ID AIMP2_HUMAN Reviewed; 320 AA. AC Q13155; F8W950; Q75MR1; Q96CZ5; Q9P1L2; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2001, sequence version 2. DT 28-JAN-2026, entry version 206. DE RecName: Full=Aminoacyl tRNA synthase complex-interacting multifunctional protein 2; DE AltName: Full=Multisynthase complex auxiliary component p38; DE AltName: Full=Protein JTV-1; GN Name=AIMP2; Synonyms=JTV1; ORFNames=PRO0992; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8666379; DOI=10.1006/geno.1995.9997; RA Nicolaides N.C., Kinzler K.W., Vogelstein B.; RT "Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a RT novel overlapping gene."; RL Genomics 29:329-334(1995). 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 GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-129. RC TISSUE=Lymph, and 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 [6] RP PROTEIN SEQUENCE OF 1-17 AND 34-58, ALTERNATIVE SPLICING, IDENTIFICATION IN RP THE MSC COMPLEX, INTERACTION WITH TARS3, AND IDENTIFICATION BY MASS RP SPECTROMETRY (ISOFORMS 1 AND 2). RX PubMed=24312579; DOI=10.1371/journal.pone.0081734; RA Kim K., Park S.J., Na S., Kim J.S., Choi H., Kim Y.K., Paek E., Lee C.; RT "Reinvestigation of aminoacyl-tRNA synthetase core complex by affinity RT purification-mass spectrometry reveals TARSL2 as a potential member of the RT complex."; RL PLoS ONE 8:E81734-E81734(2013). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 197-320. RC TISSUE=Fetal liver; RA Zhang C., Yu Y., Zhang S., Wei H., Zhou G., Ouyang S., Luo L., Bi J., RA Liu M., He F.; RT "Functional prediction of the coding sequences of 121 new genes deduced by RT analysis of cDNA clones from human fetal liver."; RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases. RN [8] RP INTERACTION WITH KARS1. RX PubMed=9878398; DOI=10.1006/jmbi.1998.2316; RA Quevillon S., Robinson J.-C., Berthonneau E., Siatecka M., Mirande M.; RT "Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of RT protein-protein interactions and characterization of a core protein."; RL J. Mol. Biol. 285:183-195(1999). RN [9] RP INTERACTION WITH FUBP1. RX PubMed=12819782; DOI=10.1038/ng1182; RA Kim M.J., Park B.-J., Kang Y.-S., Kim H.J., Park J.-H., Kang J.W., RA Lee S.W., Han J.M., Lee H.-W., Kim S.; RT "Downregulation of FUSE-binding protein and c-myc by tRNA synthetase RT cofactor p38 is required for lung cell differentiation."; RL Nat. Genet. 34:330-336(2003). RN [10] RP INTERACTION WITH KARS1. RX PubMed=15220430; DOI=10.1128/jvi.78.14.7553-7564.2004; RA Halwani R., Cen S., Javanbakht H., Saadatmand J., Kim S., Shiba K., RA Kleiman L.; RT "Cellular distribution of Lysyl-tRNA synthetase and its interaction with RT Gag during human immunodeficiency virus type 1 assembly."; RL J. Virol. 78:7553-7564(2004). RN [11] RP FUNCTION, INTERACTION WITH PRKN, AND UBIQUITINATION. 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 [12] RP INTERACTION WITH KARS1. RX PubMed=18029264; DOI=10.1016/j.bbrc.2007.11.028; RA Guzzo C.M., Yang D.C.H.; RT "Lysyl-tRNA synthetase interacts with EF1alpha, aspartyl-tRNA synthetase RT and p38 in vitro."; RL Biochem. Biophys. Res. Commun. 365:718-723(2008). RN [13] RP INTERACTION WITH TP53, VARIANTS VAL-92; 97-GLU--THR-99 DELINS ASP-LEU-SER RP AND SER-209, AND MUTAGENESIS OF 163-GLU-ASN-164 AND 172-GLN-ASN-173. RX PubMed=18695251; DOI=10.1073/pnas.0800297105; RA Han J.M., Park B.-J., Park S.G., Oh Y.S., Choi S.J., Lee S.W., Hwang S.-K., RA Chang S.-H., Cho M.-H., Kim S.; RT "AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to RT genotoxic stresses via p53."; RL Proc. Natl. Acad. Sci. U.S.A. 105:11206-11211(2008). RN [14] RP FUNCTION, SUBUNIT, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19131329; DOI=10.1074/jbc.m809636200; RA Kaminska M., Havrylenko S., Decottignies P., Gillet S., Le Marechal P., RA Negrutskii B., Mirande M.; RT "Dissection of the structural organization of the aminoacyl-tRNA synthetase RT complex."; RL J. Biol. Chem. 284:6053-6060(2009). RN [15] RP SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=19289464; DOI=10.1074/jbc.m900480200; RA Kaminska M., Havrylenko S., Decottignies P., Le Marechal P., Negrutskii B., RA Mirande M.; RT "Dynamic Organization of Aminoacyl-tRNA Synthetase Complexes in the RT Cytoplasm of Human Cells."; RL J. Biol. Chem. 284:13746-13754(2009). RN [16] 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 [17] 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 [18] {ECO:0007744|PDB:4DPG} RP X-RAY CRYSTALLOGRAPHY (2.84 ANGSTROMS) OF 1-48 IN COMPLEX WITH KARS1, AND RP SUBUNIT. RX PubMed=23159739; DOI=10.1016/j.molcel.2012.10.010; RA Ofir-Birin Y., Fang P., Bennett S.P., Zhang H.M., Wang J., Rachmin I., RA Shapiro R., Song J., Dagan A., Pozo J., Kim S., Marshall A.G., Schimmel P., RA Yang X.L., Nechushtan H., Razin E., Guo M.; RT "Structural switch of lysyl-tRNA synthetase between translation and RT transcription."; RL Mol. Cell 49:30-42(2013). RN [19] {ECO:0007744|PDB:4YCU, ECO:0007744|PDB:4YCW} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-36 IN COMPLEX WITH KARS1. RX PubMed=26074468; DOI=10.1016/j.chembiol.2015.05.007; RA Fang P., Han H., Wang J., Chen K., Chen X., Guo M.; RT "Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP RT Competitive Inhibitor."; RL Chem. Biol. 22:734-744(2015). RN [20] {ECO:0007744|PDB:5A34} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-320 IN COMPLEX WITH EPRS1, RP SUBUNIT, AND MUTAGENESIS OF ARG-215 AND ASP-238. RX PubMed=26472928; DOI=10.1074/jbc.m115.690867; RA Cho H.Y., Maeng S.J., Cho H.J., Choi Y.S., Chung J.M., Lee S., Kim H.K., RA Kim J.H., Eom C.Y., Kim Y.G., Guo M., Jung H.S., Kang B.S., Kim S.; RT "Assembly of Multi-tRNA Synthetase Complex via Heterotetrameric Glutathione RT Transferase-homology Domains."; RL J. Biol. Chem. 290:29313-29328(2015). RN [21] RP INVOLVEMENT IN HLD17, AND VARIANT HLD17 35-TYR--LYS-320 DEL. RX PubMed=29215095; DOI=10.1038/s10038-017-0363-1; RA Shukla A., Das Bhowmik A., Hebbar M., Rajagopal K.V., Girisha K.M., RA Gupta N., Dalal A.; RT "Homozygosity for a nonsense variant in AIMP2 is associated with a RT progressive neurodevelopmental disorder with microcephaly, seizures, and RT spastic quadriparesis."; RL J. Hum. Genet. 63:19-25(2018). CC -!- FUNCTION: Required for assembly and stability of the aminoacyl-tRNA CC synthase complex (PubMed:19131329). Mediates ubiquitination and CC degradation of FUBP1, a transcriptional activator of MYC, leading to CC MYC down-regulation which is required for aveolar type II cell CC differentiation. Blocks MDM2-mediated ubiquitination and degradation of CC p53/TP53. Functions as a proapoptotic factor. CC {ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:19131329}. CC -!