrane transport; ISS:UniProtKB. DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0030003; P:intracellular monoatomic cation homeostasis; IBA:GO_Central. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:BHF-UCL. DR GO; GO:0033212; P:iron import into cell; IMP:UniProtKB. DR GO; GO:0034755; P:iron ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0055071; P:manganese ion homeostasis; ISS:UniProtKB. DR GO; GO:0071421; P:manganese ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0010817; P:regulation of hormone levels; ISS:UniProtKB. DR GO; GO:0071578; P:zinc ion import across plasma membrane; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:BHF-UCL. DR InterPro; IPR003689; ZIP. DR InterPro; IPR050799; ZIP_Transporter. DR PANTHER; PTHR12191:SF5; METAL CATION SYMPORTER ZIP14; 1. DR PANTHER; PTHR12191; SOLUTE CARRIER FAMILY 39; 1. DR Pfam; PF02535; Zip; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Disease variant; Dystonia; Endosome; KW Glycoprotein; Ion transport; Lysosome; Membrane; Neurodegeneration; KW Parkinsonism; Proteomics identification; Reference proteome; Signal; KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation; Zinc; KW Zinc transport. FT SIGNAL 1..30 FT /evidence="ECO:0000255" FT CHAIN 31..492 FT /note="Metal cation symporter ZIP14" FT /id="PRO_0000312194" FT TOPO_DOM 31..157 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 158..178 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 179..186 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 187..207 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 208..224 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 225..245 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 246..397 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 398..418 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 419..424 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 425..445 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 446..460 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 461..481 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 482..492 FT /note="Extracellular" FT /evidence="ECO:0000255" FT MOTIF 251..258 FT /note="HHHGHXHX-motif" FT /evidence="ECO:0000305|PubMed:27231142" FT MOTIF 376..381 FT /note="XEXPHE-motif" FT /evidence="ECO:0000305|PubMed:12659941" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:24927598" FT CARBOHYD 87 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24927598" FT CARBOHYD 102 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973, FT ECO:0000269|PubMed:24927598" FT VAR_SEQ 156..199 FT /note="YGLLCVTVISLCSLLGASVVPFMKKTFYKRLLLYFIALAIGTLY -> FGFL FT SVSLINLASLLGVLVLPCTEKAFFSRVLTYFIALSIGTLL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_040139" FT VAR_SEQ 445..492 FT /note="FPEMNEVCQEDERKGSILIPFIIQNLGLLTGFTIMVVLTMYSGQIQIG -> FT MEFCSVAQAGVQWCHLSSLQPLPLGLKRLSCLSLPSN (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029728" FT VARIANT 33 FT /note="L -> P (in dbSNP:rs896378)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_037450" FT VARIANT 98 FT /note="F -> V (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs879253763)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077004" FT VARIANT 383 FT /note="G -> R (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs879253766)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077005" FT VARIANT 441 FT /note="L -> R (in HCIN; loss of localization at the plasma FT membrane; loss of Zn uptake activity; dbSNP:rs1554520924)" FT /evidence="ECO:0000269|PubMed:29621230" FT /id="VAR_080794" FT VARIANT 469 FT /note="N -> K (in HMNDYT2; no effect on protein abundance; FT no effect on subcellular localization at the plasma FT membrane and within the cytoplasm; decreased manganese ion FT transmembrane transporter activity; dbSNP:rs750281602)" FT /evidence="ECO:0000269|PubMed:27231142" FT /id="VAR_077006" FT MUTAGEN 77 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT MUTAGEN 87 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT MUTAGEN 102 FT /note="N->A: Decreased N-glycosylation." FT /evidence="ECO:0000269|PubMed:24927598" FT CONFLICT 57 FT /note="L -> P (in Ref. 2; BAD18780)" FT /evidence="ECO:0000305" FT CONFLICT 314 FT /note="D -> G (in Ref. 2; BAG58625)" FT /evidence="ECO:0000305" FT CONFLICT 380 FT /note="H -> R (in Ref. 2; BAD18780)" FT /evidence="ECO:0000305" SQ SEQUENCE 492 AA; 54212 MW; F2ACE1DA4656A5F0 CRC64; MKLLLLHPAF QSCLLLTLLG LWRTTPEAHA SSLGAPAISA ASFLQDLIHR YGEGDSLTLQ QLKALLNHLD VGVGRGNVTQ HVQGHRNLST CFSSGDLFTA HNFSEQSRIG SSELQEFCPT ILQQLDSRAC TSENQENEEN EQTEEGRPSA VEVWGYGLLC VTVISLCSLL GASVVPFMKK TFYKRLLLYF IALAIGTLYS NALFQLIPEA FGFNPLEDYY VSKSAVVFGG FYLFFFTEKI LKILLKQKNE HHHGHSHYAS ESLPSKKDQE EGVMEKLQNG DLDHMIPQHC SSELDGKAPM VDEKVIVGSL SVQDLQASQS ACYWLKGVRY SDIGTLAWMI TLSDGLHNFI DGLAIGASFT VSVFQGISTS VAILCEEFPH ELGDFVILLN AGMSIQQALF FNFLSACCCY LGLAFGILAG SHFSANWIFA LAGGMFLYIS LADMFPEMNE VCQEDERKGS ILIPFIIQNL GLLTGFTIMV VLTMYSGQIQ IG // ID SC6A3_HUMAN Reviewed; 620 AA. AC Q01959; A2RUN4; Q14996; DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot. DT 01-APR-1993, sequence version 1. DT 28-JAN-2026, entry version 231. DE RecName: Full=Sodium-dependent dopamine transporter; DE Short=DA transporter; DE Short=DAT {ECO:0000303|PubMed:39112701, ECO:0000303|PubMed:39112703, ECO:0000303|PubMed:39112705}; DE AltName: Full=Solute carrier family 6 member 3; GN Name=SLC6A3; Synonyms=DAT1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1359373; DOI=10.1016/0169-328x(92)90165-8; RA Vandenbergh D.J., Persico A.M., Uhl G.R.; RT "A human dopamine transporter cDNA predicts reduced glycosylation, displays RT a novel repetitive element and provides racially-dimorphic TaqI RFLPs."; RL Brain Res. Mol. Brain Res. 15:161-166(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES. RC TISSUE=Brain; RX PubMed=1406597; RA Giros B., el Mestikawy S., Godinot N., Zheng K., Han H., Yang-Feng T., RA Caron M.G.; RT "Cloning, pharmacological characterization, and chromosome assignment of RT the human dopamine transporter."; RL Mol. Pharmacol. 42:383-390(1992). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES. RC TISSUE=Brain; RX PubMed=8302271; RA Pristupa Z.B., Wilson J.M., Hoffman B.J., Kish S.J., Niznik H.B.; RT "Pharmacological heterogeneity of the cloned and native human dopamine RT transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding."; RL Mol. Pharmacol. 45:125-135(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9300814; DOI=10.1016/s0378-1119(97)00131-5; RA Kawarai T., Kawakami H., Yamamura Y., Nakamura S.; RT "Structure and organization of the gene encoding human dopamine RT transporter."; RL Gene 195:11-18(1997). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10889531; DOI=10.1038/sj.mp.4000701; RA Vandenbergh D.J., Thompson M.D., Cook E.H., Bendahhou E., Nguyen T., RA Krasowski M.D., Zarrabian D., Comings D., Sellers E.M., Tyndale R.F., RA George S.R., O'Dowd B.F., Uhl G.R.; RT "Human dopamine transporter gene: coding region conservation among normal, RT Tourette's disorder, alcohol dependence and attention-deficit hyperactivity RT disorder populations."; RL Mol. Psychiatry 5:283-292(2000). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11304827; RX DOI=10.1002/1096-8628(2001)9999:9999<::aid-ajmg1161>3.0.co;2-8; RA Greenwood T.A., Alexander M., Keck P.E., McElroy S., Sadovnick A.D., RA Remick R.A., Kelsoe J.R.; RT "Evidence for linkage disequilibrium between the dopamine transporter and RT bipolar disorder."; RL Am. J. Med. Genet. 105:145-151(2001). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=17934207; DOI=10.1093/molbev/msm219; RA Miller-Butterworth C.M., Kaplan J.R., Shaffer J., Devlin B., Manuck S.B., RA Ferrell R.E.; RT "Sequence variation in the primate dopamine transporter gene and its RT relationship to social dominance."; RL Mol. Biol. Evol. 25:18-28(2008). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 PRELIMINARY NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-385, AND TISSUE RP SPECIFICITY. RX PubMed=7637582; DOI=10.1016/0169-328x(95)00018-n; RA Donovan D.M., Vandenbergh D.J., Perry M.P., Bird G.S., Ingersoll R., RA Nanthakumar E., Uhl G.R.; RT "Human and mouse dopamine transporter genes: conservation of 5'-flanking RT sequence elements and gene structures."; RL Brain Res. Mol. Brain Res. 30:327-335(1995). RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 164-255. RX PubMed=1353885; DOI=10.1073/pnas.89.15.7095; RA Bannon M.J., Poosch M.S., Xia Y., Goebel D.J., Cassin B., Kapatos G.; RT "Dopamine transporter mRNA content in human substantia nigra decreases RT precipitously with age."; RL Proc. Natl. Acad. Sci. U.S.A. 89:7095-7099(1992). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY RP REGULATION. RX PubMed=10375632; DOI=10.1016/s0378-1119(99)00143-2; RA Wu X., Gu H.H.; RT "Molecular cloning of the mouse dopamine transporter and pharmacological RT comparison with the human homologue."; RL Gene 233:163-170(1999). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=11093780; DOI=10.1124/mol.58.6.1404; RA Syringas M., Janin F., Mezghanni S., Giros B., Costentin J., Bonnet J.J.; RT "Structural domains of chimeric dopamine-noradrenaline human transporters RT involved in the Na(+)- and Cl(-)-dependence of dopamine transport."; RL Mol. Pharmacol. 58:1404-1411(2000). RN [15] RP INTERACTION WITH PRKCABP, AND SUBCELLULAR LOCATION. RX PubMed=11343649; DOI=10.1016/s0896-6273(01)00267-7; RA Torres G.E., Yao W.-D., Mohn A.R., Quan H., Kim K.-M., Levey A.I., RA Staudinger J., Caron M.G.; RT "Functional interaction between monoamine plasma membrane transporters and RT the synaptic PDZ domain-containing protein PICK1."; RL Neuron 30:121-134(2001). RN [16] RP INTERCHAIN DISULFIDE BOND, AND SUBUNIT. RA Hastrup H., Karlin A., Javitch J.A.; RT "Symmetrical homodimer of the human dopamine transporter revealed by cross- RT linking Cys306 at the extracellular end of TM6."; RL Abstr. - Soc. Neurosci. 27:1866-1866(2001). RN [17] RP INTERACTION WITH TGFB1I1. RX PubMed=12177201; DOI=10.1523/jneurosci.22-16-07045.2002; RA Carneiro A.M.D., Ingram S.L., Beaulieu J.-M., Sweeney A., Amara S.G., RA Thomas S.M., Caron M.G., Torres G.E.; RT "The multiple LIM domain-containing adaptor protein Hic-5 synaptically RT colocalizes and interacts with the dopamine transporter."; RL J. Neurosci. 22:7045-7054(2002). RN [18] RP FUNCTION AS DOPAMINE TRANSPORTER, INTERACTION WITH TOR1A, SUBCELLULAR RP LOCATION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=15505207; DOI=10.1073/pnas.0308088101; RA Torres G.E., Sweeney A.L., Beaulieu J.M., Shashidharan P., Caron M.G.; RT "Effect of torsinA on membrane proteins reveals a loss of function and a RT dominant-negative phenotype of the dystonia-associated DeltaE-torsinA RT mutant."; RL Proc. Natl. Acad. Sci. U.S.A. 101:15650-15655(2004). RN [19] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17296554; DOI=10.1016/j.neuron.2007.01.019; RA Ihara M., Yamasaki N., Hagiwara A., Tanigaki A., Kitano A., Hikawa R., RA Tomimoto H., Noda M., Takanashi M., Mori H., Hattori N., Miyakawa T., RA Kinoshita M.; RT "Sept4, a component of presynaptic scaffold and Lewy bodies, is required RT for the suppression of alpha-synuclein neurotoxicity."; RL Neuron 53:519-533(2007). RN [20] RP INTERACTION WITH ALPHA-SYNUCLEIN/SNCA. RX PubMed=26442590; DOI=10.1074/jbc.m115.691592; RA Butler B., Saha K., Rana T., Becker J.P., Sambo D., Davari P., RA Goodwin J.S., Khoshbouei H.; RT "Dopamine Transporter Activity Is Modulated by alpha-Synuclein."; RL J. Biol. Chem. 290:29542-29554(2015). RN [21] RP VARIANT GLN-237. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions of RT human genes."; RL Nat. Genet. 22:231-238(1999). RN [22] RP ERRATUM OF PUBMED:10391209. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [23] RP VARIANTS [LARGE SCALE ANALYSIS] SER-121 AND SER-544. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP VARIANTS PKDYS1 GLN-368 AND LEU-395, CHARACTERIZATION OF VARIANTS PKDYS1 RP GLN-368 AND LEU-395, FUNCTION, AND TRANSPORTER ACTIVITY. RX PubMed=19478460; DOI=10.1172/jci39060; RA Kurian M.A., Zhen J., Cheng S.Y., Li Y., Mordekar S.R., Jardine P., RA Morgan N.V., Meyer E., Tee L., Pasha S., Wassmer E., Heales S.J., RA Gissen P., Reith M.E., Maher E.R.; RT "Homozygous loss-of-function mutations in the gene encoding the dopamine RT transporter are associated with infantile parkinsonism-dystonia."; RL J. Clin. Invest. 119:1595-1603(2009). RN [25] RP VARIANT ILE-471. RX PubMed=21179162; DOI=10.1038/nature09629; RA Bevilacqua L., Doly S., Kaprio J., Yuan Q., Tikkanen R., Paunio T., RA Zhou Z., Wedenoja J., Maroteaux L., Diaz S., Belmer A., Hodgkinson C.A., RA Dell'osso L., Suvisaari J., Coccaro E., Rose R.J., Peltonen L., RA Virkkunen M., Goldman D.; RT "A population-specific HTR2B stop codon predisposes to severe RT impulsivity."; RL Nature 468:1061-1066(2010). RN [26] {ECO:0007744|PDB:8VBY} RP STRUCTURE BY ELECTRON MICROSCOPY (3.19 ANGSTROMS) OF 57-620 IN COMPLEX WITH RP SODIUM; ZINC; INHIBITOR AND COCAINE ANALOG, FUNCTION, TRANSPORTER ACTIVITY, RP ACTIVITY REGULATION, SUBUNIT, SUBCELLULAR LOCATION, TOPOLOGY, DISULFIDE RP BONDS, AND MUTAGENESIS OF THR-211; VAL-364; ILE-390; TYR-394 AND MET-414. RX PubMed=39112705; DOI=10.1038/s41586-024-07739-9; RA Srivastava D.K., Navratna V., Tosh D.K., Chinn A., Sk M.F., Tajkhorshid E., RA Jacobson K.A., Gouaux E.; RT "Structure of the human dopamine transporter and mechanisms of RT inhibition."; RL Nature 632:672-677(2024). RN [27] {ECO:0007744|PDB:9EO4} RP STRUCTURE BY ELECTRON MICROSCOPY (2.66 ANGSTROMS) IN COMPLEX WITH SODIUM; RP CHLORIDE AND COCAINE, FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, SUBCELLULAR LOCATION, TOPOLOGY, AND DISULFIDE BONDS. RX PubMed=39112703; DOI=10.1038/s41586-024-07804-3; RA Nielsen J.C., Salomon K., Kalenderoglou I.E., Bargmeyer S., Pape T., RA Shahsavar A., Loland C.J.; RT "Structure of the human dopamine transporter in complex with cocaine."; RL Nature 632:678-685(2024). RN [28] {ECO:0007744|PDB:8Y2C, ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G} RP STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) OF 68-620 IN COMPLEXES RP WITH SODIUM; CHLORIDE; DOPAMINE; INHIBITORS AMPHETAMINE AND BENZTROPINE, RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBUNIT, SUBCELLULAR RP LOCATION, GLYCOSYLATION AT ASN-181 AND ASN-188, TOPOLOGY, DISULFIDE BONDS, RP AND MUTAGENESIS OF ASP-79; VAL-152; GLN-317; PHE-320; SER-321; PHE-326; RP ASN-353; SER-357; ASP-421; SER-422 AND GLY-426. RX PubMed=39112701; DOI=10.1038/s41586-024-07796-0; RA Li Y., Wang X., Meng Y., Hu T., Zhao J., Li R., Bai Q., Yuan P., Han J., RA Hao K., Wei Y., Qiu Y., Li N., Zhao Y.; RT "Dopamine reuptake and inhibitory mechanisms in human dopamine RT transporter."; RL Nature 632:686-694(2024). CC -!- FUNCTION: Mediates sodium- and chloride-dependent transport of dopamine CC (PubMed:10375632, PubMed:11093780, PubMed:1406597, PubMed:15505207, CC PubMed:19478460, PubMed:39112701, PubMed:39112703, PubMed:39112705, CC PubMed:8302271). Also mediates sodium- and chloride-dependent transport CC of norepinephrine (also known as noradrenaline) (By similarity). CC Regulator of light-dependent retinal hyaloid vessel regression, CC downstream of OPN5 signaling (By similarity). CC {ECO:0000250|UniProtKB:P23977, ECO:0000250|UniProtKB:Q61327, CC ECO:0000269|PubMed:10375632, ECO:0000269|PubMed:11093780, CC ECO:0000269|PubMed:1406597, ECO:0000269|PubMed:15505207, CC ECO:0000269|PubMed:19478460, ECO:0000269|PubMed:39112701, CC ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, CC ECO:0000269|PubMed:8302271}. CC -!- CATALYTIC ACTIVITY: CC Reaction=dopamine(out) + chloride(out) + Na(+)(out) = dopamine(in) + CC chloride(in) + Na(+)(in); Xref=Rhea:RHEA:70919, ChEBI:CHEBI:17996, CC ChEBI:CHEBI:29101, ChEBI:CHEBI:59905; CC Evidence={ECO:0000269|PubMed:10375632, ECO:0000269|PubMed:11093780, CC ECO:0000269|PubMed:1406597, ECO:0000269|PubMed:15505207, CC ECO:0000269|PubMed:19478460, ECO:0000269|PubMed:39112703, CC ECO:0000269|PubMed:39112705, ECO:0000269|PubMed:8302271}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dopamine(out) + chloride(out) + 2 Na(+)(out) = dopamine(in) + CC chloride(in) + 2 Na(+)(in); Xref=Rhea:RHEA:70931, ChEBI:CHEBI:17996, CC ChEBI:CHEBI:29101, ChEBI:CHEBI:59905; CC Evidence={ECO:0000269|PubMed:39112701}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-noradrenaline(out) + chloride(out) + Na(+)(out) = (R)- CC noradrenaline(in) + chloride(in) + Na(+)(in); Xref=Rhea:RHEA:70923, CC ChEBI:CHEBI:17996, ChEBI:CHEBI:29101, ChEBI:CHEBI:72587; CC Evidence={ECO:0000250|UniProtKB:P23977}; CC -!- ACTIVITY REGULATION: Inhibited by cocaine, which occupies the same CC binding site as dopamine (PubMed:1406597, PubMed:39112701, CC PubMed:39112703, PubMed:39112705, PubMed:8302271). Inhibited by zinc CC ions (PubMed:39112705). Enhanced by the antibiotic valinomycin CC (PubMed:39112703). Inhibited by benztropine (PubMed:39112701, CC PubMed:39112705). Inhibited by GBR 12909 dihydrochloride and CC amphetamine (PubMed:1406597, PubMed:39112701, PubMed:8302271). CC Inhibited by mazindol, GBR 12783 dihydrochloride, nomifensine, CC diclofensine, amfonelic acid, Lu 19005, Win-35428, bupropion and CC ritalin (PubMed:1406597, PubMed:8302271). {ECO:0000269|PubMed:1406597, CC ECO:0000269|PubMed:39112701, ECO:0000269|PubMed:39112703, CC ECO:0000269|PubMed:39112705, ECO:0000269|PubMed:8302271}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=58 mM for Na(+) in dopamine transport CC {ECO:0000269|PubMed:11093780}; CC KM=53 mM for Cl(-) in dopamine transport CC {ECO:0000269|PubMed:11093780}; CC KM=1.2 uM for dopamine {ECO:0000269|PubMed:1406597}; CC KM=2.4 uM for dopamine {ECO:0000269|PubMed:10375632, CC ECO:0000269|PubMed:8302271}; CC KM=2.5 uM for dopamine {ECO:0000269|PubMed:15505207}; CC -!- SUBUNIT: Monomer (PubMed:39112701, PubMed:39112703, PubMed:39112705). CC Homooligomer; disulfide-linked (Ref.16). Interacts with PRKCABP and CC TGFB1I1 (PubMed:11343649, PubMed:12177201). Interacts (via N-terminus) CC with SYNGR3 (via N-terminus) (By similarity). Interacts with SLC18A2 CC (By similarity). Interacts with TOR1A (ATP-bound); TOR1A regulates CC SLC6A3 subcellular location (PubMed:15505207). Interacts with alpha- CC synuclein/SNCA (PubMed:26442590). Interacts with SEPTIN4 (By CC similarity). {ECO:0000250|UniProtKB:Q61327, CC ECO:0000269|PubMed:11343649, ECO:0000269|PubMed:12177201, CC ECO:0000269|PubMed:15505207, ECO:0000269|PubMed:26442590, CC ECO:0000269|PubMed:39112701, ECO:0000269|PubMed:39112703, CC ECO:0000269|PubMed:39112705, ECO:0000269|Ref.16}. CC -!- INTERACTION: CC Q01959; P14416: DRD2; NbExp=4; IntAct=EBI-6661445, EBI-2928178; CC Q01959; O15354: GPR37; NbExp=2; IntAct=EBI-6661445, EBI-15639515; CC Q01959; Q9NRD5: PICK1; NbExp=4; IntAct=EBI-6661445, EBI-79165; CC Q01959; Q99578: RIT2; NbExp=5; IntAct=EBI-6661445, EBI-365914; CC Q01959; P37840: SNCA; NbExp=3; IntAct=EBI-6661445, EBI-985879; CC Q01959; Q5T9L3: WLS; NbExp=2; IntAct=EBI-6661445, EBI-2868748; CC Q01959; Q9EP80: Pick1; Xeno; NbExp=2; IntAct=EBI-6661445, EBI-77728; CC Q01959; Q5BJQ5: Rit2; Xeno; NbExp=2; IntAct=EBI-6661445, EBI-11686902; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11343649, CC ECO:0000269|PubMed:15505207, ECO:0000269|PubMed:39112701}; Multi-pass CC membrane protein {ECO:0000269|PubMed:39112701, CC ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705}. Cell CC projection, neuron projection {ECO:0000250|UniProtKB:P23977}. Cell CC projection, axon {ECO:0000269|PubMed:17296554}. Note=Localizes to CC neurite tips in neuronal cells (By similarity). Colocalizes with CC SEPTIN4 at axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:P23977, CC ECO:0000250|UniProtKB:Q61327}. CC -!