- SUBUNIT: Part of the multisynthetase complex (MSC), a multisubunit CC complex that groups tRNA ligases for Arg (RARS1), Asp (DARS1), Gln CC (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the CC bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits CC AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, PubMed:19289464, CC PubMed:24312579). Interacts (via N-terminus) with KARS1 CC (PubMed:15220430, PubMed:18029264, PubMed:23159739, PubMed:26074468, CC PubMed:9878398). Interacts with EPRS1 (PubMed:26472928). Forms a linear CC complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the CC core of the multisubunit complex (PubMed:26472928). Binds FUBP1 (via C- CC terminus). Interacts in both its unphosphorylated and phosphorylated CC forms with p53/TP53 (via N-terminus) in the nucleus following UV CC irradiation. Interacts (via N-terminus) with PRKN/parkin (via first CC RING-type domain) (PubMed:16135753). Interacts with TARS3 CC (PubMed:24312579). {ECO:0000269|PubMed:12819782, CC ECO:0000269|PubMed:15220430, ECO:0000269|PubMed:16135753, CC ECO:0000269|PubMed:18029264, ECO:0000269|PubMed:18695251, CC ECO:0000269|PubMed:19131329, ECO:0000269|PubMed:19289464, CC ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:24312579, CC ECO:0000269|PubMed:26074468, ECO:0000269|PubMed:26472928, CC ECO:0000269|PubMed:9878398}. CC -!- INTERACTION: CC Q13155; Q12904: AIMP1; NbExp=6; IntAct=EBI-745226, EBI-1045802; CC Q13155; Q12904-2: AIMP1; NbExp=5; IntAct=EBI-745226, EBI-12412735; CC Q13155; P05067: APP; NbExp=3; IntAct=EBI-745226, EBI-77613; CC Q13155; O75934: BCAS2; NbExp=12; IntAct=EBI-745226, EBI-1050106; CC Q13155; Q0VDD7: BRME1; NbExp=8; IntAct=EBI-745226, EBI-741210; CC Q13155; Q13895: BYSL; NbExp=5; IntAct=EBI-745226, EBI-358049; CC Q13155; Q8TAB5: C1orf216; NbExp=3; IntAct=EBI-745226, EBI-747505; CC Q13155; Q8NA61-2: CBY2; NbExp=5; IntAct=EBI-745226, EBI-11524851; CC Q13155; Q96L14: CEP170P1; NbExp=5; IntAct=EBI-745226, EBI-743488; CC Q13155; P14868: DARS1; NbExp=10; IntAct=EBI-745226, EBI-358730; CC Q13155; Q9NRI5-2: DISC1; NbExp=3; IntAct=EBI-745226, EBI-11988027; CC Q13155; Q494R4-2: DRC12; NbExp=3; IntAct=EBI-745226, EBI-11974185; CC Q13155; Q8IYI6: EXOC8; NbExp=5; IntAct=EBI-745226, EBI-742102; CC Q13155; Q13643: FHL3; NbExp=13; IntAct=EBI-745226, EBI-741101; CC Q13155; Q96AE4: FUBP1; NbExp=4; IntAct=EBI-745226, EBI-711404; CC Q13155; P13807: GYS1; NbExp=3; IntAct=EBI-745226, EBI-740553; CC Q13155; Q15046: KARS1; NbExp=23; IntAct=EBI-745226, EBI-356367; CC Q13155; Q15046-1: KARS1; NbExp=2; IntAct=EBI-745226, EBI-21457670; CC Q13155; Q15323: KRT31; NbExp=3; IntAct=EBI-745226, EBI-948001; CC Q13155; Q14525: KRT33B; NbExp=3; IntAct=EBI-745226, EBI-1049638; CC Q13155; O76011: KRT34; NbExp=3; IntAct=EBI-745226, EBI-1047093; CC Q13155; O76013-2: KRT36; NbExp=3; IntAct=EBI-745226, EBI-11958506; CC Q13155; P25791: LMO2; NbExp=3; IntAct=EBI-745226, EBI-739696; CC Q13155; P25791-3: LMO2; NbExp=6; IntAct=EBI-745226, EBI-11959475; CC Q13155; Q8TBB1: LNX1; NbExp=8; IntAct=EBI-745226, EBI-739832; CC Q13155; Q9NYP9: MIS18A; NbExp=6; IntAct=EBI-745226, EBI-1104552; CC Q13155; Q9GZM8: NDEL1; NbExp=3; IntAct=EBI-745226, EBI-928842; CC Q13155; Q7Z6G3-2: NECAB2; NbExp=3; IntAct=EBI-745226, EBI-10172876; CC Q13155; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-745226, EBI-741158; CC Q13155; P22061: PCMT1; NbExp=3; IntAct=EBI-745226, EBI-353343; CC Q13155; O15212: PFDN6; NbExp=3; IntAct=EBI-745226, EBI-356973; CC Q13155; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-745226, EBI-742388; CC Q13155; P54646: PRKAA2; NbExp=3; IntAct=EBI-745226, EBI-1383852; CC Q13155; Q15276: RABEP1; NbExp=3; IntAct=EBI-745226, EBI-447043; CC Q13155; P0C264: SBK3; NbExp=3; IntAct=EBI-745226, EBI-17181801; CC Q13155; O95391: SLU7; NbExp=3; IntAct=EBI-745226, EBI-750559; CC Q13155; Q8TC71: SPATA18; NbExp=3; IntAct=EBI-745226, EBI-11334239; CC Q13155; Q8WWU5-7: TCP11; NbExp=3; IntAct=EBI-745226, EBI-17721485; CC Q13155; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-745226, EBI-750109; CC Q13155; Q9BXU0: TEX12; NbExp=3; IntAct=EBI-745226, EBI-12090309; CC Q13155; Q9UBB9: TFIP11; NbExp=6; IntAct=EBI-745226, EBI-1105213; CC Q13155; P04637: TP53; NbExp=6; IntAct=EBI-745226, EBI-366083; CC Q13155; A0A0S2Z6H0: ZGPAT; NbExp=3; IntAct=EBI-745226, EBI-16428984; CC Q13155; Q8N5A5: ZGPAT; NbExp=3; IntAct=EBI-745226, EBI-3439227; CC Q13155; Q8N5A5-2: ZGPAT; NbExp=12; IntAct=EBI-745226, EBI-10183064; CC Q13155; PRO_0000038593 [P04591]: gag; Xeno; NbExp=3; IntAct=EBI-745226, EBI-6179719; CC Q13155; P32502: GCD7; Xeno; NbExp=3; IntAct=EBI-745226, EBI-6260; CC Q13155; P38340: TAE1; Xeno; NbExp=3; IntAct=EBI-745226, EBI-21116; CC Q13155; P53930: YAF9; Xeno; NbExp=3; IntAct=EBI-745226, EBI-28841; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:19289464}. CC Nucleus {ECO:0000250|UniProtKB:Q8R010}. Note=Following DNA damage, CC dissociates from the aminoacyl-tRNA synthase complex and translocates CC from the cytoplasm to the nucleus. {ECO:0000250|UniProtKB:Q8R010}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13155-1; Sequence=Displayed; CC Name=2; Synonyms=DX2 {ECO:0000303|PubMed:24312579}; CC IsoId=Q13155-2; Sequence=VSP_059914; CC -!- PTM: Phosphorylated on serine residues in response to UV irradiation. CC {ECO:0000250}. CC -!- PTM: Ubiquitinated by PRKN, leading to its degradation by the CC proteasome. Mutant PRKN fails to ubiquitinate AIMP2 efficiently, CC allowing its accumulation which may contribute to neurodegeneration CC associated with Parkinson disease. {ECO:0000269|PubMed:16135753}. CC -!- DISEASE: Leukodystrophy, hypomyelinating, 17 (HLD17) [MIM:618006]: An CC autosomal recessive neurodevelopmental disorder characterized by CC atrophy of cerebral cortex, spinal cord and cerebellum, thin corpus CC callosum, abnormal signals in the basal ganglia, and features CC suggesting hypo- or demyelination observed on brain imaging. Clinical CC manifestations include lack of development, absent speech, CC microcephaly, spasticity, seizures, and contractures. CC {ECO:0000269|PubMed:29215095}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Accumulates in brains affected by autosomal-recessive CC juvenile parkinsonism, idiopathic Parkinson disease and diffuse Lewy CC body disease. CC -!- SEQUENCE CAUTION: CC Sequence=AAC50391.1; 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; U24169; AAC50391.1; ALT_FRAME; mRNA. DR EMBL; AC005995; AAS00389.1; -; Genomic_DNA. DR EMBL; CH236963; EAL23713.1; -; Genomic_DNA. DR EMBL; CH878731; EAW55053.1; -; Genomic_DNA. DR EMBL; BC002853; AAH02853.1; -; mRNA. DR EMBL; BC010156; AAH10156.1; -; mRNA. DR EMBL; BC013630; AAH13630.1; -; mRNA. DR EMBL; AF116615; AAF71039.1; -; mRNA. DR CCDS; CCDS5344.1; -. [Q13155-1] DR CCDS; CCDS87475.1; -. [Q13155-2] DR RefSeq; NP_001313536.1; NM_001326607.2. [Q13155-2] DR RefSeq; NP_006294.2; NM_006303.3. [Q13155-1] DR PDB; 4DPG; X-ray; 2.84 A; I/J/K/L=1-48. DR PDB; 4YCU; X-ray; 2.10 A; C=1-36. DR PDB; 4YCW; X-ray; 2.90 A; C/D/G/H=1-36. DR PDB; 5A1N; X-ray; 2.10 A; B=90-320. DR PDB; 5A34; X-ray; 2.60 A; B/D/F/H=90-320. DR PDB; 5A5H; X-ray; 2.32 A; B/D/F/H=90-320. DR PDB; 5Y6L; X-ray; 2.90 A; D=89-320. DR PDB; 6ILD; X-ray; 1.88 A; C=1-36. DR PDB; 6IY6; X-ray; 3.60 A; C/D/I/J=115-320. DR PDB; 6JPV; X-ray; 2.15 A; A/B=24-32. DR PDB; 6K39; X-ray; 1.40 A; A/B=25-32. DR PDB; 8J9S; X-ray; 3.01 A; C=50-90. DR PDB; 9DPL; EM; 2.80 A; D/E=1-36. DR PDBsum; 4DPG; -. DR PDBsum; 4YCU; -. DR PDBsum; 4YCW; -. DR PDBsum; 5A1N; -. DR PDBsum; 5A34; -. DR PDBsum; 5A5H; -. DR PDBsum; 5Y6L; -. DR PDBsum; 6ILD; -. DR PDBsum; 6IY6; -. DR PDBsum; 6JPV; -. DR PDBsum; 6K39; -. DR PDBsum; 8J9S; -. DR PDBsum; 9DPL; -. DR AlphaFoldDB; Q13155; -. DR EMDB; EMD-47106; -. DR SMR; Q13155; -. DR BioGRID; 113684; 459. DR ComplexPortal; CPX-2469; Multiaminoacyl-tRNA synthetase complex. DR CORUM; Q13155; -. DR DIP; DIP-34421N; -. DR FunCoup; Q13155; 619. DR IntAct; Q13155; 111. DR MINT; Q13155; -. DR STRING; 9606.ENSP00000223029; -. DR BindingDB; Q13155; -. DR ChEMBL; CHEMBL4523285; -. DR GlyGen; Q13155; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q13155; -. DR PhosphoSitePlus; Q13155; -. DR SwissPalm; Q13155; -. DR BioMuta; AIMP2; -. DR jPOST; Q13155; -. DR MassIVE; Q13155; -. DR PaxDb; 9606-ENSP00000223029; -. DR PeptideAtlas; Q13155; -. DR ProteomicsDB; 30261; -. DR ProteomicsDB; 59195; -. DR Pumba; Q13155; -. DR ABCD; Q13155; 1 sequenced antibody. DR Antibodypedia; 11563; 206 antibodies from 32 providers. DR DNASU; 7965; -. DR Ensembl; ENST00000223029.8; ENSP00000223029.3; ENSG00000106305.11. [Q13155-1] DR Ensembl; ENST00000395236.2; ENSP00000378658.2; ENSG00000106305.11. [Q13155-2] DR GeneID; 7965; -. DR KEGG; hsa:7965; -. DR MANE-Select; ENST00000223029.8; ENSP00000223029.3; NM_006303.4; NP_006294.2. DR UCSC; uc003spo.4; human. [Q13155-1] DR AGR; HGNC:20609; -. DR CIViC; 7965; 1 evidence item across 1 molecular profile. DR ClinPGx; PA165617609; -. DR CTD; 7965; -. DR DisGeNET; 7965; -. DR GeneCards; AIMP2; -. DR HGNC; HGNC:20609; AIMP2. DR HPA; ENSG00000106305; Tissue enhanced (skeletal). DR MalaCards; AIMP2; -. DR MIM; 600859; gene. DR MIM; 618006; phenotype. DR OpenTargets; ENSG00000106305; -. DR VEuPathDB; HostDB:ENSG00000106305; -. DR eggNOG; ENOG502QUNJ; Eukaryota. DR GeneTree; ENSGT00390000015826; -. DR HOGENOM; CLU_076114_0_0_1; -. DR InParanoid; Q13155; -. DR OMA; LCQHYRV; -. DR OrthoDB; 2309723at2759; -. DR PAN-GO; Q13155; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q13155; -. DR PathwayCommons; Q13155; -. DR Reactome; R-HSA-2408522; Selenoamino acid metabolism. DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation. DR Reactome; R-HSA-9856649; Transcriptional and post-translational regulation of MITF-M expression and activity. DR SignaLink; Q13155; -. DR SIGNOR; Q13155; -. DR Agora; ENSG00000106305; -. DR BioGRID-ORCS; 7965; 17 hits in 1160 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; AIMP2; human. DR EvolutionaryTrace; Q13155; -. DR GeneWiki; Multisynthetase_complex_auxiliary_component_p38; -. DR GenomeRNAi; 7965; -. DR Pharos; Q13155; Tchem. DR PRO; PR:Q13155; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q13155; protein. DR Bgee; ENSG00000106305; Expressed in oocyte and 219 other cell types or tissues. DR ExpressionAtlas; Q13155; baseline and differential. DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:MGI. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl. DR GO; GO:0016567; P:protein ubiquitination; IEA:Ensembl. DR GO; GO:0065003; P:protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0006412; P:translation; IEA:UniProtKB-KW. DR GO; GO:0060510; P:type II pneumocyte differentiation; IEA:Ensembl. DR CDD; cd03200; GST_C_AIMP2; 1. DR FunFam; 1.20.1050.130:FF:000002; aminoacyl tRNA synthase complex-interacting multifunctional protein 2 isoform X2; 1. DR Gene3D; 1.20.1050.130; -; 1. DR InterPro; IPR042360; AIMP2. DR InterPro; IPR031889; AIMP2_LysRS-bd. DR InterPro; IPR041503; AIMP2_thioredoxin. DR InterPro; IPR036282; Glutathione-S-Trfase_C_sf. DR InterPro; IPR004046; GST_C. DR PANTHER; PTHR13438; AMINOACYL TRNA SYNTHASE COMPLEX-INTERACTING MULTIFUNCTIONAL PROTEIN; 1. DR PANTHER; PTHR13438:SF2; AMINOACYL TRNA SYNTHASE COMPLEX-INTERACTING MULTIFUNCTIONAL PROTEIN 2; 1. DR Pfam; PF16780; AIMP2_LysRS_bd; 1. DR Pfam; PF00043; GST_C; 1. DR Pfam; PF18569; Thioredoxin_16; 1. DR SUPFAM; SSF47616; GST C-terminal domain-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Cytoplasm; KW Developmental protein; Differentiation; Direct protein sequencing; KW Disease variant; Leukodystrophy; Nucleus; Phosphoprotein; KW Protein biosynthesis; Proteomics identification; Reference proteome; KW Ubl conjugation. FT CHAIN 1..320 FT /note="Aminoacyl tRNA synthase complex-interacting FT multifunctional protein 2" FT /id="PRO_0000221129" FT DOMAIN 220..317 FT /note="GST C-terminal" FT REGION 82..162 FT /note="Interaction with PRKN" FT /evidence="ECO:0000269|PubMed:16135753" FT REGION 162..225 FT /note="Interaction with TP53" FT /evidence="ECO:0000269|PubMed:18695251" FT VAR_SEQ 46..114 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:24312579" FT /id="VSP_059914" FT VARIANT 35..320 FT /note="Missing (in HLD17)" FT /evidence="ECO:0000269|PubMed:29215095" FT /id="VAR_081108" FT VARIANT 92 FT /note="I -> V (in a lung cancer cell line; reduced FT interaction with TP53, loss of TP53 activation and loss of FT proapoptotic activity)" FT /evidence="ECO:0000269|PubMed:18695251" FT /id="VAR_058392" FT VARIANT 97..99 FT /note="EPT -> DLS (in a lung cancer cell line; no effect on FT proapoptotic activity)" FT /evidence="ECO:0000269|PubMed:18695251" FT /id="VAR_058393" FT VARIANT 129 FT /note="A -> G (in dbSNP:rs17855441)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_025521" FT VARIANT 166 FT /note="L -> I (in dbSNP:rs34525431)" FT /id="VAR_050125" FT VARIANT 209 FT /note="G -> S (in a lung cancer cell line; no effect on FT proapoptotic activity; dbSNP:rs982080297)" FT /evidence="ECO:0000269|PubMed:18695251" FT /id="VAR_058394" FT MUTAGEN 163..164 FT /note="EN->AA: Reduced interaction with TP53, loss of TP53 FT activation and loss of proapoptotic activity." FT /evidence="ECO:0000269|PubMed:18695251" FT MUTAGEN 172..173 FT /note="QN->AA: Reduced interaction with TP53, loss of TP53 FT activation and loss of proapoptotic activity." FT /evidence="ECO:0000269|PubMed:18695251" FT MUTAGEN 215 FT /note="R->A: Nearly abolishes interaction with EPRS1." FT /evidence="ECO:0000269|PubMed:26472928" FT MUTAGEN 238 FT /note="D->R: Nearly abolishes interaction with EPRS1." FT /evidence="ECO:0000269|PubMed:26472928" FT STRAND 12..14 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 52..79 FT /evidence="ECO:0007829|PDB:8J9S" FT HELIX 108..112 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 113..115 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 116..119 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 120..126 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 128..130 FT /evidence="ECO:0007829|PDB:5A34" FT HELIX 133..143 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 148..154 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 163..166 FT /evidence="ECO:0007829|PDB:5A1N" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:5A5H" FT