- TISSUE SPECIFICITY: Highly expressed in substantia nigra CC (PubMed:7637582). Expressed in axonal varicosities in dopaminergic CC nerve terminals (at protein level) (PubMed:17296554). Expressed in the CC striatum (at protein level) (PubMed:17296554). CC {ECO:0000269|PubMed:17296554, ECO:0000269|PubMed:7637582}. CC -!- DISEASE: Parkinsonism-dystonia 1, infantile-onset (PKDYS1) CC [MIM:613135]: An autosomal recessive neurodegenerative disorder CC characterized by infantile onset of parkinsonism and dystonia. Other CC neurologic features include global developmental delay, bradykinesia CC and pyramidal tract signs. {ECO:0000269|PubMed:19478460}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: This protein is the target of psychomotor stimulants CC such as amphetamines or cocaine. CC -!- SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) (TC CC 2.A.22) family. SLC6A3 subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Dopamine transporter entry; CC URL="https://en.wikipedia.org/wiki/Dopamine_transporter"; 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; M95167; AAC41720.1; -; mRNA. DR EMBL; S46955; AAA11754.1; -; mRNA. DR EMBL; S44626; AAB23443.1; -; mRNA. DR EMBL; L24178; AAA19560.1; -; mRNA. DR EMBL; D88570; BAA22511.1; -; Genomic_DNA. DR EMBL; AF119117; AAC50179.2; -; Genomic_DNA. DR EMBL; AF321321; AAG33844.1; -; Genomic_DNA. DR EMBL; AF306558; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF321320; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306559; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306560; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306561; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306562; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306563; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; AF306564; AAG33844.1; JOINED; Genomic_DNA. DR EMBL; EF174603; ABO77644.1; -; mRNA. DR EMBL; AY623110; AAT38106.1; -; Genomic_DNA. DR EMBL; CH471102; EAX08159.1; -; Genomic_DNA. DR EMBL; BC132977; AAI32978.1; -; mRNA. DR EMBL; BC133003; AAI33004.1; -; mRNA. DR EMBL; M96670; AAA35770.1; -; mRNA. DR CCDS; CCDS3863.1; -. DR PIR; A48980; A48980. DR PIR; I57937; I57937. DR PIR; I84455; I84455. DR RefSeq; NP_001035.1; NM_001044.5. DR PDB; 8VBY; EM; 3.19 A; A=57-620. DR PDB; 8Y2C; EM; 3.16 A; A=66-620. DR PDB; 8Y2D; EM; 2.80 A; A=68-620. DR PDB; 8Y2E; EM; 3.03 A; A=66-620. DR PDB; 8Y2F; EM; 2.97 A; A=66-620. DR PDB; 8Y2G; EM; 2.83 A; A=59-620. DR PDB; 9EO4; EM; 2.66 A; B=1-620. DR PDBsum; 8VBY; -. DR PDBsum; 8Y2C; -. DR PDBsum; 8Y2D; -. DR PDBsum; 8Y2E; -. DR PDBsum; 8Y2F; -. DR PDBsum; 8Y2G; -. DR PDBsum; 9EO4; -. DR AlphaFoldDB; Q01959; -. DR EMDB; EMD-19845; -. DR EMDB; EMD-38850; -. DR EMDB; EMD-38851; -. DR EMDB; EMD-38852; -. DR EMDB; EMD-38853; -. DR EMDB; EMD-38854; -. DR EMDB; EMD-43128; -. DR SMR; Q01959; -. DR BioGRID; 112422; 58. DR CORUM; Q01959; -. DR DIP; DIP-41827N; -. DR FunCoup; Q01959; 234. DR IntAct; Q01959; 58. DR MINT; Q01959; -. DR STRING; 9606.ENSP00000270349; -. DR BindingDB; Q01959; -. DR ChEMBL; CHEMBL238; -. DR DrugBank; DB01472; 4-Methoxyamphetamine. DR DrugBank; DB04947; Altropane. DR DrugBank; DB04836; Amineptine. DR DrugBank; DB05964; Amitifadine. DR DrugBank; DB00543; Amoxapine. DR DrugBank; DB00182; Amphetamine. DR DrugBank; DB01238; Aripiprazole. DR DrugBank; DB06413; Armodafinil. DR DrugBank; DB00245; Benzatropine. DR DrugBank; DB00865; Benzphetamine. DR DrugBank; DB01156; Bupropion. DR DrugBank; DB01161; Chloroprocaine. DR DrugBank; DB01114; Chlorpheniramine. DR DrugBank; DB00907; Cocaine. DR DrugBank; DB12305; Dasotraline. DR DrugBank; DB06700; Desvenlafaxine. DR DrugBank; DB06701; Dexmethylphenidate. DR DrugBank; DB01576; Dextroamphetamine. DR DrugBank; DB00937; Diethylpropion. DR DrugBank; DB01146; Diphenylpyraline. DR DrugBank; DB00988; Dopamine. DR DrugBank; DB00476; Duloxetine. DR DrugBank; DB01363; Ephedra sinica root. DR DrugBank; DB01175; Escitalopram. DR DrugBank; DB09194; Etoperidone. DR DrugBank; DB01463; Fencamfamin. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB17032; Indatraline. DR DrugBank; DB08824; Ioflupane I-123. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB00579; Mazindol. DR DrugBank; DB00454; Meperidine. DR DrugBank; DB01577; Metamfetamine. DR DrugBank; DB00422; Methylphenidate. DR DrugBank; DB06148; Mianserin. DR DrugBank; DB01454; Midomafetamine. DR DrugBank; DB01442; MMDA. DR DrugBank; DB00745; Modafinil. DR DrugBank; DB01149; Nefazodone. DR DrugBank; DB09186; Nisoxetine. DR DrugBank; DB04821; Nomifensine. DR DrugBank; DB05805; NS-2359. DR DrugBank; DB00830; Phenmetrazine. DR DrugBank; DB00191; Phentermine. DR DrugBank; DB00721; Procaine. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB11790; Radafaxine. DR DrugBank; DB06731; Seproxetine. DR DrugBank; DB16629; Serdexmethylphenidate. DR DrugBank; DB01104; Sertraline. DR DrugBank; DB01105; Sibutramine. DR DrugBank; DB14754; Solriamfetol. DR DrugBank; DB01509; Tenamfetamine. DR DrugBank; DB06156; Tesofensine. DR DrugBank; DB00726; Trimipramine. DR DrugBank; DB06333; Trodusquemine. DR DrugBank; DB03701; Vanoxerine. DR DrugBank; DB00285; Venlafaxine. DR DrugCentral; Q01959; -. DR GuidetoPHARMACOLOGY; 927; -. DR TCDB; 2.A.22.1.3; the neurotransmitter:sodium symporter (nss) family. DR GlyCosmos; Q01959; 3 sites, No reported glycans. DR GlyGen; Q01959; 3 sites. DR iPTMnet; Q01959; -. DR PhosphoSitePlus; Q01959; -. DR SwissPalm; Q01959; -. DR BioMuta; SLC6A3; -. DR DMDM; 266667; -. DR jPOST; Q01959; -. DR MassIVE; Q01959; -. DR PaxDb; 9606-ENSP00000270349; -. DR PeptideAtlas; Q01959; -. DR Antibodypedia; 2799; 457 antibodies from 46 providers. DR DNASU; 6531; -. DR Ensembl; ENST00000270349.12; ENSP00000270349.9; ENSG00000142319.20. DR Ensembl; ENST00000621716.2; ENSP00000479597.1; ENSG00000276996.2. DR GeneID; 6531; -. DR KEGG; hsa:6531; -. DR MANE-Select; ENST00000270349.12; ENSP00000270349.9; NM_001044.5; NP_001035.1. DR UCSC; uc003jck.4; human. DR AGR; HGNC:11049; -. DR ClinPGx; PA311; -. DR CTD; 6531; -. DR DisGeNET; 6531; -. DR GeneCards; SLC6A3; -. DR GeneReviews; SLC6A3; -. DR HGNC; HGNC:11049; SLC6A3. DR HPA; ENSG00000142319; Tissue enriched (brain). DR MalaCards; SLC6A3; -. DR MIM; 126455; gene. DR MIM; 613135; phenotype. DR OpenTargets; ENSG00000142319; -. DR Orphanet; 238455; Infantile dystonia-parkinsonism. DR VEuPathDB; HostDB:ENSG00000142319; -. DR eggNOG; KOG3659; Eukaryota. DR GeneTree; ENSGT00940000161224; -. DR HOGENOM; CLU_006855_9_0_1; -. DR InParanoid; Q01959; -. DR OMA; LAWAMVY; -. DR OrthoDB; 6581954at2759; -. DR PAN-GO; Q01959; 9 GO annotations based on evolutionary models. DR PhylomeDB; Q01959; -. DR PathwayCommons; Q01959; -. DR Reactome; R-HSA-379401; Dopamine clearance from the synaptic cleft. DR Reactome; R-HSA-442660; Na+/Cl- dependent neurotransmitter transporters. DR Reactome; R-HSA-5619081; Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS). DR Reactome; R-HSA-5660724; Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS). DR SABIO-RK; Q01959; -. DR SignaLink; Q01959; -. DR SIGNOR; Q01959; -. DR Agora; ENSG00000142319; -. DR BioGRID-ORCS; 6531; 11 hits in 1153 CRISPR screens. DR GeneWiki; Dopamine_transporter; -. DR GenomeRNAi; 6531; -. DR Pharos; Q01959; Tclin. DR PRO; PR:Q01959; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q01959; protein. DR Bgee; ENSG00000142319; Expressed in substantia nigra and 64 other cell types or tissues. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; IEA:Ensembl. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0016600; C:flotillin complex; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0045121; C:membrane raft; IDA:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0045211; C:postsynaptic membrane; IEA:Ensembl. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0043176; F:amine binding; IEA:Ensembl. DR GO; GO:0035240; F:dopamine binding; IEA:Ensembl. DR GO; GO:0005330; F:dopamine:sodium symporter activity; IDA:UniProtKB. DR GO; GO:1901363; F:heterocyclic compound binding; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IDA:MGI. DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; ISS:ARUK-UCL. DR GO; GO:0005334; F:norepinephrine:sodium symporter activity; IEA:Ensembl. DR GO; GO:0002020; F:protease binding; IEA:Ensembl. DR GO; GO:0051721; F:protein phosphatase 2A binding; IEA:Ensembl. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; IEA:Ensembl. DR GO; GO:0021984; P:adenohypophysis development; IEA:Ensembl. DR GO; GO:0006865; P:amino acid transport; IBA:GO_Central. DR GO; GO:0050890; P:cognition; IEA:Ensembl. DR GO; GO:0042416; P:dopamine biosynthetic process; IEA:Ensembl. DR GO; GO:0042420; P:dopamine catabolic process; IEA:Ensembl. DR GO; GO:0015872; P:dopamine transport; IDA:UniProtKB. DR GO; GO:0090494; P:dopamine uptake; IDA:ParkinsonsUK-UCL. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:Reactome. DR GO; GO:1990384; P:hyaloid vascular plexus regression; ISS:UniProtKB. DR GO; GO:0007595; P:lactation; IEA:Ensembl. DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl. DR GO; GO:0015844; P:monoamine transport; IDA:MGI. DR GO; GO:0006836; P:neurotransmitter transport; ISS:ARUK-UCL. DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0060134; P:prepulse inhibition; IEA:Ensembl. DR GO; GO:0042053; P:regulation of dopamine metabolic process; IEA:Ensembl. DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl. DR GO; GO:0042220; P:response to cocaine; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0010039; P:response to iron ion; IEA:Ensembl. DR GO; GO:0035094; P:response to nicotine; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0007608; P:sensory perception of smell; IEA:Ensembl. DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central. DR CDD; cd11514; SLC6sbd_DAT1; 1. DR InterPro; IPR000175; Na/ntran_symport. DR InterPro; IPR002436; Na/ntran_symport_dopamine. DR InterPro; IPR037272; SNS_sf. DR NCBIfam; NF037979; Na_transp; 1. DR PANTHER; PTHR11616:SF38; SODIUM-DEPENDENT DOPAMINE TRANSPORTER; 1. DR PANTHER; PTHR11616; SODIUM/CHLORIDE DEPENDENT TRANSPORTER; 1. DR Pfam; PF00209; SNF; 1. DR PRINTS; PR01202; DOPTRANSPORT. DR PRINTS; PR00176; NANEUSMPORT. DR SUPFAM; SSF161070; SNF-like; 1. DR PROSITE; PS00610; NA_NEUROTRAN_SYMP_1; 1. DR PROSITE; PS00754; NA_NEUROTRAN_SYMP_2; 1. DR PROSITE; PS50267; NA_NEUROTRAN_SYMP_3; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cell projection; Disease variant; KW Disulfide bond; Dystonia; Glycoprotein; Membrane; Metal-binding; KW Neurodegeneration; Neurotransmitter transport; Parkinsonism; KW Proteomics identification; Reference proteome; Sodium; Symport; KW Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..620 FT /note="Sodium-dependent dopamine transporter" FT /id="PRO_0000214751" FT TOPO_DOM 1..56 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 57..95 FT /note="Discontinuously helical; Name=1" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 96..127 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 128..171 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 172..236 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 237..256 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 257..287 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 288..306 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 307..335 FT /note="Discontinuously helical; Name=6" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 336..376 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 377..400 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 401..442 FT /note="Helical; Name=8" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 443..466 FT /note="Helical; Name=9" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 467..499 FT /note="Helical; Name=10" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 500..516 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 517..542 FT /note="Helical; Name=11" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 543..553 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TRANSMEM 554..583 FT /note="Helical; Name=12" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT TOPO_DOM 584..620 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT REGION 561..590 FT /note="Interaction with TGFB1I1" FT /evidence="ECO:0000269|PubMed:12177201" FT BINDING 75 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 77 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2G" FT BINDING 78 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 79 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT BINDING 79 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 79 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2G" FT BINDING 82 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2G" FT BINDING 149 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT BINDING 153 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT BINDING 317 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0007744|PDB:8Y2D, FT ECO:0007744|PDB:8Y2G, ECO:0007744|PDB:9EO4" FT BINDING 320 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT BINDING 321 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0007744|PDB:8Y2D, FT ECO:0007744|PDB:8Y2G, ECO:0007744|PDB:9EO4" FT BINDING 321 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2G" FT BINDING 353 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2G" FT BINDING 357 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0007744|PDB:8Y2D, FT ECO:0007744|PDB:8Y2G, ECO:0007744|PDB:9EO4" FT BINDING 418 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 421 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 422 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT BINDING 422 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:39112703, FT ECO:0000269|PubMed:39112705, ECO:0007744|PDB:8VBY, FT ECO:0007744|PDB:9EO4" FT BINDING 423 FT /ligand="dopamine" FT /ligand_id="ChEBI:CHEBI:59905" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2D" FT SITE 105 FT /note="Contributes to high-affinity binding to cocaine" FT /evidence="ECO:0000250|UniProtKB:Q61327" FT CARBOHYD 181 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2C, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G" FT CARBOHYD 188 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0007744|PDB:8Y2C, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G" FT CARBOHYD 205 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 180..189 FT /evidence="ECO:0000269|PubMed:39112701, FT ECO:0000269|PubMed:39112703, ECO:0000269|PubMed:39112705, FT ECO:0007744|PDB:8VBY, ECO:0007744|PDB:8Y2C, FT ECO:0007744|PDB:8Y2D, ECO:0007744|PDB:8Y2E, FT ECO:0007744|PDB:8Y2F, ECO:0007744|PDB:8Y2G, FT ECO:0007744|PDB:9EO4" FT DISULFID 306 FT /note="Interchain" FT /evidence="ECO:0000269|Ref.16" FT VARIANT 121 FT /note="G -> S (in a breast cancer sample; somatic mutation; FT dbSNP:rs760871529)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036158" FT VARIANT 237 FT /note="R -> Q (in dbSNP:rs6345)" FT /evidence="ECO:0000269|PubMed:10391209" FT /id="VAR_014180" FT VARIANT 368 FT /note="L -> Q (in PKDYS1; loss of dopamine:sodium symporter FT activity; dbSNP:rs267607068)" FT /evidence="ECO:0000269|PubMed:19478460" FT /id="VAR_063771" FT VARIANT 395 FT /note="P -> L (in PKDYS1; loss of dopamine:sodium symporter FT activity; dbSNP:rs267607069)" FT /evidence="ECO:0000269|PubMed:19478460" FT /id="VAR_063772" FT VARIANT 471 FT /note="V -> I (in dbSNP:rs75916702)" FT /evidence="ECO:0000269|PubMed:21179162" FT /id="VAR_064580" FT VARIANT 544 FT /note="R -> S (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036159" FT MUTAGEN 79 FT /note="D->A: Abolishes dopamine uptake." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 152 FT /note="V->I: Reduces dopamine uptake." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 211 FT /note="T->E,H: Enhances the inhibition on dopamine uptake FT by zinc ions." FT /evidence="ECO:0000269|PubMed:39112705" FT MUTAGEN 317 FT /note="Q->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 320 FT /note="F->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 321 FT /note="S->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 326 FT /note="F->A: Reduces the inhibition on dopamine uptake by FT amphetamine. Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 353 FT /note="N->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 357 FT /note="S->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 364 FT /note="V->I: No effect on dopamine uptake. Reduces dopamine FT uptake; when associated with L-390." FT /evidence="ECO:0000269|PubMed:39112705" FT MUTAGEN 390 FT /note="I->L: Reduces dopamine uptake. Reduces dopamine FT uptake; when associated with I-364." FT /evidence="ECO:0000269|PubMed:39112705" FT MUTAGEN 394 FT /note="Y->F: Reduces dopamine uptake." FT /evidence="ECO:0000269|PubMed:39112705" FT MUTAGEN 414 FT /note="M->L: Reduces dopamine uptake." FT /evidence="ECO:0000269|PubMed:39112705" FT MUTAGEN 421 FT /note="D->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 422 FT /note="S->A: Reduces the inhibition on dopamine uptake by FT amphetamine. Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT MUTAGEN 426 FT /note="G->A: Reduces dopamine uptake. Reduces glycosylation FT and cell surface expression." FT /evidence="ECO:0000269|PubMed:39112701" FT CONFLICT 35 FT /note="K -> M (in Ref. 2; AAB23443)" FT /evidence="ECO:0000305" FT CONFLICT 354 FT /note="S -> C (in Ref. 2; AAB23443)" FT /evidence="ECO:0000305" FT HELIX 66..77 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 80..84 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 86..92 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 96..98 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 99..108 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 110..124 FT /evidence="ECO:0007829|PDB:9EO4" FT TURN 128..133 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 136..139 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 140..152 FT /evidence="ECO:0007829|PDB:9EO4" FT TURN 153..155 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 156..168 FT /evidence="ECO:0007829|PDB:9EO4" FT STRAND 171..174 FT /evidence="ECO:0007829|PDB:9EO4" FT STRAND 176..178 FT /evidence="ECO:0007829|PDB:8Y2E" FT HELIX 212..219 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 224..226 FT /evidence="ECO:0007829|PDB:9EO4" FT STRAND 229..231 FT /evidence="ECO:0007829|PDB:8Y2E" FT HELIX 238..255 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 259..269 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 272..285 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 290..298 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 302..306 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 308..321 FT /evidence="ECO:0007829|PDB:9EO4" FT TURN 323..325 FT /evidence="ECO:0007829|PDB:8Y2D" FT HELIX 328..333 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 342..375 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 379..382 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 389..399 FT /evidence="ECO:0007829|PDB:9EO4" FT STRAND 401..403 FT /evidence="ECO:0007829|PDB:8Y2D" FT HELIX 404..437 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 439..441 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 445..459 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 460..462 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 468..478 FT /evidence="ECO:0007829|PDB:9EO4" FT STRAND 479..481 FT /evidence="ECO:0007829|PDB:8Y2E" FT HELIX 482..496 FT /evidence="ECO:0007829|PDB:9EO4" FT TURN 497..500 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 501..512 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 518..525 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 527..541 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 555..569 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 571..582 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 587..595 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 598..600 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 601..606 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 610..612 FT /evidence="ECO:0007829|PDB:9EO4" FT HELIX 614..618 FT /evidence="ECO:0007829|PDB:9EO4" SQ SEQUENCE 620 AA; 68495 MW; CD95009B6BA93108 CRC64; MSKSKCSVGL MSSVVAPAKE PNAVGPKEVE LILVKEQNGV QLTSSTLTNP RQSPVEAQDR ETWGKKIDFL LSVIGFAVDL ANVWRFPYLC YKNGGGAFLV PYLLFMVIAG MPLFYMELAL GQFNREGAAG VWKICPILKG VGFTVILISL YVGFFYNVII AWALHYLFSS FTTELPWIHC NNSWNSPNCS DAHPGDSSGD SSGLNDTFGT TPAAEYFERG VLHLHQSHGI DDLGPPRWQL TACLVLVIVL LYFSLWKGVK TSGKVVWITA TMPYVVLTAL LLRGVTLPGA IDGIRAYLSV DFYRLCEASV WIDAATQVCF SLGVGFGVLI AFSSYNKFTN NCYRDAIVTT SINSLTSFSS GFVVFSFLGY MAQKHSVPIG DVAKDGPGLI FIIYPEAIAT LPLSSAWAVV FFIMLLTLGI DSAMGGMESV ITGLIDEFQL LHRHRELFTL FIVLATFLLS LFCVTNGGIY VFTLLDHFAA GTSILFGVLI EAIGVAWFYG VGQFSDDIQQ MTGQRPSLYW RLCWKLVSPC FLLFVVVVSI VTFRPPHYGA YIFPDWANAL GWVIATSSMA MVPIYAAYKF CSLPGSFREK LAYAIAPEKD RELVDRGEVR QFTLRHWLKV // ID SQSTM_HUMAN Reviewed; 440 AA. AC Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 237. DE RecName: Full=Sequestosome-1 {ECO:0000305}; DE AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575}; DE Short=EBIAP; DE Short=p60 {ECO:0000303|PubMed:8551575}; DE AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207}; DE AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207}; DE Short=p62 {ECO:0000303|PubMed:30266909}; GN Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280}; GN Synonyms=ORCA, OSIL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND RP 394-411, AND INTERACTION WITH EBI3. RC TISSUE=B-cell; RX PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996; RA Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., RA Birkenbach M.; RT "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr RT virus infection in B lymphocytes."; RL J. Virol. 70:1143-1153(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; RP 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND RP MUTAGENESIS OF TYR-9. RC TISSUE=Cervix carcinoma; RX PubMed=8650207; DOI=10.1073/pnas.93.12.5991; RA Joung I., Strominger J.L., Shin J.; RT "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck RT SH2 domain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Caudate nucleus, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Pancreas, Placenta, Skin, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION. RX PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7; RA Vadlamudi R.K., Shin J.; RT "Genomic structure and promoter analysis of the p62 gene encoding a non- RT proteasomal multiubiquitin chain binding protein."; RL FEBS Lett. 435:138-142(1998). RN [7] RP PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388. RX PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0; RA Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., RA Zatloukal K., Denk H.; RT "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. RT Demonstration of p62 as major constituent."; RL Am. J. Pathol. 154:1701-1710(1999). RN [8] RP INTERACTION WITH LCK AND RASA1. RX PubMed=8618896; DOI=10.1073/pnas.92.26.12338; RA Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.; RT "Phosphotyrosine-independent binding of a 62-kDa protein to the src RT homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of RT Ser-59 in the lck unique N-terminal region."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995). RN [9] RP INTERACTION WITH UBIQUITIN. RX PubMed=8702753; DOI=10.1074/jbc.271.34.20235; RA Vadlamudi R.K., Joung I., Strominger J.L., Shin J.; RT "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, RT belongs to a new class of ubiquitin-binding proteins."; RL J. Biol. Chem. 271:20235-20237(1996). RN [10] RP INTERACTION WITH NR2F2. RX PubMed=8910285; DOI=10.1074/jbc.271.44.27197; RA Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.; RT "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone RT receptor."; RL J. Biol. Chem. 271:27197-27200(1996). RN [11] RP INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION. RX PubMed=9566925; DOI=10.1128/mcb.18.5.3069; RA Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.; RT "Localization of atypical protein kinase C isoforms into lysosome-targeted RT endosomes through interaction with p62."; RL Mol. Cell. Biol. 18:3069-3080(1998). RN [12] RP INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND RP FUNCTION. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [13] RP INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [14] RP INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [15] RP INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [16] RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6; RA Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., RA Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.; RT "p62 Is a common component of cytoplasmic inclusions in protein aggregation RT diseases."; RL Am. J. Pathol. 160:255-263(2002). RN [17] RP INTERACTION WITH PAWR AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=11981755; DOI=10.1053/jhep.2002.32674; RA Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.; RT "Mallory body -- a disease-associated type of sequestosome."; RL Hepatology 35:1053-1062(2002). RN [19] RP INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=12471037; DOI=10.1074/jbc.m208468200; RA Geetha T., Wooten M.W.; RT "Association of the atypical protein kinase C-interacting protein p62/ZIP RT with nerve growth factor receptor TrkA regulates receptor trafficking and RT Erk5 signaling."; RL J. Biol. Chem. 278:4730-4739(2003). RN [20] RP INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF RP LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND RP GLU-82, AND DIMERIZATION. RX PubMed=12813044; DOI=10.1074/jbc.m303221200; RA Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., RA Michaelsen E., Bjoerkoey G., Johansen T.; RT "Interaction codes within the family of mammalian Phox and Bem1p domain- RT containing proteins."; RL J. Biol. Chem. 278:34568-34581(2003). RN [21] RP INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7; RP ASP-69 AND ASP-73. RX PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6; RA Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.; RT "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling RT complexes of atypical protein kinase C with Par6 and p62."; RL Mol. Cell 12:39-50(2003). RN [22] RP INDUCTION. RX PubMed=12700667; DOI=10.1038/sj.onc.1206325; RA Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.; RT "p62 overexpression in breast tumors and regulation by prostate-derived Ets RT factor in breast cancer cells."; RL Oncogene 22:2322-2333(2003). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029; RA Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K., RA Araga S., Yanagawa T., Ishii T., Nakashima K.; RT "Transcriptional activation of p62/A170/ZIP during the formation of the RT aggregates: possible mechanisms and the role in Lewy body formation in RT Parkinson's disease."; RL Brain Res. 1012:42-51(2004). RN [24] RP INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398; RP PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION. RX PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004; RA Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R., RA Wooten M.W.; RT "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in RT ubiquitin proteasome degradation."; RL Mol. Cell. Biol. 24:8055-8068(2004). RN [25] RP FUNCTION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH RP MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND RP ILE-431. RX PubMed=16286508; DOI=10.1083/jcb.200507002; RA Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A., RA Stenmark H., Johansen T.; RT "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a RT protective effect on huntingtin-induced cell death."; RL J. Cell Biol. 171:603-614(2005). RN [27] RP INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [28] RP INTERACTION WITH AJUBA AND LIMD1. RX PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005; RA Feng Y., Longmore G.D.; RT "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB RT activation by affecting the assembly and activity of the protein kinase RT Czeta/p62/TRAF6 signaling complex."; RL Mol. Cell. Biol. 25:4010-4022(2005). RN [29] RP INDUCTION, AND FUNCTION. RX PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011; RA Wang Z., Figueiredo-Pereira M.E.; RT "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of RT ubiquitinated proteins induced by prostaglandin J2 without reducing its RT neurotoxicity."; RL Mol. Cell. Neurosci. 29:222-231(2005). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [31] RP INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION. RX PubMed=15802564; DOI=10.1126/science.1110463; RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., RA Udd B., Gautel M.; RT "The kinase domain of titin controls muscle gene expression and protein RT turnover."; RL Science 308:1599-1603(2005). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [34] RP FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND RP MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337; RP TRP-338 AND SER-342. RX PubMed=17580304; DOI=10.1074/jbc.m702824200; RA Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H., RA Overvatn A., Bjorkoy G., Johansen T.; RT "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of RT ubiquitinated protein aggregates by autophagy."; RL J. Biol. Chem. 282:24131-24145(2007). RN [35] RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION). RX PubMed=24331465; DOI=10.1016/j.chom.2013.11.003; RA Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N., RA Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.; RT "The globally disseminated M1T1 clone of group A Streptococcus evades RT autophagy for intracellular replication."; RL Cell Host Microbe 14:675-682(2013). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [41] RP FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION. RX PubMed=20168092; DOI=10.4161/auto.6.3.11226; RA Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A., RA Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.; RT "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 RT bodies/ALIS and their degradation by autophagy."; RL Autophagy 6:330-344(2010). RN [42] RP INTERACTION WITH KEAP1. RX PubMed=20495340; DOI=10.4161/auto.6.5.12189; RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.; RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via RT autophagy."; RL Autophagy 6:614-621(2010). RN [43] RP FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347; RP THR-350; GLY-351 AND GLU-352. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [44] RP INTERACTION WITH FHOD3. RX PubMed=21149568; DOI=10.1083/jcb.201005060; RA Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.; RT "Formin follows function: a muscle-specific isoform of FHOD3 is regulated RT by CK2 phosphorylation and promotes myofibril maintenance."; RL J. Cell Biol. 191:1159-1172(2010). RN [45] RP INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION. RX PubMed=20357094; DOI=10.1128/jvi.02412-09; RA O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J., RA Campbell E.M.; RT "p62/sequestosome-1 associates with and sustains the expression of RT retroviral restriction factor TRIM5alpha."; RL J. Virol. 84:5997-6006(2010). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249; RP SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; RP LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425. RX PubMed=22084127; DOI=10.1001/archneurol.2011.250; RA Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., RA Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L., RA Heller S.L., Deng H.X., Siddique T.; RT "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:1440-1446(2011). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [49] RP IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR RP LOCATION. RX PubMed=21923101; DOI=10.1021/bi201137e; RA Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B., RA Layfield R., Searle M.S.; RT "Independent interactions of ubiquitin-binding domains in a ubiquitin- RT mediated ternary complex."; RL Biochemistry 50:9076-9087(2011). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207; RP THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF RP SER-403. RX PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039; RA Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.; RT "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic RT clearance of ubiquitinated proteins."; RL Mol. Cell 44:279-289(2011). RN [51] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [52] RP FUNCTION. RX PubMed=22622177; DOI=10.4161/auto.19381; RA Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D., RA Faure M., Fauvarque M.O.; RT "The deubiquitinating enzyme USP36 controls selective autophagy activation RT by ubiquitinated proteins."; RL Autophagy 8:767-779(2012). RN [53] RP INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION. RX PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015; RA Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.; RT "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the RT cells."; RL Biochim. Biophys. Acta 1823:316-326(2012). RN [54] RP INTERACTION WITH MAP1LC3A. RX PubMed=22421968; DOI=10.1038/cdd.2012.30; RA Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M., RA Carrier A., Iovanna J.L., Dusetti N.J.; RT "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins RT through the LC3-interacting region (LIR) and promotes autophagy-dependent RT cell death."; RL Cell Death Differ. 19:1525-1535(2012). RN [55] RP INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION. RX PubMed=22792322; DOI=10.1371/journal.pone.0040440; RA Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B., RA Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G., RA Reymond A., Pucci P., Merla G.; RT "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes RT the sequestration and clearance of ubiquitinated proteins into the RT aggresome."; RL PLoS ONE 7:E40440-E40440(2012). RN [56] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE RP ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [57] RP FUNCTION. RX PubMed=24128730; DOI=10.4161/auto.26085; RA Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.; RT "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody RT ring degradation by selective autophagy."; RL Autophagy 9:1955-1964(2013). RN [58] RP INTERACTION WITH SESN1 AND SESN2. RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002; RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., RA Kang D., Rhee S.G.; RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation RT of Keap1 and prevent oxidative liver damage."; RL Cell Metab. 17:73-84(2013). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [60] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND RP LEU-392. RX PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849; RG French Clinical and Genetic Research Network on FTD/FTD-ALS; RA Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G., RA Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T., RA Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.; RT "SQSTM1 mutations in French patients with frontotemporal dementia or RT frontotemporal dementia with amyotrophic lateral sclerosis."; RL JAMA Neurol. 70:1403-1410(2013). RN [61] RP LIR MOTIF. RX PubMed=23908376; DOI=10.1242/jcs.126128; RA Birgisdottir A.B., Lamark T., Johansen T.; RT "The LIR motif - crucial for selective autophagy."; RL J. Cell Sci. 126:3237-3247(2013). RN [62] RP INTERACTION WITH MAP1LC3B. RX PubMed=24089205; DOI=10.1038/nature12606; RA Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B., RA Zhong Q.; RT "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar RT satellites."; RL Nature 502:254-257(2013). RN [63] RP FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE. RX PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033; RA Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.; RT "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated RT sequestration and degradation."; RL Cell. Signal. 26:2470-2480(2014). RN [64] RP INTERACTION WITH TRIM5. RX PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013; RA Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C., RA Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B., RA Johansen T., Deretic V.; RT "TRIM proteins regulate autophagy and can target autophagic substrates by RT direct recognition."; RL Dev. Cell 30:394-409(2014). RN [65] RP INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1. RX PubMed=25040165; DOI=10.1111/febs.12905; RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S., RA Lee J.H.; RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of RT p62/sequestosome-1."; RL FEBS J. 281:3816-3827(2014). RN [66] RP INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338. RX PubMed=24668264; DOI=10.1002/embr.201338003; RA Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y., RA Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.; RT "Structural determinants in GABARAP required for the selective binding and RT recruitment of ALFY to LC3B-positive structures."; RL EMBO Rep. 15:557-565(2014). RN [67] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306 RP AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [68] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [69] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214. RX PubMed=20851865; DOI=10.3324/haematol.2010.029769; RA Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C., RA Crescenzi B., Santoro A., Chiaretti S., Mecucci C.; RT "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic RT leukemia."; RL Haematologica 95:2161-2163(2010). RN [70] RP INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL. RX PubMed=25114083; DOI=10.3233/jad-141512; RA Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K., RA Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E., RA Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.; RT "A phenotype of atypical apraxia of speech in a family carrying SQSTM1 RT mutation."; RL J. Alzheimers Dis. 43:625-630(2015). RN [71] RP FUNCTION, AND INTERACTION WITH PEX5. RX PubMed=26344566; DOI=10.1038/ncb3230; RA Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T., RA Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K., RA Pandita T.K., Kastan M.B., Walker C.L.; RT "ATM functions at the peroxisome to induce pexophagy in response to ROS."; RL Nat. Cell Biol. 17:1259-1269(2015). RN [72] RP INVOLVEMENT IN DMRV. RX PubMed=26208961; DOI=10.1212/wnl.0000000000001864; RA Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M., RA Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.; RT "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."; RL Neurology 85:665-674(2015). RN [73] RP INVOLVEMENT IN NADGP. RX PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026; RA Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P., RA Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S., RA Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H., RA Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V., RA Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C., RA Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J., RA Klopstock T.; RT "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset RT neurodegeneration with ataxia, dystonia, and gaze palsy."; RL Am. J. Hum. Genet. 