STRAND 182..189 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 196..198 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 202..204 FT /evidence="ECO:0007829|PDB:5A5H" FT STRAND 207..209 FT /evidence="ECO:0007829|PDB:5A5H" FT HELIX 210..219 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 227..242 FT /evidence="ECO:0007829|PDB:5A1N" FT TURN 243..246 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 249..262 FT /evidence="ECO:0007829|PDB:5A1N" FT TURN 263..265 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 271..273 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 276..286 FT /evidence="ECO:0007829|PDB:5A1N" FT STRAND 291..293 FT /evidence="ECO:0007829|PDB:5Y6L" FT HELIX 297..307 FT /evidence="ECO:0007829|PDB:5A1N" FT HELIX 310..318 FT /evidence="ECO:0007829|PDB:5A1N" SQ SEQUENCE 320 AA; 35349 MW; F253726B63C12BAB CRC64; MPMYQVKPYH GGGAPLRVEL PTCMYRLPNV HGRSYGPAPG AGHVQEESNL SLQALESRQD DILKRLYELK AAVDGLSKMI QTPDADLDVT NIIQADEPTT LTTNALDLNS VLGKDYGALK DIVINANPAS PPLSLLVLHR LLCEHFRVLS TVHTHSSVKS VPENLLKCFG EQNKKQPRQD YQLGFTLIWK NVPKTQMKFS IQTMCPIEGE GNIARFLFSL FGQKHNAVNA TLIDSWVDIA IFQLKEGSSK EKAAVFRSMN SALGKSPWLA GNELTVADVV LWSVLQQIGG CSVTVPANVQ RWMRSCENLA PFNTALKLLK // 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 AUXI_HUMAN Reviewed; 913 AA. AC O75061; B7Z3V8; D3DQ65; D3DQ66; Q32M66; Q4G0K1; Q5T614; Q5T615; DT 27-JUN-2006, integrated into UniProtKB/Swiss-Prot. DT 27-JUN-2006, sequence version 3. DT 28-JAN-2026, entry version 197. DE RecName: Full=Auxilin {ECO:0000303|PubMed:18489706}; DE EC=3.1.3.- {ECO:0000305}; DE AltName: Full=DnaJ homolog subfamily C member 6 {ECO:0000312|HGNC:HGNC:15469}; GN Name=DNAJC6 {ECO:0000312|HGNC:HGNC:15469}; GN Synonyms=KIAA0473 {ECO:0000312|EMBL:BAA32318.2}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=9455484; DOI=10.1093/dnares/4.5.345; RA Seki N., Ohira M., Nagase T., Ishikawa K., Miyajima N., Nakajima D., RA Nomura N., Ohara O.; RT "Characterization of cDNA clones in size-fractionated cDNA libraries from RT human brain."; RL DNA Res. 4:345-349(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). 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 [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 GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 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 [6] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-563 AND SER-570, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [7] RP FUNCTION. RX PubMed=18489706; DOI=10.1111/j.1600-0854.2008.00764.x; RA Hirst J., Sahlender D.A., Li S., Lubben N.B., Borner G.H., Robinson M.S.; RT "Auxilin depletion causes self-assembly of clathrin into membraneless cages RT in vivo."; RL Traffic 9:1354-1371(2008). RN [8] 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 [9] RP INVOLVEMENT IN PARK19A. RX PubMed=22563501; DOI=10.1371/journal.pone.0036458; RA Edvardson S., Cinnamon Y., Ta-Shma A., Shaag A., Yim Y.I., Zenvirt S., RA Jalas C., Lesage S., Brice A., Taraboulos A., Kaestner K.H., Greene L.E., RA Elpeleg O.; RT "A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin- RT uncoating co-chaperone auxilin, is associated with juvenile parkinsonism."; RL PLoS ONE 7:E36458-E36458(2012). RN [10] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 (ISOFORMS 3 AND 4), AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-112 AND SER-570, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP TISSUE SPECIFICITY, AND INVOLVEMENT IN PARK19A. RX PubMed=23211418; DOI=10.1016/j.parkreldis.2012.11.006; RA Koroglu C., Baysal L., Cetinkaya M., Karasoy H., Tolun A.; RT "DNAJC6 is responsible for juvenile parkinsonism with phenotypic RT variability."; RL Parkinsonism Relat. Disord. 19:320-324(2013). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT SER-570, RP INTERACTION WITH CLTC, MUTAGENESIS OF SER-570, AND PTM. RX PubMed=29735704; DOI=10.1073/pnas.1717590115; RA Nguyen M., Krainc D.; RT "LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic RT neurons from patients with Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 115:5576-5581(2018). RN [15] RP INVOLVEMENT IN PARK19B, VARIANT PARK19B GLY-870, VARIANTS LEU-76; PRO-152; RP VAL-264; SER-441 AND CYS-562, AND CHARACTERIZATION OF VARIANT PARK19B RP GLY-870. RX PubMed=26528954; DOI=10.1002/ana.24553; RG International Parkinsonism Genetics Network; RA Olgiati S., Quadri M., Fang M., Rood J.P., Saute J.A., Chien H.F., RA Bouwkamp C.G., Graafland J., Minneboo M., Breedveld G.J., Zhang J., RA Verheijen F.W., Boon A.J., Kievit A.J., Jardim L.B., Mandemakers W., RA Barbosa E.R., Rieder C.R., Leenders K.L., Wang J., Bonifati V.; RT "DNAJC6 mutations associated with early-onset Parkinson's disease."; RL Ann. Neurol. 79:244-256(2016). RN [16] RP INVOLVEMENT IN PARK19A. RX PubMed=26703368; DOI=10.1002/ana.24591; RA Elsayed L.E., Drouet V., Usenko T., Mohammed I.N., Hamed A.A., Elseed M.A., RA Salih M.A., Koko M.E., Mohamed A.Y., Siddig R.A., Elbashir M.I., RA Ibrahim M.E., Durr A., Stevanin G., Lesage S., Ahmed A.E., Brice A.; RT "A novel nonsense mutation in DNAJC6 expands the phenotype of autosomal- RT recessive juvenile-onset Parkinson's disease."; RL Ann. Neurol. 79:335-337(2016). CC -!- FUNCTION: May act as a protein phosphatase and/or a lipid phosphatase. CC Co-chaperone that recruits HSPA8/HSC70 to clathrin-coated vesicles CC (CCVs) and promotes the ATP-dependent dissociation of clathrin from CC CCVs and participates in clathrin-mediated endocytosis of synaptic CC vesicles and their recycling and also in intracellular trafficking CC (PubMed:18489706). Firstly, binds tightly to the clathrin cages, at a CC ratio of one DNAJC6 per clathrin triskelion. The HSPA8:ATP complex then CC binds to the clathrin-auxilin cage, initially at a ratio of one HSPA8 CC per triskelion leading to ATP hydrolysis stimulation and causing a CC conformational change in the HSPA8. This cycle is repeated three times CC to drive to a complex containing the clathrin-auxilin cage associated CC to three HSPA8:ADP complex. The ATP hydrolysis of the third HSPA8:ATP CC complex leads to a concerted dismantling of the cage into component CC triskelia. Then, dissociates from the released triskelia and be CC recycled to initiate another cycle of HSPA8's recruitment. Also acts CC during the early steps of clathrin-coated vesicle (CCV) formation CC through its interaction with the GTP bound form of DNM1 (By CC similarity). {ECO:0000250|UniProtKB:Q27974, CC ECO:0000269|PubMed:18489706}. CC -!