99:735-743(2016). RN [74] RP FUNCTION, AND UBIQUITINATION. RX PubMed=27368102; DOI=10.1016/j.cell.2016.05.078; RA Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M., RA Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M., RA Neefjes J.; RT "An ER-associated pathway defines endosomal architecture for controlled RT cargo transport."; RL Cell 166:152-166(2016). RN [75] RP INTERACTION WITH TRIM11. RX PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019; RA Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.; RT "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent RT selective autophagy."; RL Cell Rep. 16:1988-2002(2016). RN [76] RP UBIQUITINATION, AND FUNCTION. RX PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005; RA Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C., RA Jani V., Lassen K.G., Xavier R.J.; RT "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial RT Autophagy."; RL Cell Rep. 17:2183-2194(2016). RN [77] RP FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420. RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030; RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.; RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain RT ubiquitination."; RL Cell Rep. 19:188-202(2017). RN [78] RP DOMAIN, AND UBIQUITINATION. RX PubMed=28322253; DOI=10.1038/cr.2017.40; RA Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H., RA Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H., RA Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.; RT "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor RT function and controls selective autophagy upon ubiquitin stress."; RL Cell Res. 27:657-674(2017). RN [79] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [80] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF RP SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411. RX PubMed=29507397; DOI=10.1038/s41422-018-0017-7; RA Sun D., Wu R., Zheng J., Li P., Yu L.; RT "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo RT segregation."; RL Cell Res. 28:405-415(2018). RN [81] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=29343546; DOI=10.15252/embj.201798308; RA Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M., RA Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C., RA Martens S.; RT "p62 filaments capture and present ubiquitinated cargos for autophagy."; RL EMBO J. 37:0-0(2018). RN [82] RP INTERACTION WITH TRIM16. RX PubMed=30143514; DOI=10.15252/embj.201798358; RA Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A., RA Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.; RT "TRIM16 controls assembly and degradation of protein aggregates by RT modulating the p62-NRF2 axis and autophagy."; RL EMBO J. 37:0-0(2018). RN [83] RP INTERACTION WITH LRRC25. RX PubMed=29288164; DOI=10.15252/embj.201796781; RA Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.; RT "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I RT for autophagic degradation."; RL EMBO J. 37:351-366(2018). RN [84] RP FUNCTION, INTERACTION WITH WDR81, AND DOMAIN. RX PubMed=28404643; DOI=10.1083/jcb.201608039; RA Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y., RA Luo S., Guo W., Yang C.; RT "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote RT aggrephagy."; RL J. Cell Biol. 216:1301-1320(2017). RN [85] RP INTERACTION WITH TRIM23. RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2; RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F., RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O., RA Moss J., Vaughan M., Gack M.U.; RT "TRIM23 mediates virus-induced autophagy via activation of TBK1."; RL Nat. Microbiol. 2:1543-1557(2017). RN [86] RP FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403. RX PubMed=29496741; DOI=10.15252/embj.201797858; RA Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C., RA Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R., RA Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M., RA Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.; RT "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent RT autophagy pathway activated by TBK1."; RL EMBO J. 37:0-0(2018). RN [87] RP INTERACTION WITH USP12. RX PubMed=30266909; DOI=10.1038/s41467-018-05653-z; RA Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K., RA Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P., RA Finkbeiner S.; RT "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and RT confer neuroprotection in models of Huntington's disease."; RL Nat. Commun. 9:3191-3191(2018). RN [88] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435, RP AND MUTAGENESIS OF LYS-420 AND LYS-435. RX PubMed=31857589; DOI=10.1038/s41467-019-13718-w; RA You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H., RA Peng C., Zhou T., Tang C., Liu W.; RT "Requirement for p62 acetylation in the aggregation of ubiquitylated RT proteins under nutrient stress."; RL Nat. Commun. 10:5792-5792(2019). RN [89] RP INTERACTION WITH ECSIT. RX PubMed=31281713; DOI=10.4110/in.2019.19.e16; RA Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.; RT "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the RT TRAF6-ECSIT Complex."; RL Immune Netw. 19:e16-e16(2019). RN [90] RP INTERACTION WITH CYLD. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [91] RP FUNCTION, AND INTERACTION WITH MOAP1. RX PubMed=33393215; DOI=10.15252/embr.202050854; RA Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.; RT "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and RT suppresses Nrf2 signaling."; RL EMBO Rep. 22:e50854-e50854(2021). RN [92] RP FUNCTION, AND UBIQUITINATION AT LYS-435. RX PubMed=33472082; DOI=10.1016/j.celrep.2020.108659; RA Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J., RA Berlin I.; RT "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal RT control over the endolysosomal pathway."; RL Cell Rep. 34:108659-108659(2021). RN [93] RP FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 RP (MICROBIAL INFECTION). RX PubMed=33509017; DOI=10.1080/15548627.2021.1874660; RA Ylae-Anttila P., Gupta S., Masucci M.G.; RT "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit RT selective autophagy."; RL Autophagy 17:3461-3474(2021). RN [94] RP SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION. RX PubMed=34471133; DOI=10.1038/s41467-021-25572-w; RA Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M., RA Martens S.; RT "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin RT condensate formation and autophagy initiation."; RL Nat. Commun. 12:5212-5212(2021). RN [95] RP INTERACTION WITH ASB6. RX PubMed=34164402; DOI=10.3389/fcell.2021.684885; RA Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.; RT "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to RT Regulate Cell Proliferation and Autophagy."; RL Front. Cell Dev. Biol. 9:684885-684885(2021). RN [96] RP FUNCTION. RX PubMed=34893540; DOI=10.1073/pnas.2107993118; RA Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J., RA Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.; RT "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [97] RP FUNCTION, AND INTERACTION WITH GRB2. RX PubMed=35831301; DOI=10.1038/s41420-022-01106-1; RA Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.; RT "Grb2 interacts with necrosome components and is involved in rasfonin- RT induced necroptosis."; RL Cell. Death. Discov. 8:319-319(2022). RN [98] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND RP SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407. RX PubMed=37306101; DOI=10.15252/embj.2022113349; RA Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y., RA Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T., RA Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y., RA Noda N.N., Komatsu M.; RT "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox- RT independent stress response."; RL EMBO J. 42:e113349-e113349(2023). RN [99] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND RP MUTAGENESIS OF 289-CYS-CYS-290. RX PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004; RA Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X., RA Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T., RA Neculai D., Sun Q., Kong E., Tate E.W., Yang A.; RT "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in RT mammalian autophagy."; RL Mol. Cell 83:3485-3501(2023). RN [100] RP INTERACTION WITH WDR83. RX PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023; RA Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.; RT "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases."; RL Mol. Cell 0:0-0(2023). RN [101] RP STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND RP DOMAIN. RX PubMed=12857745; DOI=10.1074/jbc.m307416200; RA Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.; RT "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and RT implications for mutations that cause Paget's disease of bone."; RL J. Biol. Chem. 278:37409-37412(2003). RN [102] RP STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN. RX PubMed=18083707; DOI=10.1074/jbc.m704973200; RA Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H., RA Layfield R., Searle M.S.; RT "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a RT novel conformational switch."; RL J. Biol. Chem. 283:5427-5440(2008). RN [103] RP STRUCTURE BY NMR OF 387-436. RX PubMed=17932931; DOI=10.1002/prot.21692; RA Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.; RT "Conformation and dynamics of the three-helix bundle UBA domain of p62 from RT experiment and simulation."; RL Proteins 71:227-240(2008). RN [104] RP STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND RP GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425. RX PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032; RA Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B., RA Williamson M.P., Layfield R., Searle M.S.; RT "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and RT regulates NF-kappaB signalling."; RL J. Mol. Biol. 396:178-194(2010). RN [105] RP VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274. RX PubMed=11992264; DOI=10.1086/340731; RA Laurin N., Brown J.P., Morissette J., Raymond V.; RT "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in RT Paget disease of bone."; RL Am. J. Hum. Genet. 70:1582-1588(2002). RN [106] RP VARIANT PDB3 LEU-392. RX PubMed=12374763; DOI=10.1093/hmg/11.22.2735; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M., RA Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W., RA Ralston S.H.; RT "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and RT sporadic Paget's disease."; RL Hum. Mol. Genet. 11:2735-2739(2002). RN [107] RP VARIANT PDB3 LEU-387. RX PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748; RA Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F., RA Singer F.R., Leach R.J.; RT "Three novel mutations in SQSTM1 identified in familial Paget's disease of RT bone."; RL J. Bone Miner. Res. 18:1748-1753(2003). RN [108] RP VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425. RX PubMed=15146436; DOI=10.1002/art.20224; RA Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C., RA Kneppers A.L.J., Papapoulos S.E.; RT "Familial Paget's disease in The Netherlands: occurrence, identification of RT new mutations in the sequestosome 1 gene, and their clinical RT associations."; RL Arthritis Rheum. 50:1650-1654(2004). RN [109] RP VARIANT PDB3 LEU-392. RX PubMed=15207768; DOI=10.1016/j.bone.2004.01.010; RA Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L., RA Kesting J.B., Andersen J., Shaw J.T.E.; RT "Identification of SQSTM1 mutations in familial Paget's disease in RT Australian pedigrees."; RL Bone 35:277-282(2004). RN [110] RP VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425. RX PubMed=15125799; DOI=10.1359/jbmr.040203; RA Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C., RA Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F., RA Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B., RA Melchiorre D., Matucci-Cerinic M., Brandi M.L.; RT "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an RT Italian series of patients affected by Paget's disease of bone (PDB)."; RL J. Bone Miner. Res. 19:1013-1017(2004). RN [111] RP VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF RP VARIANTS VAL-404; SER-411 AND ARG-425. RX PubMed=15176995; DOI=10.1359/jbmr.0403015; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C., RA Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W., RA Searle M.S., Layfield R., Ralston S.H.; RT "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype RT phenotype correlation, functional analysis, and structural consequences."; RL J. Bone Miner. Res. 19:1122-1127(2004). RN [112] RP VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17488105; DOI=10.1021/pr0700908; RA Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A., RA Hendrickson R.C., Stephenson J.L. Jr.; RT "Detection and validation of non-synonymous coding SNPs from orthogonal RT analysis of shotgun proteomics data."; RL J. Proteome Res. 6:2331-2340(2007). RN [113] RP INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; RP TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; RP ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND RP VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; RP GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; RP 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 RP DEL; THR-349 AND LEU-439. RX PubMed=24899140; DOI=10.1007/s00401-014-1298-7; RA van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W., RA Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K., RA Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M., RA Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A., RA Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I., RA Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S., RA Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H., RA Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C., RA Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B., RA Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I., RA Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A., RA Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A., RA Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P., RA Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R., RA De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.; RT "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar RT degeneration."; RL Acta Neuropathol. 128:397-410(2014). CC -!- FUNCTION: Molecular adapter required for selective macroautophagy CC (aggrephagy) by acting as a bridge between polyubiquitinated proteins CC and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, CC PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, CC PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the CC recruitment of ubiquitinated cargo proteins to autophagosomes via CC multiple domains that bridge proteins and organelles in different steps CC (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, CC PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, CC PubMed:37802024). SQSTM1 first mediates the assembly and removal of CC ubiquitinated proteins by undergoing liquid-liquid phase separation CC upon binding to ubiquitinated proteins via its UBA domain, leading to CC the formation of insoluble cytoplasmic inclusions, known as p62 bodies CC (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, CC PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). CC SQSTM1 then interacts with ATG8 family proteins on autophagosomes via CC its LIR motif, leading to p62 body recruitment to autophagosomes, CC followed by autophagic clearance of ubiquitinated proteins CC (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself CC degraded along with its ubiquitinated cargos (PubMed:16286508, CC PubMed:17580304, PubMed:37802024). Also required to recruit CC ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). CC Also involved in autophagy of peroxisomes (pexophagy) in response to CC reactive oxygen species (ROS) by acting as a bridge between CC ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts CC as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: CC interaction inactivates the BCR(KEAP1) complex by sequestering the CC complex in inclusion bodies, promoting nuclear accumulation of CC NFE2L2/NRF2 and subsequent expression of cytoprotective genes CC (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). CC Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to CC autophagosomes (PubMed:29496741). Involved in endosome organization by CC retaining vesicles in the perinuclear cloud: following ubiquitination CC by RNF26, attracts specific vesicle-associated adapters, forming a CC molecular bridge that restrains cognate vesicles in the perinuclear CC region and organizes the endosomal pathway for efficient cargo CC transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 CC into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal CC degradation (PubMed:25101860). May regulate the activation of NFKB1 by CC TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, CC PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, CC PubMed:19931284). May play a role in titin/TTN downstream signaling in CC muscle cells (PubMed:15802564). Adapter that mediates the interaction CC between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, CC ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177, CC ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102, CC ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082, CC ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133, CC ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. CC -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays CC (PubMed:12887891, PubMed:19931284). Dimerization interferes with CC ubiquitin binding (PubMed:19931284). Component of a ternary complex CC with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, CC PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 CC and CYLD (By similarity). Identified in a heterotrimeric complex with CC ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the CC same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) CC with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, CC including GABARAP, GABARAPL1 and GABARAPL2; these interactions are CC necessary for the recruitment MAP1 LC3 family members to inclusion CC bodies containing polyubiquitinated protein aggregates and for their CC degradation by autophagy (PubMed:16286508, PubMed:17580304, CC PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly CC with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, CC PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, CC NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, CC PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, CC PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with CC RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF- CC R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the CC proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with CC TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked CC polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 CC (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts CC with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, CC PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with CC UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct CC and regulates the interaction of SQSTM1 with ubiquitinated proteins CC (PubMed:28404643). Interacts with WDFY3; this interaction is required CC to recruit WDFY3 to cytoplasmic bodies and to PML bodies CC (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts CC with STING1; leading to relocalization of STING1 to autophagosomes CC (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with CC KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex CC by sequestering KEAP1 in inclusion bodies, promoting its degradation CC (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with CC MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester CC KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts CC with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; CC specifically binds PEX5 ubiquitinated at 'Lys-209' in response to CC reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 CC domain) with TNS2; the interaction leads to sequestration of TNS2 in CC cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and CC proteasomal degradation (PubMed:25101860). Interacts with IRS1; the CC interaction is disrupted by the presence of tensin TNS2 CC (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, CC PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting CC AIM2 recruitment to autophagosomes and autophagy-dependent degradation CC of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). CC Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 CC (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts CC with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction CC inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT CC complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By CC similarity). Interacts with WDR83 (PubMed:38103557). Interacts with CC GRB2 (PubMed:35831301). Interacts with USP12; the interaction is CC independent of USP12 deubiquitinase activity and may be involved in CC regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 CC (PubMed:34164402). {ECO:0000250|UniProtKB:O08623, CC ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531, CC ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044, CC ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, CC ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101, CC ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085, CC ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264, CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865, CC ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090, CC ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909, CC ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402, CC ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557, CC ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896, CC ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285, CC ECO:0000269|PubMed:9566925}. CC -!- INTERACTION: CC Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613; CC Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964; CC Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185; CC Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634; CC Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440; CC Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940; CC Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310; CC Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445; CC Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462; CC Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541; CC Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505; CC Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001; CC Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969; CC Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116; CC Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499; CC Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029; CC Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279; CC Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001; CC Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863; CC Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372; CC Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768; CC Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144; CC Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996; CC Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294; CC Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698; CC Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125; CC Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226; CC Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974; CC Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987; CC Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705; CC Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199; CC Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227; CC Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453; CC Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642; CC Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595; CC Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161; CC Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879; CC Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104; CC Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085; CC Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276; CC Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864; CC Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054; CC Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357; CC Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397; CC Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256; CC Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701; CC Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773; CC Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771; CC Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684; CC Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110; CC Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238; CC Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715; CC Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771; CC Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, CC ECO:0000269|PubMed:37802024}. Preautophagosomal structure CC {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML CC body {ECO:0000269|PubMed:20168092}. Late endosome CC {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome CC {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm, CC myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac CC muscle, localizes to the sarcomeric band (By similarity). Localizes to CC cytoplasmic membraneless inclusion bodies, known as p62 bodies, CC containing polyubiquitinated protein aggregates (PubMed:11786419, CC PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:37306101, PubMed:37802024). In CC neurodegenerative diseases, detected in Lewy bodies in Parkinson CC disease, neurofibrillary tangles in Alzheimer disease, and HTT CC aggregates in Huntington disease (PubMed:15158159). In protein CC aggregate diseases of the liver, found in large amounts in Mallory CC bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in CC hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). CC Enriched in Rosenthal fibers of pilocytic astrocytoma CC (PubMed:11786419). In the cytoplasm, observed in both membrane-free CC ubiquitin-containing protein aggregates (sequestosomes) and membrane- CC surrounded autophagosomes (PubMed:15953362, PubMed:17580304). CC Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum CC (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies CC (PubMed:20357094). When nuclear export is blocked by treatment with CC leptomycin B, accumulates in PML bodies (PubMed:20168092). CC {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, CC ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, CC ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, CC ECO:0000269|PubMed:37802024}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13501-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13501-2; Sequence=VSP_015841; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:8650207}. CC -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in CC levels in fully differentiated myotubes compared to undifferentiated CC myoblasts. {ECO:0000269|PubMed:25101860}. CC -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at CC protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is CC directly activated by NFE2L2/NRF2; creating a positive feedback loop CC (PubMed:20452972). {ECO:0000269|PubMed:12700667, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:9762895}. CC -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin CC chains of polyubiquitinated substrates (PubMed:12857745, CC PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the CC interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains CC are necessary and sufficient for the localization into the ubiquitin- CC containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253, CC ECO:0000269|PubMed:31857589}. CC -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions CC with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, CC PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and CC UBA domains are necessary and sufficient for the localization into the CC ubiquitin-containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}. CC -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1. CC {ECO:0000269|PubMed:10747026}. CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction CC with ATG8 family proteins. {ECO:0000269|PubMed:23908376}. CC -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer CC interface and increases binding affinity to ubiquitinated proteins (By CC similarity). Phosphorylation at Ser-407 also primes for subsequent CC phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 CC by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing CC the affinity between the UBA domain and polyubiquitin chains CC (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 CC is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by CC TBK1, leading to promote relocalization of 'Lys-63'-linked CC ubiquitinated STING1 to autophagosomes (PubMed:29496741). CC Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and CC inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear CC accumulation and expression of phase II detoxifying enzymes CC (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564). CC {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165, CC ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}. CC -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 CC attracts specific vesicle-associated adapters, forming a molecular CC bridge that restrains cognate vesicles in the perinuclear region and CC organizes the endosomal pathway for efficient cargo transport CC (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 CC increases its ability to bind polyubiquitin chains by destabilizing the CC UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 CC releases target vesicles for fast transport into the cell periphery CC (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, CC increasing SQSTM1 sequestering activity and promoting its degradation CC (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked CC polyubiquitination leading to xenophagic targeting of bacteria and CC inhibition of their replication (PubMed:27880896). CC {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896, CC ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357, CC ECO:0000269|PubMed:33472082}. CC -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity CC by destabilizing the UBA dimer interface and increases binding affinity CC to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 CC (PubMed:31857589). {ECO:0000269|PubMed:31857589}. CC -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for CC efficient autophagic degradation of SQSTM1-cargo complexes by promoting CC affinity for ATG8 proteins and recruitment of p62 bodies to CC autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 CC by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}. CC -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading CC to its degradation (PubMed:24331465). Degradation by SpeB prevents CC autophagy, promoting to S.pyogenes intracellular replication CC (PubMed:24331465). {ECO:0000269|PubMed:24331465}. CC -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; CC leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1- CC positive structures. {ECO:0000269|PubMed:33509017}. CC -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of CC bone remodeling characterized by increased bone turnover affecting one CC or more sites throughout the skeleton, primarily the axial skeleton. CC Osteoclastic overactivity followed by compensatory osteoblastic CC activity leads to a structurally disorganized mosaic of bone (woven CC bone), which is mechanically weaker, larger, less compact, more CC vascular, and more susceptible to fracture than normal adult lamellar CC bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, CC ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, CC ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, CC ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to CC form a shell surrounding aggregates of mutant HTT that may protect CC cells from apoptosis, possibly by recruiting autophagosomal components CC to the polyubiquitinated protein aggregates. CC {ECO:0000269|PubMed:16286508}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 CC (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia is characterized by frontal and temporal lobe CC atrophy associated with neuronal loss, gliosis, and dementia. Patients CC exhibit progressive changes in social, behavioral, and/or language CC function. Amyotrophic lateral sclerosis is characterized by the death CC of motor neurons in the brain, brainstem, and spinal cord, resulting in CC fatal paralysis. Some FTDALS3 patients may also develop Paget disease CC of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, CC ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, CC childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder CC characterized by gait abnormalities, ataxia, dysarthria, dystonia, CC vertical gaze palsy, and cognitive decline. Disease onset is in CC childhood or adolescence. NADGP transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An CC autosomal dominant myopathy with adult onset, characterized by muscle CC weakness of the distal upper and lower limbs, walking difficulties, and CC proximal weakness of the shoulder girdle muscles. Muscle biopsy shows CC rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a CC form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) CC with NUP214. {ECO:0000269|PubMed:20851865}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U41806; AAA93299.1; -; mRNA. DR EMBL; U46751; AAC52070.1; -; mRNA. DR EMBL; AK098077; BAG53577.1; -; mRNA. DR EMBL; AK312451; BAG35358.1; -; mRNA. DR EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000951; AAH00951.1; -; mRNA. DR EMBL; BC001874; AAH01874.1; -; mRNA. DR EMBL; BC003139; AAH03139.1; -; mRNA. DR EMBL; BC017222; AAH17222.1; -; mRNA. DR EMBL; BC019111; AAH19111.1; -; mRNA. DR EMBL; AF060494; AAC64516.1; -; Genomic_DNA. DR CCDS; CCDS34317.1; -. [Q13501-1] DR CCDS; CCDS47355.1; -. [Q13501-2] DR RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2] DR RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2] DR RefSeq; NP_003891.1; NM_003900.5. [Q13501-1] DR PDB; 1Q02; NMR; -; A=387-436. DR PDB; 2JY7; NMR; -; A=387-436. DR PDB; 2JY8; NMR; -; A=387-436. DR PDB; 2K0B; NMR; -; X=387-436. DR PDB; 2KNV; NMR; -; A/B=387-436. DR PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102. DR PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102. DR PDB; 4UF9; EM; 10.30 A; A/B/D=1-122. DR PDB; 5YP7; X-ray; 1.42 A; A/D=126-180. DR PDB; 5YP8; X-ray; 1.45 A; A/B=126-180. DR PDB; 5YPA; X-ray; 2.50 A; A/B=126-180. DR PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180. DR PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180. DR PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180. DR PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180. DR PDB; 5YPG; X-ray; 2.20 A; A/B=126-180. DR PDB; 5YPH; X-ray; 1.63 A; A/B=126-180. DR PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102. DR PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169. DR PDB; 6MIU; X-ray; 1.90 A; A/B=120-171. DR PDB; 6MJ7; X-ray; 1.41 A; A=120-171. DR PDB; 6TGY; EM; 3.50 A; A=1-122. DR PDB; 6TH3; EM; 4.00 A; A/B/C=1-122. DR PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172. DR PDBsum; 1Q02; -. DR PDBsum; 2JY7; -. DR PDBsum; 2JY8; -. DR PDBsum; 2K0B; -. DR PDBsum; 2KNV; -. DR PDBsum; 4MJS; -. DR PDBsum; 4UF8; -. DR PDBsum; 4UF9; -. DR PDBsum; 5YP7; -. DR PDBsum; 5YP8; -. DR PDBsum; 5YPA; -. DR PDBsum; 5YPB; -. DR PDBsum; 5YPC; -. DR PDBsum; 5YPE; -. DR PDBsum; 5YPF; -. DR PDBsum; 5YPG; -. DR PDBsum; 5YPH; -. DR PDBsum; 6JM4; -. DR PDBsum; 6KHZ; -. DR PDBsum; 6MIU; -. DR PDBsum; 6MJ7; -. DR PDBsum; 6TGY; -. DR PDBsum; 6TH3; -. DR PDBsum; 7R1O; -. DR AlphaFoldDB; Q13501; -. DR BMRB; Q13501; -. DR EMDB; EMD-10501; -. DR EMDB; EMD-10502; -. DR EMDB; EMD-2936; -. DR EMDB; EMD-2937; -. DR SMR; Q13501; -. DR BioGRID; 114397; 1356. DR CORUM; Q13501; -. DR DIP; DIP-34443N; -. DR ELM; Q13501; -. DR FunCoup; Q13501; 2230. DR IntAct; Q13501; 311. DR MINT; Q13501; -. DR STRING; 9606.ENSP00000374455; -. DR BindingDB; Q13501; -. DR ChEMBL; CHEMBL4295816; -. DR GuidetoPHARMACOLOGY; 3213; -. DR MoonDB; Q13501; Predicted. DR GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13501; -. DR PhosphoSitePlus; Q13501; -. DR SwissPalm; Q13501; -. DR BioMuta; SQSTM1; -. DR DMDM; 74735628; -. DR jPOST; Q13501; -. DR MassIVE; Q13501; -. DR PaxDb; 9606-ENSP00000374455; -. DR PeptideAtlas; Q13501; -. DR ProteomicsDB; 59496; -. [Q13501-1] DR ProteomicsDB; 59497; -. [Q13501-2] DR Pumba; Q13501; -. DR Antibodypedia; 761; 1362 antibodies from 49 providers. DR DNASU; 8878; -. DR YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers. DR Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2] DR Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1] DR Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1] DR Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1] DR GeneID; 8878; -. DR KEGG; hsa:8878; -. DR MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1. DR UCSC; uc003mkw.5; human. [Q13501-1] DR AGR; HGNC:11280; -. DR ClinPGx; PA36109; -. DR CTD; 8878; -. DR DisGeNET; 8878; -. DR GeneCards; SQSTM1; -. DR HGNC; HGNC:11280; SQSTM1. DR HPA; ENSG00000161011; Tissue enhanced (skeletal). DR MalaCards; SQSTM1; -. DR MIM; 167250; phenotype. DR MIM; 601530; gene. DR MIM; 616437; phenotype. DR MIM; 617145; phenotype. DR MIM; 617158; phenotype. DR OpenTargets; ENSG00000161011; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 603; Distal myopathy, Welander type. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR VEuPathDB; HostDB:ENSG00000161011; -. DR eggNOG; KOG4582; Eukaryota. DR GeneTree; ENSGT00390000002781; -. DR HOGENOM; CLU_038011_1_0_1; -. DR InParanoid; Q13501; -. DR OMA; NCNGWLT; -. DR OrthoDB; 441278at2759; -. DR PAN-GO; Q13501; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13501; -. DR PathwayCommons; Q13501; -. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9664873; Pexophagy. DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; Q13501; -. DR SIGNOR; Q13501; -. DR Agora; ENSG00000161011; -. DR BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens. DR CD-CODE; 1822EB5E; Synthetic Condensate 000092. DR CD-CODE; 5D6181E1; Synthetic Condensate 000293. DR CD-CODE; 718A9EC3; P62 body. DR CD-CODE; 98C8800A; Synthetic Condensate 000338. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; EF6CBD8C; Synthetic Condensate 000070. DR CD-CODE; F17BA747; P62 cluster. DR CD-CODE; F5639AB0; Synthetic Condensate 000096. DR ChiTaRS; SQSTM1; human. DR EvolutionaryTrace; Q13501; -. DR GeneWiki; Sequestosome_1; -. DR GenomeRNAi; 8878; -. DR Pharos; Q13501; Tbio. DR PRO; PR:Q13501; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13501; protein. DR Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues. DR ExpressionAtlas; Q13501; baseline and differential. DR GO; GO:0016235; C:aggresome; IBA:GO_Central. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0097413; C:Lewy body; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000932; C:P-body; IDA:UniProtKB. DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB. DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc. DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0035973; P:aggrephagy; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0006914; P:autophagy; IDA:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0033554; P:cellular response to stress; IDA:UniProt. DR GO; GO:0016197; P:endosomal transport; TAS:UniProtKB. DR GO; GO:0007032; P:endosome organization; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IDA:UniProtKB. DR GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB. DR GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL. DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd06402; PB1_p62; 1. DR CDD; cd14320; UBA_SQSTM; 1. DR CDD; cd02340; ZZ_NBR1_like; 1. DR DisProt; DP01111; -. DR FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1. DR FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1. DR FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1. DR Gene3D; 3.30.60.90; -; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00383; -. DR InterPro; IPR052260; Autophagy_Rcpt_SigReg. DR InterPro; IPR053793; PB1-like. DR InterPro; IPR000270; PB1_dom. DR InterPro; IPR034866; PB1_p62. DR InterPro; IPR033741; SQSTM_UBA. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR000433; Znf_ZZ. DR InterPro; IPR043145; Znf_ZZ_sf. DR PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1. DR PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1. DR Pfam; PF00564; PB1; 1. DR Pfam; PF16577; UBA_5; 1. DR Pfam; PF00569; ZZ; 1. DR SMART; SM00666; PB1; 1. DR SMART; SM00165; UBA; 1. DR SMART; SM00291; ZnF_ZZ; 1. DR SUPFAM; SSF54277; CAD & PB1 domains; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51745; PB1; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS01357; ZF_ZZ_1; 1. DR PROSITE; PS50135; ZF_ZZ_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; KW Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm; KW Cytoplasmic vesicle; Differentiation; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Endosome; Immunity; KW Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration; KW Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT CHAIN 2..440 FT /note="Sequestosome-1" FT /id="PRO_0000072176" FT DOMAIN 3..102 FT /note="PB1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081" FT DOMAIN 389..434 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 123..173 FT /note="ZZ-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT REGION 2..50 FT /note="Interaction with LCK" FT /evidence="ECO:0000269|PubMed:8650207" FT REGION 43..107 FT /note="Interaction with PRKCZ and dimerization" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 50..80 FT /note="Interaction with PAWR" FT /evidence="ECO:0000269|PubMed:11755531" FT REGION 122..224 FT /note="Interaction with GABRR3" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 170..220 FT /note="LIM protein-binding (LB)" FT REGION 196..235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..390 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..440 FT /note="Interaction with NTRK1" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 321..342 FT /note="MAP1LC3B-binding" FT /evidence="ECO:0000269|PubMed:17580304" FT REGION 347..352 FT /note="Interaction with KEAP1" FT /evidence="ECO:0000269|PubMed:20452972" FT MOTIF 228..233 FT /note="TRAF6-binding" FT MOTIF 336..341 FT /note="LIR" FT COMPBIAS 283..296 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 310..324 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 337..347 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 351..373 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 154 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 160 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT SITE 252..253 FT /note="Breakpoint for translocation to form the NUP214- FT SQSTM1 fusion protein" FT /evidence="ECO:0000269|PubMed:20851865" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:24275569" FT MOD_RES 148 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 176 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:20068231" FT MOD_RES 233 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 249 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 266 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 269 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 282 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 332 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 349 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 355 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 361 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 365 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64337" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 403 FT /note="Phosphoserine; by CK2, ULK1 and TBK1" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741, FT ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101" FT MOD_RES 407 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 420 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT MOD_RES 435 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT LIPID 289 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT LIPID 290 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT CROSSLNK 91 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 189 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 420 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:28380357" FT CROSSLNK 435 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000269|PubMed:33472082, FT ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..84 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015841" FT VARIANT 16 FT /note="A -> V (in FTDALS3; dbSNP:rs1554162295)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073899" FT VARIANT 17 FT /note="A -> V (in dbSNP:rs141502868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073900" FT VARIANT 33 FT /note="A -> V (in FTDALS3; dbSNP:rs200396166)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_073901" FT VARIANT 80 FT /note="D -> E (in FTDALS3; dbSNP:rs148366738)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073902" FT VARIANT 90 FT /note="V -> M (in FTDALS3; dbSNP:rs181263868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073903" FT VARIANT 103 FT /note="K -> R (in dbSNP:rs748170760)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073904" FT VARIANT 107 FT /note="R -> Q" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073905" FT VARIANT 107 FT /note="R -> W (in FTDALS3; dbSNP:rs771903158)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073906" FT VARIANT 108 FT /note="D -> Y" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073907" FT VARIANT 110 FT /note="R -> H (in dbSNP:rs1267306593)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073908" FT VARIANT 117 FT /note="A -> V (in dbSNP:rs147810437)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:24899140" FT /id="VAR_023590" FT VARIANT 118 FT /note="P -> S (in dbSNP:rs200152247)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073909" FT VARIANT 119 FT /note="R -> G (in dbSNP:rs548787835)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073910" FT VARIANT 125 FT /note="N -> S (in dbSNP:rs769325755)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073911" FT VARIANT 129 FT /note="D -> N (in FTDALS3; dbSNP:rs753212399)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073912" FT VARIANT 139 FT /note="R -> C (in dbSNP:rs750256905)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073913" FT VARIANT 153 FT /note="V -> I (in FTDALS3; dbSNP:rs145056421)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073914" FT VARIANT 180 FT /note="S -> L (in dbSNP:rs1582008478)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073915" FT VARIANT 212 FT /note="R -> C (in FTDALS3; dbSNP:rs201263163)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073916" FT VARIANT 217 FT /note="R -> H (in dbSNP:rs761822261)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073917" FT VARIANT 219 FT /note="G -> V (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073918" FT VARIANT 226 FT /note="S -> P (in FTDALS3; dbSNP:rs765200636)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073919" FT VARIANT 228 FT /note="P -> L (in FTDALS3; dbSNP:rs151191977)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073920" FT VARIANT 232 FT /note="P -> T (in FTDALS3; dbSNP:rs1225746517)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073921" FT VARIANT 238 FT /note="K -> E (confirmed at protein level; FT dbSNP:rs11548633)" FT /evidence="ECO:0000269|PubMed:17488105, FT ECO:0000269|PubMed:24899140" FT /id="VAR_068915" FT VARIANT 238 FT /note="Missing (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083" FT /id="VAR_073922" FT VARIANT 258 FT /note="D -> N (in FTDALS3; dbSNP:rs774986849)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073923" FT VARIANT 265..266 FT /note="RS -> SR" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073924" FT VARIANT 274 FT /note="E -> D (in dbSNP:rs55793208)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_061707" FT VARIANT 274 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:11992264" FT /id="VAR_023591" FT VARIANT 278 FT /note="T -> I (in dbSNP:rs200445838)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073925" FT VARIANT 308 FT /note="A -> V (in dbSNP:rs541356917)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073926" FT VARIANT 318 FT /note="S -> P (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073927" FT VARIANT 319 FT /note="E -> K (in dbSNP:rs61748794)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073928" FT VARIANT 321 FT /note="R -> C (in FTDALS3; likely benign; FT dbSNP:rs140226523)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073929" FT VARIANT 329 FT /note="D -> G (in FTDALS3; dbSNP:rs148294622)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073930" FT VARIANT 334 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073931" FT VARIANT 348 FT /note="P -> L (in FTDALS3; dbSNP:rs772889843)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073932" FT VARIANT 349 FT /note="S -> T (in dbSNP:rs774512680)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073933" FT VARIANT 370 FT /note="S -> P (in FTDALS3; dbSNP:rs143956614)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073934" FT VARIANT 381 FT /note="A -> V (in FTDALS3; dbSNP:rs772122047)" FT /evidence="ECO:0000269|PubMed:24042580" FT /id="VAR_073935" FT VARIANT 387 FT /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)" FT /evidence="ECO:0000269|PubMed:14584883, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023592" FT VARIANT 392 FT /note="P -> L (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; dbSNP:rs104893941)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745, FT ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023593" FT VARIANT 399 FT /note="S -> P (in PDB3; dbSNP:rs1561609625)" FT /evidence="ECO:0000269|PubMed:15146436" FT /id="VAR_023594" FT VARIANT 404 FT /note="M -> T (in PDB3; decreased ability to undergo FT liquid-liquid phase separation and formation of p62 body; FT dbSNP:rs1247551175)" FT /evidence="ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:29507397" FT /id="VAR_023595" FT VARIANT 404 FT /note="M -> V (in PDB3; loss of polyubiquitin-binding; FT dbSNP:rs771966860)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15176995" FT /id="VAR_023596" FT VARIANT 411 FT /note="G -> S (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; decreased ability to undergo liquid- FT liquid phase separation and formation of p62 body; FT dbSNP:rs143511494)" FT /evidence="ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397" FT /id="VAR_023597" FT VARIANT 425 FT /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin- FT binding and increased activation of NF-kappa-B; FT dbSNP:rs757212984)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127" FT /id="VAR_023598" FT VARIANT 430 FT /note="T -> P (in FTDALS3; dbSNP:rs770118706)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073936" FT VARIANT 439 FT /note="P -> L (in dbSNP:rs199854262)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073937" FT MUTAGEN 7 FT /note="K->A: Loss of interactions with PRKCZ, PRCKI and FT NBR1. Loss of dimerization; when associated with A-69." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 9 FT /note="Y->F: No effect on interaction with LCK." FT /evidence="ECO:0000269|PubMed:8650207" FT MUTAGEN 13 FT /note="K->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 21..22 FT /note="RR->AA: Loss of interaction with PRKCI. Alters FT dimerization." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 67 FT /note="Y->A: No effect on interaction with PRKCZ." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 69 FT /note="D->A: No effect on interactions with PRKCZ, PRKCI FT and NBR1. Loss of localization in cytoplasmic inclusion FT bodies. Loss of dimerization; when associated with A-7." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508" FT MUTAGEN 71 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 73 FT /note="D->A: No effect on interactions with PRKCZ and FT PRKCI." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 80 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 82 FT /note="E->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 289..290 FT /note="CC->SS: Abolished palmitoylation." FT /evidence="ECO:0000269|PubMed:37802024" FT MUTAGEN 323..324 FT /note="EE->AA: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 332 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 335..337 FT /note="DDD->ADA: 75% decrease in MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 338 FT /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts FT interaction with GABARAP." FT /evidence="ECO:0000269|PubMed:17580304, FT ECO:0000269|PubMed:24668264" FT MUTAGEN 342 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 347 FT /note="D->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 349 FT /note="S->A: Impaired phosphorylation by ULK1, leading to FT decreased p62 body formation." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 350 FT /note="T->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972, FT ECO:0000269|PubMed:37306101" FT MUTAGEN 351 FT /note="G->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 352 FT /note="E->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 398 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 403..407 FT /note="SMGFS->EMGFE: Mimics phosphorylation; increased FT phosphorylation at S-349." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 403 FT /note="S->A: Abolished phosphorylation by CK2, leading to FT decreased affinity for ubiquitinated proteins. Abolished FT ability to promote relocalization of 'Lys-63'-linked FT ubiquitinated STING1 to autophagosomes." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29496741" FT MUTAGEN 403 FT /note="S->E: Mimmics phosphorylation; increased affinity FT for ubiquitinated proteins, leading to increased p62 body FT formation and autophagic degradation." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29507397" FT MUTAGEN 406 FT /note="F->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 409 FT /note="E->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 410 FT /note="G->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 413 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 417 FT /note="L->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 420 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-435." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 420 FT /note="K->R: Decreased ubiquitination by the BCR(KEAP1) FT complex, leading to decreased sequestering activity. FT Strongly reduced acetylation; when associated with R-435." FT /evidence="ECO:0000269|PubMed:28380357, FT ECO:0000269|PubMed:31857589" FT MUTAGEN 431 FT /note="I->V: Partial loss of polyubiquitin-binding. Loss of FT localization to cytoplasmic inclusion bodies." FT /evidence="ECO:0000269|PubMed:15340068, FT ECO:0000269|PubMed:16286508" FT MUTAGEN 435 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-420." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 435 FT /note="K->R: Strongly reduced acetylation; when associated FT with R-420." FT /evidence="ECO:0000269|PubMed:31857589" FT CONFLICT 321 FT /note="R -> A (in Ref. 1; AAA93299)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 13..15 FT /evidence="ECO:0007829|PDB:6TGY" FT STRAND 19..24 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:6TGY" FT HELIX 43..54 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4MJS" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6KHZ" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:6MJ7" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 157..162 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 165..168 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:2JY7" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 412..419 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 420..422 FT /evidence="ECO:0007829|PDB:1Q02" FT HELIX 424..431 FT /evidence="ECO:0007829|PDB:1Q02" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:2JY8" FT INIT_MET Q13501-2:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q13501-2:2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 440 AA; 47687 MW; 462D94C171F337CD CRC64; MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK NYDIGAALDT IQYSKHPPPL // ID TRPM7_HUMAN Reviewed; 1865 AA. AC Q96QT4; Q6ZMF5; Q86VJ4; Q8NBW2; Q9BXB2; Q9NXQ2; DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 188. DE RecName: Full=Transient receptor potential cation channel subfamily M member 7; DE EC=2.7.11.1 {ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, ECO:0000269|PubMed:18394644}; DE AltName: Full=Channel-kinase 1; DE AltName: Full=Long transient receptor potential channel 7 {ECO:0000303|PubMed:11385574}; DE Short=LTrpC-7; DE Short=LTrpC7; DE Contains: DE RecName: Full=TRPM7 kinase, cleaved form {ECO:0000250|UniProtKB:Q923J1}; DE Short=M7CK; DE Contains: DE RecName: Full=TRPM7 channel, cleaved form {ECO:0000250|UniProtKB:Q923J1}; GN Name=TRPM7; Synonyms=CHAK1, LTRPC7 {ECO:0000303|PubMed:11385574}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY RP REGULATION. RX PubMed=11385574; DOI=10.1038/35079092; RA Nadler M.J.S., Hermosura M.C., Inabe K., Perraud A.-L., Zhu Q., RA Stokes A.J., Kurosaki T., Kinet J.-P., Penner R., Scharenberg A.M., RA Fleig A.; RT "LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell RT viability."; RL Nature 411:590-595(2001). RN [2] RP ERRATUM OF PUBMED:11385574. RA Nadler M.J.S., Hermosura M.C., Inabe K., Perraud A.-L., Zhu Q., RA Stokes A.J., Kurosaki T., Kinet J.-P., Penner R., Scharenberg A.M., RA Fleig A.; RL Nature 412:660-660(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION. RX PubMed=14594813; DOI=10.1074/jbc.m308820200; RA Ryazanova L.V., Dorovkov M.V., Ansari A., Ryazanov A.G.; RT "Characterization of the protein kinase activity of TRPM7/ChaK1, a protein RT kinase fused to the transient receptor potential ion channel."; RL J. Biol. Chem. 279:3708-3716(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-575 AND 1096-1865, AND VARIANT RP ILE-1482. RC TISSUE=Colon, and Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 464-998. RC TISSUE=Liver; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF LYS-1648 AND GLY-1799. RX PubMed=12887921; DOI=10.1016/s0092-8674(03)00556-7; RA Schmitz C., Perraud A.-L., Johnson C.O., Inabe K., Smith M.K., Penner R., RA Kurosaki T., Fleig A., Scharenberg A.M.; RT "Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7."; RL Cell 114:191-200(2003). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15485879; DOI=10.1074/jbc.c400441200; RA Dorovkov M.V., Ryazanov A.G.; RT "Phosphorylation of annexin I by TRPM7 channel-kinase."; RL J. Biol. Chem. 279:50643-50646(2004). RN [8] RP INTERACTION WITH TRPM6. RX PubMed=14976260; DOI=10.1073/pnas.0305252101; RA Chubanov V., Waldegger S., Mederos y Schnitzler M., Vitzthum H., RA Sassen M.C., Seyberth H.W., Konrad M., Gudermann T.; RT "Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 RT gene causes hypomagnesemia with secondary hypocalcemia."; RL Proc. Natl. Acad. Sci. U.S.A. 101:2894-2899(2004). RN [9] RP INTERACTION WITH TRPM6. RX PubMed=16636202; DOI=10.1085/jgp.200609502; RA Li M., Jiang J., Yue L.; RT "Functional characterization of homo- and heteromeric channel kinases TRPM6 RT and TRPM7."; RL J. Gen. Physiol. 127:525-537(2006). RN [10] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=18394644; DOI=10.1016/j.jmb.2008.02.057; RA Clark K., Middelbeek J., Lasonder E., Dulyaninova N.G., Morrice N.A., RA Ryazanov A.G., Bresnick A.R., Figdor C.G., van Leeuwen F.N.; RT "TRPM7 regulates myosin IIA filament stability and protein localization by RT heavy chain phosphorylation."; RL J. Mol. Biol. 378:790-803(2008). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND PHOSPHORYLATION AT RP THR-1163; SER-1191; SER-1193; SER-1255; SER-1258; THR-1265; SER-1287; RP SER-1358; SER-1361; SER-1387; SER-1390; SER-1396; SER-1404; THR-1405; RP SER-1407; THR-1435; SER-1446; THR-1455; SER-1456; SER-1463; SER-1468; RP THR-1471; SER-1476; SER-1477; THR-1482; SER-1493; SER-1504; THR-1508; RP SER-1513; SER-1527; SER-1533; THR-1537; THR-1542; SER-1543; THR-1551; RP SER-1567; SER-1569; THR-1583; SER-1598; SER-1615; SER-1660; THR-1685; RP SER-1779; THR-1830 AND SER-1860. RX PubMed=18365021; DOI=10.1371/journal.pone.0001876; RA Clark K., Middelbeek J., Morrice N.A., Figdor C.G., Lasonder E., RA van Leeuwen F.N.; RT "Massive autophosphorylation of the Ser/Thr-rich domain controls protein RT kinase activity of TRPM6 and TRPM7."; RL PLoS ONE 3:e1876-e1876(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1477, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [14] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-101; SER-1387; SER-1390; RP SER-1395; SER-1404; SER-1477; SER-1527 AND SER-1569, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [16] RP FUNCTION. RX PubMed=24316671; DOI=10.1038/ncb2883; RA Cai Z., Jitkaew S., Zhao J., Chiang H.C., Choksi S., Liu J., Ward Y., RA Wu L.G., Liu Z.G.; RT "Plasma membrane translocation of trimerized MLKL protein is required for RT TNF-induced necroptosis."; RL Nat. Cell Biol. 16:55-65(2014). RN [17] RP PALMITOYLATION AT CYS-1143; CYS-1144 AND CYS-1146, FUNCTION, AND RP TRANSPORTER ACTIVITY. RX PubMed=36027648; DOI=10.1016/j.ceca.2022.102639; RA Gao X., Kuo C.W., Main A., Brown E., Rios F.J., Camargo L.L., Mary S., RA Wypijewski K., Goek C., Touyz R.M., Fuller W.; RT "Palmitoylation regulates cellular distribution of and transmembrane Ca RT flux through TrpM7."; RL Cell Calcium 106:102639-102639(2022). RN [18] RP VARIANT ILE-1482, CHARACTERIZATION OF VARIANT ILE-1482, AND ACTIVITY RP REGULATION. RX PubMed=16051700; DOI=10.1073/pnas.0505149102; RA Hermosura M.C., Nayakanti H., Dorovkov M.V., Calderon F.R., Ryazanov A.G., RA Haymer D.S., Garruto R.M.; RT "A TRPM7 variant shows altered sensitivity to magnesium that may contribute RT to the pathogenesis of two Guamanian neurodegenerative disorders."; RL Proc. Natl. Acad. Sci. U.S.A. 102:11510-11515(2005). RN [19] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-68; CYS-406; THR-459; ASN-574; SER-720; RP VAL-830; TYR-949; ARG-1064; THR-1211; VAL-1254; GLU-1306; LYS-1444 AND RP ILE-1482. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [20] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, VARIANT ASP-1046, RP CHARACTERIZATION OF VARIANT ASP-1046, AND INVOLVEMENT IN HYPOMAGNESEMIA RP WITH SECONDARY HYPOCALCEMIA. RX PubMed=35561741; DOI=10.1093/ndt/gfac182; RA Vargas-Poussou R., Claverie-Martin F., Prot-Bertoye C., Carotti V., RA van der Wijst J., Perdomo-Ramirez A., Fraga-Rodriguez G.M., Hureaux M., RA Bos C., Latta F., Houillier P., Hoenderop J., de Baaij J.; RT "Possible role for rare TRPM7 variants in patients with hypomagnesemia with RT secondary hypocalcemia."; RL Nephrol. Dial. Transplant. 0:0-0(2022). CC -!- FUNCTION: Bifunctional protein that combines an ion channel with an CC intrinsic kinase domain, enabling it to modulate cellular functions CC either by conducting ions through the pore or by phosphorylating CC downstream proteins via its kinase domain. The channel is highly CC permeable to divalent cations, specifically calcium (Ca2+), magnesium CC (Mg2+) and zinc (Zn2+) and mediates their influx (PubMed:11385574, CC PubMed:12887921, PubMed:15485879, PubMed:24316671, PubMed:35561741, CC PubMed:36027648). Controls a wide range of biological processes such as CC Ca2(+), Mg(2+) and Zn(2+) homeostasis, vesicular Zn(2+) release channel CC and intracellular Ca(2+) signaling, embryonic development, immune CC responses, cell motility, proliferation and differentiation (By CC similarity). The C-terminal alpha-kinase domain autophosphorylates CC cytoplasmic residues of TRPM7 (PubMed:18365021). In vivo, TRPM7 CC phosphorylates SMAD2, suggesting that TRPM7 kinase may play a role in CC activating SMAD signaling pathways. In vitro, TRPM7 kinase CC phosphorylates ANXA1 (annexin A1), myosin II isoforms and a variety of CC proteins with diverse cellular functions (PubMed:15485879, CC PubMed:18394644). {ECO:0000250|UniProtKB:Q923J1, CC ECO:0000269|PubMed:11385574, ECO:0000269|PubMed:12887921, CC ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, CC ECO:0000269|PubMed:18394644, ECO:0000269|PubMed:24316671, CC ECO:0000269|PubMed:35561741, ECO:0000269|PubMed:36027648}. CC -!- FUNCTION: [TRPM7 channel, cleaved form]: The cleaved channel exhibits CC substantially higher current and potentiates Fas receptor signaling. CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- FUNCTION: [TRPM7 kinase, cleaved form]: The C-terminal kinase domain CC can be cleaved from the channel segment in a cell-type-specific CC fashion. In immune cells, the TRPM7 kinase domain is clipped from the CC channel domain by caspases in response to Fas-receptor stimulation. The CC cleaved kinase fragments can translocate to the nucleus, and bind CC chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to CC ultimately phosphorylate specific Ser/Thr residues of histones known to CC be functionally important for cell differentiation and embryonic CC development. {ECO:0000250|UniProtKB:Q923J1}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:15485879, ECO:0000269|PubMed:18365021, CC ECO:0000269|PubMed:18394644}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18365021, ECO:0000269|PubMed:18394644}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Mg(2+)(in) = Mg(2+)(out); Xref=Rhea:RHEA:29827, CC ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:11385574, CC ECO:0000269|PubMed:12887921, ECO:0000269|PubMed:35561741}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671, CC ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:11385574, CC ECO:0000269|PubMed:36027648}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000250|UniProtKB:Q923J1}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:Q923J1}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:Q923J1}; CC -!- ACTIVITY REGULATION: Channel displays constitutive activity. Channel CC activity is negatively regulated by cytosolic Mg(2+) and Mg-ATP CC (PubMed:11385574, PubMed:16051700). Channel activity is negatively CC regulated by low intracellular pH (By similarity). Resting free CC cytosolic Mg(2+) and Mg-ATP concentrations seem to be sufficient to CC block native TRPM7 channel activity (By similarity). TRPM7 channel CC activity is highly dependent on membrane levels of phosphatidylinositol CC 4,5 bisphosphate (PIP2). PIP2 hydrolysis negatively regulates TRPM7 CC channel activity (By similarity). TRPM7 kinase activity does not affect CC channel activity (By similarity). The kinase activity is controlled CC through the autophosphorylation of a serine/threonine-rich region CC located N-terminal to the catalytic domain (PubMed:18365021). CC {ECO:0000250|UniProtKB:Q923J1, ECO:0000250|UniProtKB:Q925B3, CC ECO:0000269|PubMed:11385574, ECO:0000269|PubMed:16051700, CC ECO:0000269|PubMed:18365021}. CC -!- SUBUNIT: Homotetramer (By similarity). Interacts with PLCB1 (By CC similarity). Forms heteromers with TRPM6; heteromeric channels are CC functionally different from the homomeric channels (PubMed:14976260, CC PubMed:16636202). {ECO:0000250|UniProtKB:Q923J1, CC ECO:0000250|UniProtKB:Q925B3, ECO:0000269|PubMed:14976260, CC ECO:0000269|PubMed:16636202}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24316671, CC ECO:0000269|PubMed:35561741}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q923J1}. Cytoplasmic vesicle membrane CC {ECO:0000250|UniProtKB:Q923J1}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:Q923J1}. Note=Localized largely in intracellular CC Zn(2+)-storage vesicles. {ECO:0000250|UniProtKB:Q923J1}. CC -!- SUBCELLULAR LOCATION: [TRPM7 kinase, cleaved form]: Nucleus CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- PTM: Palmitoylated; palmitoylation at Cys-1143, Cys-1144 and Cys-1146 CC promotes TRPM7 trafficking from the Golgi to the surface membrane. CC {ECO:0000269|PubMed:36027648}. CC -!- PTM: Autophosphorylated; autophosphorylation of C-terminus regulates CC TRPM7 kinase activity towards its substrates. CC {ECO:0000269|PubMed:18365021}. CC -!- PTM: The C-terminal kinase domain can be cleaved from the channel CC segment in a cell-type-specific fashion. TRPM7 is cleaved by caspase-8, CC dissociating the kinase from the ion-conducting pore. The cleaved CC kinase fragments (M7CKs) can translocate to the cell nucleus and binds CC chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to CC ultimately phosphorylate specific Ser/Thr residues of histones. CC {ECO:0000250|UniProtKB:Q923J1}. CC -!- DISEASE: Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1 CC (ALS-PDC1) [MIM:105500]: A neurodegenerative disorder characterized by CC chronic, progressive and uniformly fatal amyotrophic lateral sclerosis CC and parkinsonism-dementia. Both diseases are known to occur in the same CC kindred, the same sibship and even the same individual. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Note=TRPM7 variants have been identified as a potential cause CC of disease in patients suffering from seizures and muscle cramps due to CC magnesium deficiency and episodes of hypocalcemia. CC {ECO:0000269|PubMed:35561741}. CC -!- SIMILARITY: In the C-terminal section; belongs to the protein kinase CC superfamily. Alpha-type protein kinase family. ALPK subfamily. CC {ECO:0000305}. CC -!- SIMILARITY: In the N-terminal section; belongs to the transient CC receptor (TC 1.A.4) family. LTrpC subfamily. TRPM7 sub-subfamily. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC11462.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=BAD18773.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY032950; AAK44211.1; -; mRNA. DR EMBL; AF346629; AAK19738.2; -; mRNA. DR EMBL; AK000124; BAA90958.1; -; mRNA. DR EMBL; AK172800; BAD18773.1; ALT_INIT; mRNA. DR EMBL; AK075193; BAC11462.1; ALT_INIT; mRNA. DR EMBL; BC051024; AAH51024.1; -; mRNA. DR CCDS; CCDS42035.1; -. DR RefSeq; NP_001288141.1; NM_001301212.1. DR RefSeq; NP_060142.3; NM_017672.5. DR AlphaFoldDB; Q96QT4; -. DR SMR; Q96QT4; -. DR BioGRID; 120177; 153. DR CORUM; Q96QT4; -. DR FunCoup; Q96QT4; 1775. DR IntAct; Q96QT4; 44. DR MINT; Q96QT4; -. DR STRING; 9606.ENSP00000495860; -. DR BindingDB; Q96QT4; -. DR ChEMBL; CHEMBL1250412; -. DR DrugBank; DB04447; 1,4-Dithiothreitol. DR DrugBank; DB14513; Magnesium. DR DrugBank; DB09481; Magnesium carbonate. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB00179; Masoprocol. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR GuidetoPHARMACOLOGY; 499; -. DR TCDB; 1.A.4.5.1; the transient receptor potential ca2+/cation channel (trp-cc) family. DR CarbonylDB; Q96QT4; -. DR iPTMnet; Q96QT4; -. DR PhosphoSitePlus; Q96QT4; -. DR SwissPalm; Q96QT4; -. DR BioMuta; TRPM7; -. DR DMDM; 56404941; -. DR jPOST; Q96QT4; -. DR MassIVE; Q96QT4; -. DR PaxDb; 9606-ENSP00000320239; -. DR PeptideAtlas; Q96QT4; -. DR ProteomicsDB; 77898; -. DR Pumba; Q96QT4; -. DR Antibodypedia; 24755; 465 antibodies from 40 providers. DR DNASU; 54822; -. DR Ensembl; ENST00000646667.1; ENSP00000495860.1; ENSG00000092439.16. DR GeneID; 54822; -. DR KEGG; hsa:54822; -. DR MANE-Select; ENST00000646667.1; ENSP00000495860.1; NM_017672.6; NP_060142.3. DR UCSC; uc001zyt.5; human. DR AGR; HGNC:17994; -. DR ClinPGx; PA38273; -. DR CTD; 54822; -. DR DisGeNET; 54822; -. DR GeneCards; TRPM7; -. DR HGNC; HGNC:17994; TRPM7. DR HPA; ENSG00000092439; Tissue enriched (parathyroid). DR MalaCards; TRPM7; -. DR MIM; 105500; phenotype. DR MIM; 605692; gene. DR OpenTargets; ENSG00000092439; -. DR Orphanet; 140957; Autosomal dominant macrothrombocytopenia. DR Orphanet; 90020; Parkinson-dementia complex of Guam. DR VEuPathDB; HostDB:ENSG00000092439; -. DR eggNOG; KOG3614; Eukaryota. DR GeneTree; ENSGT00940000157091; -. DR InParanoid; Q96QT4; -. DR OMA; SSKDPHX; -. DR OrthoDB; 301415at2759; -. DR PAN-GO; Q96QT4; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q96QT4; -. DR PathwayCommons; Q96QT4; -. DR Reactome; R-HSA-3295583; TRP channels. DR SignaLink; Q96QT4; -. DR SIGNOR; Q96QT4; -. DR Agora; ENSG00000092439; -. DR BioGRID-ORCS; 54822; 406 hits in 1198 CRISPR screens. DR ChiTaRS; TRPM7; human. DR GeneWiki; TRPM7; -. DR GenomeRNAi; 54822; -. DR Pharos; Q96QT4; Tchem. DR PRO; PR:Q96QT4; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q96QT4; protein. DR Bgee; ENSG00000092439; Expressed in left ventricle myocardium and 179 other cell types or tissues. DR ExpressionAtlas; Q96QT4; baseline and differential. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB. DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0001726; C:ruffle; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005262; F:calcium channel activity; IDA:UniProtKB. DR GO; GO:0015095; F:magnesium ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0017022; F:myosin binding; IEA:Ensembl. DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IEA:Ensembl. DR GO; GO:0031032; P:actomyosin structure organization; IEA:Ensembl. DR GO; GO:0070588; P:calcium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:0006816; P:calcium ion transport; IBA:GO_Central. DR GO; GO:0016340; P:calcium-dependent cell-matrix adhesion; IEA:Ensembl. DR GO; GO:0010961; P:intracellular magnesium ion homeostasis; ISS:UniProtKB. DR GO; GO:0010960; P:magnesium ion homeostasis; IDA:UniProtKB. DR GO; GO:0015693; P:magnesium ion transport; IDA:UniProtKB. DR GO; GO:0098655; P:monoatomic cation transmembrane transport; IBA:GO_Central. DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0051289; P:protein homotetramerization; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0006829; P:zinc ion transport; ISS:UniProtKB. DR CDD; cd16971; Alpha_kinase_ChaK1_TRMP7; 1. DR FunFam; 1.20.5.1010:FF:000002; Transient receptor potential cation channel subfamily M member 7; 1. DR FunFam; 3.20.200.10:FF:000001; Transient receptor potential cation channel, subfamily M, member 7; 1. DR FunFam; 3.30.200.20:FF:000129; Transient receptor potential cation channel, subfamily M, member 7; 1. DR Gene3D; 3.20.200.10; MHCK/EF2 kinase; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.20.5.1010; TRPM, tetramerisation domain; 1. DR InterPro; IPR004166; a-kinase_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR050927; TRPM. DR InterPro; IPR057366; TRPM-like. DR InterPro; IPR029601; TRPM7_a-kinase_dom. DR InterPro; IPR041491; TRPM_SLOG. DR InterPro; IPR032415; TRPM_tetra. DR InterPro; IPR037162; TRPM_tetra_sf. DR PANTHER; PTHR13800:SF8; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY M MEMBER 7; 1. DR PANTHER; PTHR13800; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 6; 1. DR Pfam; PF02816; Alpha_kinase; 1. DR Pfam; PF18139; LSDAT_euk; 1. DR Pfam; PF25508; TRPM2; 2. DR Pfam; PF16519; TRPM_tetra; 1. DR SMART; SM00811; Alpha_kinase; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS51158; ALPHA_KINASE; 1. PE 1: Evidence at protein level; KW Acetylation; Amyotrophic lateral sclerosis; ATP-binding; Calcium; KW Calcium channel; Calcium transport; Cell membrane; Coiled coil; KW Cytoplasmic vesicle; Disease variant; Ion channel; Ion transport; Kinase; KW Lipoprotein; Membrane; Metal-binding; Necrosis; Neurodegeneration; KW Nucleotide-binding; Nucleus; Palmitate; Parkinsonism; Phosphoprotein; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Transmembrane; KW Transmembrane helix; Transport; Zinc. FT CHAIN 1..1865 FT /note="Transient receptor potential cation channel FT subfamily M member 7" FT /id="PRO_0000215331" FT CHAIN 1..? FT /note="TRPM7 channel, cleaved form" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT /id="PRO_0000461294" FT CHAIN ?..1865 FT /note="TRPM7 kinase, cleaved form" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT /id="PRO_0000461295" FT TOPO_DOM 1..850 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 851..876 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 877..882 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 883..904 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 905..923 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 924..943 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 944..956 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 957..980 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 981..999 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 1000..1023 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1024..1025 FT /note="Extracellular" FT /evidence="ECO:0000305" FT INTRAMEM 1026..1066 FT /note="Pore-forming" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1067..1069 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 