- SUBUNIT: Forms a complex composed of HSPA8, CLTC and DNAJC6. Interacts CC with HSPA8/HSC70 in an ATP-dependent manner; this interaction CC stimulates the HSPA8's ATPase activity (By similarity). Interacts with CC CLTC; this interaction produces a local change in heavy-chain contacts, CC creating a detectable global distortion of the clathrin coat CC (PubMed:29735704). Interacts with AP2A2. Interacts with DNM1(GTP-bound CC form); this interaction allows clathrin-coated vesicle (CCV) formation CC at the plasma membrane (By similarity). {ECO:0000250|UniProtKB:Q27974, CC ECO:0000269|PubMed:29735704}. CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, clathrin-coated vesicle CC {ECO:0000250|UniProtKB:Q27974}. Note=Appears on coated vesicles in CC successive transient bursts, immediately after the vesicle release from CC the plasma membrane. Recruitment to clathrin-coated vesicles depends on CC temporal variations in phosphoinositide composition of clathrin-coated CC vesicles. {ECO:0000250|UniProtKB:Q27974}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=O75061-1; Sequence=Displayed; CC Name=2; CC IsoId=O75061-2; Sequence=VSP_019580; CC Name=3; CC IsoId=O75061-3; Sequence=VSP_019579, VSP_019581; CC Name=4; CC IsoId=O75061-4; Sequence=VSP_019579; CC -!- TISSUE SPECIFICITY: Expressed in various brain regions, including CC cerebellum, corpus callosum, cortex, striatum, brainstem, pons, CC putamen, spinal cord and substantia nigra. Very low expression in non- CC neural tissues such as leukocytes, liver, adipose tissue, skeletal CC muscle and bone marrow. {ECO:0000269|PubMed:23211418}. CC -!- DOMAIN: The J domain mediates interaction with HSPA8/HSC70 and is CC required for basket dissociation. {ECO:0000250|UniProtKB:Q27974}. CC -!- PTM: Phosphorylation at Ser-570 modulates its ability to bind CLTC and CC therefore the synaptic vesicle endocytosis (SVE). CC {ECO:0000269|PubMed:29735704}. CC -!- PTM: The N-terminus is blocked. {ECO:0000250|UniProtKB:Q27974}. CC -!- DISEASE: Parkinson disease 19A, juvenile-onset (PARK19A) [MIM:615528]: CC A juvenile form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability, as well as by a clinically CC significant response to treatment with levodopa. The pathology involves CC the loss of dopaminergic neurons in the substantia nigra and the CC presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. PARK19A CC is characterized by onset of parkinsonian symptoms in the first or CC second decade of life. Some patients may have additional neurologic CC features, including intellectual disability and seizures. CC {ECO:0000269|PubMed:22563501, ECO:0000269|PubMed:23211418, CC ECO:0000269|PubMed:26703368}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Parkinson disease 19B, early-onset (PARK19B) [MIM:615528]: An CC early-onset form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability, as well as by a clinically CC significant response to treatment with levodopa. The pathology involves CC the loss of dopaminergic neurons in the substantia nigra and the CC presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. PARK19B CC is characterized by symptoms onset in the third-to-fifth decade, slow CC disease progression, and prominent. response to dopaminergic therapies. CC Inheritance is autosomal recessive. {ECO:0000269|PubMed:26528954}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAA32318.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB007942; BAA32318.2; ALT_INIT; mRNA. DR EMBL; AK296408; BAH12344.1; -; mRNA. DR EMBL; AC119800; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL139294; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL355487; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL356212; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471059; EAX06533.1; -; Genomic_DNA. DR EMBL; CH471059; EAX06534.1; -; Genomic_DNA. DR EMBL; CH471059; EAX06536.1; -; Genomic_DNA. DR EMBL; CH471059; EAX06537.1; -; Genomic_DNA. DR EMBL; BC051722; AAH51722.1; -; mRNA. DR EMBL; BC109279; AAI09280.2; -; mRNA. DR EMBL; BC109280; AAI09281.2; -; mRNA. DR CCDS; CCDS30739.1; -. [O75061-1] DR CCDS; CCDS58004.1; -. [O75061-2] DR CCDS; CCDS58005.1; -. [O75061-4] DR RefSeq; NP_001243793.1; NM_001256864.2. [O75061-2] DR RefSeq; NP_001243794.1; NM_001256865.2. [O75061-4] DR RefSeq; NP_055602.1; NM_014787.4. [O75061-1] DR AlphaFoldDB; O75061; -. DR BMRB; O75061; -. DR SMR; O75061; -. DR BioGRID; 115167; 65. DR FunCoup; O75061; 1518. DR IntAct; O75061; 32. DR MINT; O75061; -. DR STRING; 9606.ENSP00000360108; -. DR DEPOD; DNAJC6; -. DR GlyGen; O75061; 2 sites. DR iPTMnet; O75061; -. DR PhosphoSitePlus; O75061; -. DR SwissPalm; O75061; -. DR BioMuta; DNAJC6; -. DR jPOST; O75061; -. DR MassIVE; O75061; -. DR PaxDb; 9606-ENSP00000360108; -. DR PeptideAtlas; O75061; -. DR ProteomicsDB; 12747; -. DR ProteomicsDB; 49731; -. [O75061-1] DR ProteomicsDB; 49732; -. [O75061-2] DR ProteomicsDB; 49733; -. [O75061-3] DR Pumba; O75061; -. DR Antibodypedia; 33368; 129 antibodies from 25 providers. DR DNASU; 9829; -. DR Ensembl; ENST00000263441.11; ENSP00000263441.7; ENSG00000116675.16. [O75061-4] DR Ensembl; ENST00000371069.5; ENSP00000360108.4; ENSG00000116675.16. [O75061-2] DR Ensembl; ENST00000395325.7; ENSP00000378735.3; ENSG00000116675.16. [O75061-1] DR GeneID; 9829; -. DR KEGG; hsa:9829; -. DR MANE-Select; ENST00000371069.5; ENSP00000360108.4; NM_001256864.2; NP_001243793.1. [O75061-2] DR UCSC; uc001dcd.3; human. [O75061-1] DR AGR; HGNC:15469; -. DR ClinPGx; PA27423; -. DR CTD; 9829; -. DR DisGeNET; 9829; -. DR GeneCards; DNAJC6; -. DR GeneReviews; DNAJC6; -. DR HGNC; HGNC:15469; DNAJC6. DR HPA; ENSG00000116675; Group enriched (brain, retina). DR MalaCards; DNAJC6; -. DR MIM; 608375; gene. DR MIM; 615528; phenotype. DR OpenTargets; ENSG00000116675; -. DR Orphanet; 391411; Atypical juvenile parkinsonism. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000116675; -. DR eggNOG; KOG0431; Eukaryota. DR eggNOG; KOG2283; Eukaryota. DR GeneTree; ENSGT00940000158755; -. DR HOGENOM; CLU_007537_1_0_1; -. DR InParanoid; O75061; -. DR OMA; XPELDAC; -. DR OrthoDB; 1717591at2759; -. DR PAN-GO; O75061; 7 GO annotations based on evolutionary models. DR PhylomeDB; O75061; -. DR PathwayCommons; O75061; -. DR Reactome; R-HSA-432720; Lysosome Vesicle Biogenesis. DR Reactome; R-HSA-432722; Golgi Associated Vesicle Biogenesis. DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis. DR SignaLink; O75061; -. DR SIGNOR; O75061; -. DR Agora; ENSG00000116675; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 9829; 12 hits in 1157 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DNAJC6; human. DR GeneWiki; Auxilin; -. DR GenomeRNAi; 9829; -. DR Pharos; O75061; Tbio. DR PRO; PR:O75061; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; O75061; protein. DR Bgee; ENSG00000116675; Expressed in endothelial cell and 153 other cell types or tissues. DR ExpressionAtlas; O75061; baseline and differential. DR GO; GO:0030136; C:clathrin-coated vesicle; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0098894; C:extrinsic component of presynaptic endocytic zone membrane; IEA:Ensembl. DR GO; GO:0014069; C:postsynaptic density; IBA:GO_Central. DR GO; GO:0031982; C:vesicle; IBA:GO_Central. DR GO; GO:0030276; F:clathrin binding; ISS:UniProtKB. DR GO; GO:0032050; F:clathrin heavy chain binding; ISS:UniProtKB. DR GO; GO:0031072; F:heat shock protein binding; ISS:UniProtKB. DR GO; GO:0004721; F:phosphoprotein phosphatase activity; IEA:UniProtKB-KW. DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW. DR GO; GO:0072318; P:clathrin coat disassembly; ISS:UniProtKB. DR GO; GO:0072583; P:clathrin-dependent endocytosis; IMP:UniProtKB. DR GO; GO:0046907; P:intracellular transport; IMP:UniProtKB. DR GO; GO:1905443; P:regulation of clathrin coat assembly; IMP:UniProtKB. DR GO; GO:2000369; P:regulation of clathrin-dependent endocytosis; IEA:Ensembl. DR GO; GO:0036465; P:synaptic vesicle recycling; ISS:UniProtKB. DR GO; GO:0016191; P:synaptic vesicle uncoating; ISS:BHF-UCL. DR CDD; cd06257; DnaJ; 1. DR CDD; cd14563; PTP_auxilin_N; 1. DR FunFam; 2.60.40.1110:FF:000001; cyclin-G-associated kinase isoform X2; 1. DR FunFam; 3.90.190.10:FF:000255; putative tyrosine-protein phosphatase auxilin; 1. DR FunFam; 1.10.287.110:FF:000002; putative tyrosine-protein phosphatase auxilin isoform X2; 1. DR Gene3D; 2.60.40.1110; -; 1. DR Gene3D; 1.10.287.110; DnaJ domain; 1. DR Gene3D; 3.90.190.10; Protein tyrosine phosphatase superfamily; 1. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR001623; DnaJ_domain. DR InterPro; IPR036869; J_dom_sf. DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like. DR InterPro; IPR014020; Tensin_C2-dom. DR InterPro; IPR029023; Tensin_phosphatase. DR InterPro; IPR000387; Tyr_Pase_dom. DR PANTHER; PTHR23172; AUXILIN/CYCLIN G-ASSOCIATED KINASE-RELATED; 1. DR PANTHER; PTHR23172:SF4; TYROSINE-PROTEIN PHOSPHATASE AUXILIN-RELATED; 1. DR Pfam; PF10409; PTEN_C2; 1. DR SMART; SM00271; DnaJ; 1. DR SMART; SM01326; PTEN_C2; 1. DR SUPFAM; SSF52799; (Phosphotyrosine protein) phosphatases II; 1. DR SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 1. DR SUPFAM; SSF46565; Chaperone J-domain; 1. DR PROSITE; PS51182; C2_TENSIN; 1. DR PROSITE; PS50076; DNAJ_2; 1. DR PROSITE; PS51181; PPASE_TENSIN; 1. DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Chaperone; Cytoplasmic vesicle; KW Disease variant; Hydrolase; Neurodegeneration; Parkinson disease; KW Parkinsonism; Phosphoprotein; Protein phosphatase; KW Proteomics identification; Reference proteome; Repeat; SH3-binding. FT CHAIN 1..913 FT /note="Auxilin" FT /id="PRO_0000244516" FT REPEAT 36..39 FT /note="1" FT REPEAT 40..43 FT /note="2" FT REPEAT 44..47 FT /note="3" FT DOMAIN 55..222 FT /note="Phosphatase tensin-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00590" FT DOMAIN 228..366 FT /note="C2 tensin-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00589" FT DOMAIN 849..913 FT /note="J" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00286" FT REGION 36..47 FT /note="3 X 4 AA approximate tandem repeats" FT REGION 451..776 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 409..417 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT COMPBIAS 506..523 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 554..572 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 599..629 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 654..669 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 164 FT /note="Phosphocysteine intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00590" FT MOD_RES 112 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 453 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q80TZ3" FT MOD_RES 456 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q80TZ3" FT MOD_RES 563 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 570 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29735704, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..13 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_019579" FT VAR_SEQ 1..7 FT /note="MKDSENK -> MSLLGSYRKKTSNDGYESLQLVDSNGDLSAGSGGVGGKQRV FT NAGAAARSPARQPPDRASTMDSS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_019580" FT VAR_SEQ 456..913 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_019581" FT VARIANT 76 FT /note="M -> L (in dbSNP:rs61757223)" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077924" FT VARIANT 152 FT /note="L -> P" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077925" FT VARIANT 264 FT /note="I -> V" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077926" FT VARIANT 441 FT /note="C -> S (in dbSNP:rs145329294)" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077927" FT VARIANT 562 FT /note="R -> C (in dbSNP:rs770127313)" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077928" FT VARIANT 671 FT /note="S -> N (in dbSNP:rs4915691)" FT /id="VAR_026908" FT VARIANT 870 FT /note="R -> G (in PARK19B; patient fibroblasts show FT decreased levels of the protein; dbSNP:rs879255630)" FT /evidence="ECO:0000269|PubMed:26528954" FT /id="VAR_077929" FT MUTAGEN 570 FT /note="S->A: Increase interaction with CLTC. Does not FT affect interaction with HSPA8." FT /evidence="ECO:0000269|PubMed:29735704" FT MUTAGEN 570 FT /note="S->D: Does not affect interaction with CLTC. Does FT not affect interaction with HSPA8." FT /evidence="ECO:0000269|PubMed:29735704" FT CONFLICT 178 FT /note="M -> V (in Ref. 2; BAH12344)" FT /evidence="ECO:0000305" FT CONFLICT 425 FT /note="F -> S (in Ref. 5; AAH51722)" FT /evidence="ECO:0000305" FT MOD_RES O75061-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES O75061-4:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 913 AA; 99997 MW; 7B7187AAC8ADF2E4 CRC64; MKDSENKGAS SPDMEPSYGG GLFDMVKGGA GRLFSNLKDN LKDTLKDTSS RVIQSVTSYT KGDLDFTYVT SRIIVMSFPL DNVDIGFRNQ VDDIRSFLDS RHLDHYTVYN LSPKSYRTAK FHSRVSECSW PIRQAPSLHN LFAVCRNMYN WLLQNPKNVC VVHCLDGRAA SSILVGAMFI FCNLYSTPGP AIRLLYAKRP GIGLSPSHRR YLGYMCDLLA DKPYRPHFKP LTIKSITVSP IPFFNKQRNG CRPYCDVLIG ETKIYSTCTD FERMKEYRVQ DGKIFIPLNI TVQGDVVVSM YHLRSTIGSR LQAKVTNTQI FQLQFHTGFI PLDTTVLKFT KPELDACDVP EKYPQLFQVT LDVELQPHDK VIDLTPPWEH YCTKDVNPSI LFSSHQEHQD TLALGGQAPI DIPPDNPRHY GQSGFFASLC WQDQKSEKSF CEEDHAALVN QESEQSDDEL LTLSSPHGNA NGDKPHGVKK PSKKQQEPAA PPPPEDVDLL GLEGSAMSNS FSPPAAPPTN SELLSDLFGG GGAAGPTQAG QSGVEDVFHP SGPASTQSTP RRSATSTSAS PTLRVGEGAT FDPFGAPSKP SGQDLLGSFL NTSSASSDPF LQPTRSPSPT VHASSTPAVN IQPDVSGGWD WHAKPGGFGM GSKSAATSPT GSSHGTPTHQ SKPQTLDPFA DLGTLGSSSF ASKPTTPTGL GGGFPPLSSP QKASPQPMGG GWQQGGAYNW QQPQPKPQPS MPHSSPQNRP NYNVSFSAMP GGQNERGKGS SNLEGKQKAA DFEDLLSGQG FNAHKDKKGP RTIAEMRKEE MAKEMDPEKL KILEWIEGKE RNIRALLSTM HTVLWAGETK WKPVGMADLV TPEQVKKVYR KAVLVVHPDK ATGQPYEQYA KMIFMELNDA WSEFENQGQK PLY // ID CHCH2_HUMAN Reviewed; 151 AA. AC Q9Y6H1; Q498C3; Q6NZ50; DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 167. DE RecName: Full=Coiled-coil-helix-coiled-coil-helix domain-containing protein 2; DE AltName: Full=Aging-associated gene 10 protein; DE AltName: Full=HCV NS2 trans-regulated protein; DE Short=NS2TP; GN Name=CHCHD2; Synonyms=C7orf17; ORFNames=AAG10; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Pituitary; RA Peng Y., Song H., Dai M., Huang Q., Mao Y., Zhang Q., Mao M., Fu G., RA Luo M., Chen J., Hu R.; RT "Human 16.7Kd protein, complete cds."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Zhang L.