1070..1098 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT TOPO_DOM 1099..1865 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT DOMAIN 1594..1824 FT /note="Alpha-type protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00501" FT REGION 544..575 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1386..1407 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1492..1511 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1524..1543 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1836..1865 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 1198..1250 FT /evidence="ECO:0000250" FT COMPBIAS 544..555 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 560..573 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1386..1398 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1494..1511 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1844..1865 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 1767 FT /note="Proton acceptor" FT /evidence="ECO:0000250" FT BINDING 1621 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1622 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1623 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1624 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1648 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1720 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1721 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1723 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1753 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1777 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1810 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1812 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT BINDING 1816 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 101 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1163 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1191 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1193 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1224 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1255 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1258 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1265 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1287 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1301 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1358 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1361 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1386 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1387 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1390 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1395 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1396 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1404 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1405 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1407 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1435 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1446 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1455 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1456 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1463 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1467 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1468 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1471 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1476 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1477 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 1482 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1493 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1500 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1504 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1508 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1513 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1527 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1533 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1537 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1542 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1543 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1551 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1567 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1569 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1583 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1598 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1615 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1660 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1685 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1779 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1830 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT MOD_RES 1851 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q923J1" FT MOD_RES 1860 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18365021" FT LIPID 1143 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT LIPID 1144 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT LIPID 1146 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000305|PubMed:36027648" FT VARIANT 68 FT /note="G -> V (in dbSNP:rs56064201)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042395" FT VARIANT 406 FT /note="S -> C (in an ovarian serous carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042396" FT VARIANT 459 FT /note="I -> T (in dbSNP:rs55924090)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042397" FT VARIANT 574 FT /note="K -> N (in dbSNP:rs56040619)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042398" FT VARIANT 720 FT /note="T -> S (in a breast infiltrating ductal carcinoma FT sample; somatic mutation; dbSNP:rs1040254222)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042399" FT VARIANT 830 FT /note="M -> V (in a gastric adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042400" FT VARIANT 949 FT /note="F -> Y (in dbSNP:rs55681028)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042401" FT VARIANT 1033 FT /note="A -> G (in dbSNP:rs34530969)" FT /id="VAR_052381" FT VARIANT 1046 FT /note="G -> D (found in a patient with hypomagnesemia and FT secondary hypocalcemia; likely pathogenic; de novo variant; FT causes severely reduced Mg(2+) uptake in transfected cells; FT dbSNP:rs2059709974)" FT /evidence="ECO:0000269|PubMed:35561741" FT /id="VAR_086707" FT VARIANT 1064 FT /note="Q -> R (in dbSNP:rs56298128)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042402" FT VARIANT 1145 FT /note="I -> V (in dbSNP:rs34711809)" FT /id="VAR_052382" FT VARIANT 1211 FT /note="I -> T (in dbSNP:rs56090496)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042403" FT VARIANT 1254 FT /note="A -> V (in dbSNP:rs56288221)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042404" FT VARIANT 1306 FT /note="D -> E (in dbSNP:rs55970334)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042405" FT VARIANT 1444 FT /note="R -> K (in dbSNP:rs55840070)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042406" FT VARIANT 1482 FT /note="T -> I (mutant channels are functional but show FT increased susceptibility to inhibition by intracellular FT Mg(2+) concentrations compared to wild-type channels; FT dbSNP:rs8042919)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:16051700, ECO:0000269|PubMed:17344846" FT /id="VAR_019967" FT MUTAGEN 1648 FT /note="K->R: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:12887921" FT MUTAGEN 1799 FT /note="G->D: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:12887921" FT CONFLICT 573..575 FT /note="EKM -> KKK (in Ref. 4; BAD18773)" FT /evidence="ECO:0000305" FT CONFLICT 998 FT /note="A -> S (in Ref. 5)" FT /evidence="ECO:0000305" FT CONFLICT 1496 FT /note="Missing (in Ref. 3; AAK19738)" FT /evidence="ECO:0000305" FT CONFLICT 1520 FT /note="D -> V (in Ref. 3; AAK19738)" FT /evidence="ECO:0000305" SQ SEQUENCE 1865 AA; 212697 MW; BE732674D52D7485 CRC64; MSQKSWIEST LTKRECVYII PSSKDPHRCL PGCQICQQLV RCFCGRLVKQ HACFTASLAM KYSDVKLGDH FNQAIEEWSV EKHTEQSPTD AYGVINFQGG SHSYRAKYVR LSYDTKPEVI LQLLLKEWQM ELPKLVISVH GGMQKFELHP RIKQLLGKGL IKAAVTTGAW ILTGGVNTGV AKHVGDALKE HASRSSRKIC TIGIAPWGVI ENRNDLVGRD VVAPYQTLLN PLSKLNVLNN LHSHFILVDD GTVGKYGAEV RLRRELEKTI NQQRIHARIG QGVPVVALIF EGGPNVILTV LEYLQESPPV PVVVCEGTGR AADLLAYIHK QTEEGGNLPD AAEPDIISTI KKTFNFGQNE ALHLFQTLME CMKRKELITV FHIGSDEHQD IDVAILTALL KGTNASAFDQ LILTLAWDRV DIAKNHVFVY GQQWLVGSLE QAMLDALVMD RVAFVKLLIE NGVSMHKFLT IPRLEELYNT KQGPTNPMLF HLVRDVKQGN LPPGYKITLI DIGLVIEYLM GGTYRCTYTR KRFRLIYNSL GGNNRRSGRN TSSSTPQLRK SHESFGNRAD KKEKMRHNHF IKTAQPYRPK IDTVMEEGKK KRTKDEIVDI DDPETKRFPY PLNELLIWAC LMKRQVMARF LWQHGEESMA KALVACKIYR SMAYEAKQSD LVDDTSEELK QYSNDFGQLA VELLEQSFRQ DETMAMKLLT YELKNWSNST CLKLAVSSRL RPFVAHTCTQ MLLSDMWMGR LNMRKNSWYK VILSILVPPA ILLLEYKTKA EMSHIPQSQD AHQMTMDDSE NNFQNITEEI PMEVFKEVRI LDSNEGKNEM EIQMKSKKLP ITRKFYAFYH APIVKFWFNT LAYLGFLMLY TFVVLVQMEQ LPSVQEWIVI AYIFTYAIEK VREIFMSEAG KVNQKIKVWF SDYFNISDTI AIISFFIGFG LRFGAKWNFA NAYDNHVFVA GRLIYCLNII FWYVRLLDFL AVNQQAGPYV MMIGKMVANM FYIVVIMALV LLSFGVPRKA ILYPHEAPSW TLAKDIVFHP YWMIFGEVYA YEIDVCANDS VIPQICGPGT WLTPFLQAVY LFVQYIIMVN LLIAFFNNVY LQVKAISNIV WKYQRYHFIM AYHEKPVLPP PLIILSHIVS LFCCICKRRK KDKTSDGPKL FLTEEDQKKL HDFEEQCVEM YFNEKDDKFH SGSEERIRVT FERVEQMCIQ IKEVGDRVNY IKRSLQSLDS QIGHLQDLSA LTVDTLKTLT AQKASEASKV HNEITRELSI SKHLAQNLID DGPVRPSVWK KHGVVNTLSS SLPQGDLESN NPFHCNILMK DDKDPQCNIF GQDLPAVPQR KEFNFPEAGS SSGALFPSAV SPPELRQRLH GVELLKIFNK NQKLGSSSTS IPHLSSPPTK FFVSTPSQPS CKSHLETGTK DQETVCSKAT EGDNTEFGAF VGHRDSMDLQ RFKETSNKIK ILSNNNTSEN TLKRVSSLAG FTDCHRTSIP VHSKQAEKIS RRPSTEDTHE VDSKAALIPD WLQDRPSNRE MPSEEGTLNG LTSPFKPAMD TNYYYSAVER NNLMRLSQSI PFTPVPPRGE PVTVYRLEES SPNILNNSMS SWSQLGLCAK IEFLSKEEMG GGLRRAVKVQ CTWSEHDILK SGHLYIIKSF LPEVVNTWSS IYKEDTVLHL CLREIQQQRA AQKLTFAFNQ MKPKSIPYSP RFLEVFLLYC HSAGQWFAVE ECMTGEFRKY NNNNGDEIIP TNTLEEIMLA FSHWTYEYTR GELLVLDLQG VGENLTDPSV IKAEEKRSCD MVFGPANLGE DAIKNFRAKH HCNSCCRKLK LPDLKRNDYT PDKIIFPQDE PSDLNLQPGN STKESESTNS VRLML // ID ZN746_HUMAN Reviewed; 644 AA. AC Q6NUN9; A8K6Z9; Q6ZRF9; DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 168. DE RecName: Full=Zinc finger protein 746 {ECO:0000305}; DE AltName: Full=Parkin-interacting substrate; DE Short=PARIS; GN Name=ZNF746 {ECO:0000312|HGNC:HGNC:21948}; Synonyms=PARIS; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Prostate, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, AND MUTAGENESIS OF CYS-458; RP HIS-471; CYS-518; HIS-528; CYS-543; HIS-560; CYS-571 AND HIS-584. RX PubMed=21376232; DOI=10.1016/j.cell.2011.02.010; RA Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., RA Troconso J.C., Dawson V.L., Dawson T.M.; RT "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration RT in Parkinson's disease."; RL Cell 144:689-702(2011). RN [5] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-282 AND LYS-286, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [6] RP FUNCTION, SUBUNIT, AND INTERACTION WITH TRIM28. RX PubMed=31856708; DOI=10.1186/s12860-019-0243-y; RA Al Chiblak M., Steinbeck F., Thiesen H.J., Lorenz P.; RT "DUF3669, a 'domain of unknown function' within ZNF746 and ZNF777, RT oligomerizes and contributes to transcriptional repression."; RL BMC Mol. Cell Biol. 20:60-60(2019). CC -!- FUNCTION: Transcription repressor that specifically binds to the 5'- CC TATTTT[T/G]-3' consensus sequence on promoters and repress CC transcription of PGC-1-alpha (PPARGC1A), thereby playing a role in CC regulation of neuron death. {ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:31856708}. CC -!- SUBUNIT: Homooligomer, heterooligomer with ZNF746 (PubMed:31856708). CC Interacts (via C2H2-type zinc fingers) with PRKN (By similarity). CC {ECO:0000250|UniProtKB:Q3U133, ECO:0000269|PubMed:31856708}. CC -!- SUBUNIT: [Isoform 1]: Interacts with TRIM28. CC {ECO:0000269|PubMed:31856708}. CC -!- INTERACTION: CC Q6NUN9; O60260: PRKN; NbExp=6; IntAct=EBI-3862525, EBI-716346; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21376232}. Nucleus CC {ECO:0000305|PubMed:21376232}. Note=Mainly localizes to the cytoplasm; CC probably translocates to the nucleus to repress selected genes. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6NUN9-1; Sequence=Displayed; CC Name=2; CC IsoId=Q6NUN9-2; Sequence=VSP_041053; CC Name=3; CC IsoId=Q6NUN9-3; Sequence=VSP_041052; CC -!- PTM: Ubiquitinated by PRKN. 'Lys-48'-linked polyubiquitination by PRKN CC leads to degradation by the proteasome and may play a key role in CC regulation of neuron death. {ECO:0000269|PubMed:21376232}. CC -!- MISCELLANEOUS: May act as a downstream effector of PRKN and contribute CC to neurodegeneration in Parkinson disease cases caused by defects in CC PRKN: its accumulation due to the absence of PRKN, followed by up- CC regulation of PPARGC1A, could lead to the selective loss of dopamine CC neurons in the substantia nigra. {ECO:0000305|PubMed:21376232}. CC -!- SIMILARITY: Belongs to the krueppel C2H2-type zinc-finger protein CC 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; AK128244; BAC87351.1; -; mRNA. DR EMBL; AK291814; BAF84503.1; -; mRNA. DR EMBL; AC073314; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC068505; AAH68505.1; -; mRNA. DR CCDS; CCDS55180.1; -. [Q6NUN9-2] DR CCDS; CCDS5897.1; -. [Q6NUN9-1] DR RefSeq; NP_001156946.1; NM_001163474.2. [Q6NUN9-2] DR RefSeq; NP_689770.3; NM_152557.4. [Q6NUN9-1] DR AlphaFoldDB; Q6NUN9; -. DR SMR; Q6NUN9; -. DR BioGRID; 127574; 324. DR FunCoup; Q6NUN9; 2518. DR IntAct; Q6NUN9; 58. DR MINT; Q6NUN9; -. DR STRING; 9606.ENSP00000493970; -. DR GlyGen; Q6NUN9; 2 sites. DR iPTMnet; Q6NUN9; -. DR PhosphoSitePlus; Q6NUN9; -. DR BioMuta; ZNF746; -. DR DMDM; 74736828; -. DR jPOST; Q6NUN9; -. DR MassIVE; Q6NUN9; -. DR PaxDb; 9606-ENSP00000395007; -. DR PeptideAtlas; Q6NUN9; -. DR ProteomicsDB; 66696; -. [Q6NUN9-1] DR ProteomicsDB; 66697; -. [Q6NUN9-2] DR ProteomicsDB; 66698; -. [Q6NUN9-3] DR Pumba; Q6NUN9; -. DR ABCD; Q6NUN9; 1 sequenced antibody. DR Antibodypedia; 46329; 66 antibodies from 20 providers. DR DNASU; 155061; -. DR Ensembl; ENST00000340622.8; ENSP00000345140.3; ENSG00000181220.19. [Q6NUN9-1] DR Ensembl; ENST00000685153.1; ENSP00000508891.1; ENSG00000181220.19. [Q6NUN9-2] DR GeneID; 155061; -. DR KEGG; hsa:155061; -. DR UCSC; uc003wfw.3; human. [Q6NUN9-1] DR AGR; HGNC:21948; -. DR ClinPGx; PA144596520; -. DR CTD; 155061; -. DR DisGeNET; 155061; -. DR GeneCards; ZNF746; -. DR HGNC; HGNC:21948; ZNF746. DR HPA; ENSG00000181220; Low tissue specificity. DR MIM; 613914; gene. DR OpenTargets; ENSG00000181220; -. DR VEuPathDB; HostDB:ENSG00000181220; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000161747; -. DR HOGENOM; CLU_002678_76_3_1; -. DR InParanoid; Q6NUN9; -. DR OrthoDB; 654211at2759; -. DR PAN-GO; Q6NUN9; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q6NUN9; -. DR PathwayCommons; Q6NUN9; -. DR Reactome; R-HSA-212436; Generic Transcription Pathway. DR SignaLink; Q6NUN9; -. DR SIGNOR; Q6NUN9; -. DR Agora; ENSG00000181220; -. DR BioGRID-ORCS; 155061; 7 hits in 1175 CRISPR screens. DR ChiTaRS; ZNF746; human. DR GenomeRNAi; 155061; -. DR Pharos; Q6NUN9; Tbio. DR PRO; PR:Q6NUN9; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q6NUN9; protein. DR Bgee; ENSG00000181220; Expressed in blood and 164 other cell types or tissues. DR ExpressionAtlas; Q6NUN9; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IC:ParkinsonsUK-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:0051291; P:protein heterooligomerization; IDA:UniProtKB. DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB. DR CDD; cd07765; KRAB_A-box; 1. DR FunFam; 3.30.160.60:FF:000340; zinc finger protein 473 isoform X1; 1. DR FunFam; 3.30.160.60:FF:001063; zinc finger protein 746 isoform X1; 1. DR FunFam; 3.30.160.60:FF:001242; zinc finger protein 746 isoform X1; 1. DR FunFam; 3.30.160.60:FF:001364; zinc finger protein 746 isoform X1; 1. DR Gene3D; 6.10.140.140; -; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 4. DR InterPro; IPR001909; KRAB. DR InterPro; IPR036051; KRAB_dom_sf. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24381:SF393; CHROMATIN-LINKED ADAPTOR FOR MSL PROTEINS, ISOFORM B; 1. DR PANTHER; PTHR24381; ZINC FINGER PROTEIN; 1. DR Pfam; PF01352; KRAB; 1. DR Pfam; PF00096; zf-C2H2; 4. DR SMART; SM00349; KRAB; 1. DR SMART; SM00355; ZnF_C2H2; 4. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR SUPFAM; SSF109640; KRAB domain (Kruppel-associated box); 1. DR PROSITE; PS50805; KRAB; 1. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 3. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 4. PE 1: Evidence at protein level; KW Alternative splicing; Coiled coil; Cytoplasm; DNA-binding; Isopeptide bond; KW Metal-binding; Nucleus; Proteomics identification; Reference proteome; KW Repeat; Repressor; Transcription; Transcription regulation; KW Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1..644 FT /note="Zinc finger protein 746" FT /id="PRO_0000253728" FT DOMAIN 96..167 FT /note="KRAB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00119" FT ZN_FING 453..478 FT /note="C2H2-type 1; degenerate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 510..532 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 538..560 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 566..588 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 153..176 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 324..370 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 472..503 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 581..623 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 16..92 FT /evidence="ECO:0000255" FT COMPBIAS 162..176 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 347..356 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 479..503 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 601..611 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CROSSLNK 282 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 286 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..185 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041052" FT VAR_SEQ 279 FT /note="E -> EA (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041053" FT MUTAGEN 458 FT /note="C->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 471 FT /note="H->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 518 FT /note="C->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 528 FT /note="H->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 543 FT /note="C->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 560 FT /note="H->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 571 FT /note="C->A: Impairs DNA-binding and ability to repress FT PGC-1-alpha (PPARGC1A)." FT /evidence="ECO:0000269|PubMed:21376232" FT MUTAGEN 584 FT /note="H->A: No effect." FT /evidence="ECO:0000269|PubMed:21376232" SQ SEQUENCE 644 AA; 69136 MW; 4F6723D2225D95AB CRC64; MAEAVAAPIS PWTMAATIQA MERKIESQAA RLLSLEGRTG MAEKKLADCE KTAVEFGNQL EGKWAVLGTL LQEYGLLQRR LENVENLLRN RNFWILRLPP GSKGESPKEW GKLEDWQKEL YKHVMRGNYE TLVSLDYAIS KPEVLSQIEQ GKEPCNWRRP GPKIPDVPVD PSPGSGPPVP APDLLMQIKQ EGELQLQEQQ ALGVEAWAAG QPDIGEEPWG LSQLDSGAGD ISTDATSGVH SNFSTTIPPT SWQTDLPPHH PSSACSDGTL KLNTAASTED VKIVIKTEVQ EEEVVATPVH PTDLEAHGTL FGPGQATRFF PSPAQEGAWE SQGSSFPSQD PVLGLREPAR PERDMGELSP AVAQEETPPG DWLFGGVRWG WNFRCKPPVG LNPRTGPEGL PYSSPDNGEA ILDPSQAPRP FNEPCKYPGR TKGFGHKPGL KKHPAAPPGG RPFTCATCGK SFQLQVSLSA HQRSCGAPDG SGPGTGGGGS GSGGGGGGSG GGSARDGSAL RCGECGRCFT RPAHLIRHRM LHTGERPFPC TECEKRFTER SKLIDHYRTH TGVRPFTCTV CGKSFIRKDH LRKHQRNHAA GAKTPARGQP LPTPPAPPDP FKSPASKGPL ASTDLVTDWT CGLSVLGPTD GGDM // 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 //