-Y., Cheng J., Deng H., Liu Y., Wang L.; RT "Cloning and identification of gene NS2TP transregulated by non-structural RT protein 2 of hepatitis C virus."; RL Shi Jie Hua Ren Xiao Hua Za Zhi 13:1700-1704(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kim J.W.; RT "Identification of a human aging-associated gene."; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Colon, Lung, and PNS; 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [7] RP FUNCTION IN COX4I2 TRANSCRIPTION, INTERACTION WITH RBPJ, SUBCELLULAR RP LOCATION, AND INDUCTION BY HYPOXIA. RX PubMed=23303788; DOI=10.1093/nar/gks1454; RA Aras S., Pak O., Sommer N., Finley R. Jr., Huttemann M., Weissmann N., RA Grossman L.I.; RT "Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene RT expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2."; RL Nucleic Acids Res. 41:2255-2266(2013). RN [8] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK22, VARIANTS PARK22 ILE-61 AND RP GLN-145, AND CHARACTERIZATION OF VARIANTS PARK22 ILE-61 AND GLN-145. RX PubMed=25662902; DOI=10.1016/s1474-4422(14)70266-2; RA Funayama M., Ohe K., Amo T., Furuya N., Yamaguchi J., Saiki S., Li Y., RA Ogaki K., Ando M., Yoshino H., Tomiyama H., Nishioka K., Hasegawa K., RA Saiki H., Satake W., Mogushi K., Sasaki R., Kokubo Y., Kuzuhara S., RA Toda T., Mizuno Y., Uchiyama Y., Ohno K., Hattori N.; RT "CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a RT genome-wide linkage and sequencing study."; RL Lancet Neurol. 14:274-282(2015). RN [9] RP CORRESPONDENCE ON INVOLVEMENT OF CHCHD2 IN PARKINSON'S DISEASE. RX PubMed=26067113; DOI=10.1016/s1474-4422(15)00096-4; RA Iqbal Z., Toft M.; RT "CHCHD2 and Parkinson's disease."; RL Lancet Neurol. 14:680-681(2015). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [11] RP VARIANTS LEU-2; ARG-4; SER-14; LEU-34; VAL-37; VAL-49 AND VAL-93. RX PubMed=26561290; DOI=10.1212/wnl.0000000000002170; RA Ogaki K., Koga S., Heckman M.G., Fiesel F.C., Ando M., Labbe C., RA Lorenzo-Betancor O., Moussaud-Lamodiere E.L., Soto-Ortolaza A.I., RA Walton R.L., Strongosky A.J., Uitti R.J., McCarthy A., Lynch T., Siuda J., RA Opala G., Rudzinska M., Krygowska-Wajs A., Barcikowska M., Czyzewski K., RA Puschmann A., Nishioka K., Funayama M., Hattori N., Parisi J.E., RA Petersen R.C., Graff-Radford N.R., Boeve B.F., Springer W., Wszolek Z.K., RA Dickson D.W., Ross O.A.; RT "Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk RT for Lewy body disorders."; RL Neurology 85:2016-2025(2015). CC -!- FUNCTION: Transcription factor. Binds to the oxygen responsive element CC of COX4I2 and activates its transcription under hypoxia conditions (4% CC oxygen), as well as normoxia conditions (20% oxygen) (PubMed:23303788). CC {ECO:0000269|PubMed:23303788}. CC -!- SUBUNIT: Interacts with RBPJ. {ECO:0000269|PubMed:23303788}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:23303788}. CC Mitochondrion {ECO:0000269|PubMed:25662902}. Mitochondrion CC intermembrane space {ECO:0000269|PubMed:25662902}. Note=Mainly CC localized in the intermembrane space. {ECO:0000269|PubMed:25662902}. CC -!- INDUCTION: Up-regulated by hypoxia (4% oxygen) (at protein level). CC {ECO:0000269|PubMed:23303788}. CC -!- POLYMORPHISM: Mutations in CHCHD2 are rare, and might vary by ethnic CC origin. {ECO:0000269|PubMed:26067113, ECO:0000269|PubMed:26561290}. CC -!- DISEASE: Parkinson disease 22 (PARK22) [MIM:616710]: An autosomal CC dominant form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability, as well as by a clinically CC significant response to treatment with levodopa. The pathology involves CC the loss of dopaminergic neurons in the substantia nigra and the CC presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. CC {ECO:0000269|PubMed:25662902}. Note=The gene represented in this entry CC may be involved in disease pathogenesis. 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; AY605046; AAT35813.1; -; mRNA. DR EMBL; AF078845; AAD44477.1; -; mRNA. DR EMBL; AY633613; AAV33306.1; -; mRNA. DR EMBL; AC006970; AAQ96886.1; -; Genomic_DNA. DR EMBL; BC003079; AAH03079.1; -; mRNA. DR EMBL; BC015639; AAH15639.1; -; mRNA. DR EMBL; BC066331; AAH66331.1; -; mRNA. DR EMBL; BC071985; AAH71985.1; -; mRNA. DR EMBL; BC100275; AAI00276.1; -; mRNA. DR CCDS; CCDS5526.1; -. DR RefSeq; NP_057223.1; NM_016139.4. DR PDB; 9OYR; EM; 2.03 A; A/B/C/E/F/G=1-114. DR PDB; 9OYT; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=1-114. DR PDBsum; 9OYR; -. DR PDBsum; 9OYT; -. DR AlphaFoldDB; Q9Y6H1; -. DR EMDB; EMD-71032; -. DR EMDB; EMD-71034; -. DR SMR; Q9Y6H1; -. DR BioGRID; 119326; 261. DR FunCoup; Q9Y6H1; 1819. DR MINT; Q9Y6H1; -. DR STRING; 9606.ENSP00000378812; -. DR iPTMnet; Q9Y6H1; -. DR PhosphoSitePlus; Q9Y6H1; -. DR BioMuta; CHCHD2; -. DR DMDM; 62510521; -. DR jPOST; Q9Y6H1; -. DR MassIVE; Q9Y6H1; -. DR PaxDb; 9606-ENSP00000378812; -. DR PeptideAtlas; Q9Y6H1; -. DR ProteomicsDB; 86678; -. DR Pumba; Q9Y6H1; -. DR TopDownProteomics; Q9Y6H1; -. DR Antibodypedia; 44807; 140 antibodies from 27 providers. DR DNASU; 51142; -. DR Ensembl; ENST00000395422.4; ENSP00000378812.3; ENSG00000106153.15. DR GeneID; 51142; -. DR KEGG; hsa:51142; -. DR MANE-Select; ENST00000395422.4; ENSP00000378812.3; NM_016139.4; NP_057223.1. DR UCSC; uc003tsa.4; human. DR AGR; HGNC:21645; -. DR ClinPGx; PA134974636; -. DR CTD; 51142; -. DR DisGeNET; 51142; -. DR GeneCards; CHCHD2; -. DR HGNC; HGNC:21645; CHCHD2. DR HPA; ENSG00000106153; Low tissue specificity. DR MalaCards; CHCHD2; -. DR MIM; 616244; gene. DR MIM; 616710; phenotype. DR OpenTargets; ENSG00000106153; -. DR VEuPathDB; HostDB:ENSG00000106153; -. DR eggNOG; KOG4090; Eukaryota. DR GeneTree; ENSGT00440000038159; -. DR HOGENOM; CLU_093520_2_2_1; -. DR InParanoid; Q9Y6H1; -. DR OMA; CDADARN; -. DR OrthoDB; 1106148at2759; -. DR PAN-GO; Q9Y6H1; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y6H1; -. DR PathwayCommons; Q9Y6H1; -. DR Reactome; R-HSA-1268020; Mitochondrial protein import. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR SignaLink; Q9Y6H1; -. DR Agora; ENSG00000106153; -. DR BioGRID-ORCS; 51142; 119 hits in 1157 CRISPR screens. DR ChiTaRS; CHCHD2; human. DR GenomeRNAi; 51142; -. DR Pharos; Q9Y6H1; Tbio. DR PRO; PR:Q9Y6H1; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q9Y6H1; protein. DR Bgee; ENSG00000106153; Expressed in right adrenal gland cortex and 146 other cell types or tissues. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IDA:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0034599; P:cellular response to oxidative stress; IGI:FlyBase. DR GO; GO:0007005; P:mitochondrion organization; IBA:GO_Central. DR GO; GO:1905448; P:positive regulation of mitochondrial ATP synthesis coupled electron transport; IGI:FlyBase. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:1900037; P:regulation of cellular response to hypoxia; IDA:UniProtKB. DR GO; GO:0043467; P:regulation of generation of precursor metabolites and energy; IDA:UniProtKB. DR InterPro; IPR010625; CHCH. DR InterPro; IPR055304; CHCHD2/10-like. DR PANTHER; PTHR13523; COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN CONTAINING 2/NUR77; 1. DR PANTHER; PTHR13523:SF3; COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 2-RELATED; 1. DR Pfam; PF06747; CHCH; 1. DR PROSITE; PS51808; CHCH; 1. PE 1: Evidence at protein level; KW 3D-structure; Activator; Disulfide bond; Mitochondrion; Neurodegeneration; KW Nucleus; Parkinson disease; Parkinsonism; Proteomics identification; KW Reference proteome; Transcription. FT CHAIN 1..151 FT /note="Coiled-coil-helix-coiled-coil-helix domain- FT containing protein 2" FT /id="PRO_0000129160" FT DOMAIN 111..151 FT /note="CHCH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01150" FT REGION 1..50 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 77..111 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 114..124 FT /note="Cx9C motif 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01150" FT MOTIF 134..144 FT /note="Cx9C motif 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01150" FT COMPBIAS 10..26 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 27..38 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 39..50 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 100..111 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT DISULFID 114..144 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01150" FT DISULFID 124..134 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01150" FT VARIANT 2 FT /note="P -> L (may influence risk for Lewy body disorders; FT dbSNP:rs142444896)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076293" FT VARIANT 4 FT /note="G -> R (may influence risk for Lewy body disorders; FT dbSNP:rs778328496)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076294" FT VARIANT 14 FT /note="P -> S (may influence risk for Lewy body disorders; FT dbSNP:rs137965562)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076295" FT VARIANT 34 FT /note="P -> L (may influence risk for Lewy body disorders; FT dbSNP:rs371198317)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076296" FT VARIANT 37 FT /note="A -> V (may influence risk for Lewy body disorders; FT dbSNP:rs1427631250)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076297" FT VARIANT 49 FT /note="A -> V (may influence risk for Lewy body disorders; FT dbSNP:rs151213700)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076298" FT VARIANT 61 FT /note="T -> I (in PARK22; does not affect subcellular FT location; dbSNP:rs864309650)" FT /evidence="ECO:0000269|PubMed:25662902" FT /id="VAR_076299" FT VARIANT 78 FT /note="H -> N (in dbSNP:rs11546418)" FT /id="VAR_048699" FT VARIANT 93 FT /note="A -> V (may influence risk for Lewy body disorders; FT dbSNP:rs748182315)" FT /evidence="ECO:0000269|PubMed:26561290" FT /id="VAR_076300" FT VARIANT 145 FT /note="R -> Q (in PARK22; uncertain significance; does not FT affect subcellular location; dbSNP:rs752169833)" FT /evidence="ECO:0000269|PubMed:25662902" FT /id="VAR_076301" FT CONFLICT 54 FT /note="G -> V (in Ref. 5; AAH66331)" FT /evidence="ECO:0000305" SQ SEQUENCE 151 AA; 15513 MW; 5403662D8DB4FB86 CRC64; MPRGSRSRTS RMAPPASRAP QMRAAPRPAP VAQPPAAAPP SAVGSSAAAP RQPGLMAQMA TTAAGVAVGS AVGHTLGHAI TGGFSGGSNA EPARPDITYQ EPQGTQPAQQ QQPCLYEIKQ FLECAQNQGD IKLCEGFNEV LKQCRLANGL A // ID DJC13_HUMAN Reviewed; 2243 AA. AC O75165; Q3L0T1; Q6PI82; Q6UJ77; Q6ZSW1; Q6ZUT5; Q86XG3; Q96DC1; Q9BWK9; DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 5. DT 28-JAN-2026, entry version 193. DE RecName: Full=DnaJ homolog subfamily C member 13; DE AltName: Full=Required for receptor-mediated endocytosis 8; DE Short=RME-8; GN Name=DNAJC13; Synonyms=KIAA0678, RME8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=16179350; DOI=10.1074/jbc.m505036200; RA Girard M., Poupon V., Blondeau F., McPherson P.S.; RT "The DnaJ-domain protein RME-8 functions in endosomal trafficking."; RL J. Biol. Chem. 280:40135-40143(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-1463. RC TISSUE=Brain; RX PubMed=9734811; DOI=10.1093/dnares/5.3.169; RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., RA Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. X. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:169-176(1998). RN [3] RP SEQUENCE REVISION. RC TISSUE=Aortic endothelium; RA Ohara O., Nagase T., Kikuno R., Ishikawa K., Suyama M.; RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-736 AND 1819-2243. RC TISSUE=Cervix, Placenta, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 617-2243, AND VARIANT SER-1463. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 672-1098. RA Chang H.C., Hull M.J., Mellman I.; RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases. RN [8] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=18256511; DOI=10.1247/csf.07045; RA Fujibayashi A., Taguchi T., Misaki R., Ohtani M., Dohmae N., Takio K., RA Yamada M., Gu J., Yamakami M., Fukuda M., Waguri S., Uchiyama Y., RA Yoshimori T., Sekiguchi K.; RT "Human RME-8 is involved in membrane trafficking through early endosomes."; RL Cell Struct. Funct. 33:35-50(2008). RN [9] RP FUNCTION. RX PubMed=18307993; DOI=10.1016/j.febslet.2008.02.042; RA Girard M., McPherson P.S.; RT "RME-8 regulates trafficking of the epidermal growth factor receptor."; RL FEBS Lett. 582:961-966(2008). RN [10] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-84, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP POSSIBLE INVOLVEMENT IN PARK, VARIANT PARK SER-855, VARIANTS GLN-264; RP ILE-1082 AND LEU-2115, AND CHARACTERIZATION OF VARIANT PARK SER-855. RX PubMed=24218364; DOI=10.1093/hmg/ddt570; RA Vilarino-Guell C., Rajput A., Milnerwood A.J., Shah B., Szu-Tu C., RA Trinh J., Yu I., Encarnacion M., Munsie L.N., Tapia L., Gustavsson E.K., RA Chou P., Tatarnikov I., Evans D.M., Pishotta F.T., Volta M., RA Beccano-Kelly D., Thompson C., Lin M.K., Sherman H.E., Han H.J., RA Guenther B.L., Wasserman W.W., Bernard V., Ross C.J., Appel-Cresswell S., RA Stoessl A.J., Robinson C.A., Dickson D.W., Ross O.A., Wszolek Z.K., RA Aasly J.O., Wu R.M., Hentati F., Gibson R.A., McPherson P.S., Girard M., RA Rajput M., Rajput A.H., Farrer M.J.; RT "DNAJC13 mutations in Parkinson disease."; RL Hum. Mol. Genet. 23:1794-1801(2014). RN [13] RP FUNCTION, INTERACTION WITH WASHC2C, AND SUBCELLULAR LOCATION. RX PubMed=24643499; DOI=10.1242/jcs.144659; RA Freeman C.L., Hesketh G., Seaman M.N.; RT "RME-8 coordinates the activity of the WASH complex with the function of RT the retromer SNX dimer to control endosomal tubulation."; RL J. Cell Sci. 127:2053-2070(2014). RN [14] RP POSSIBLE INVOLVEMENT IN PARK, VARIANTS SER-556; ALA-674; LYS-903; PHE-997; RP SER-1135; GLY-1291; HIS-1516; GLN-1740; SER-2057 AND TRP-2170, AND VARIANTS RP PARK LEU-722; SER-855; GLN-1266 AND MET-1895. RX PubMed=25393719; DOI=10.1002/mds.26064; RA Gustavsson E.K., Trinh J., Guella I., Vilarino-Gueell C., RA Appel-Cresswell S., Stoessl A.J., Tsui J.K., McKeown M., Rajput A., RA Rajput A.H., Aasly J.O., Farrer M.J.; RT "DNAJC13 genetic variants in parkinsonism."; RL Mov. Disord. 30:273-278(2015). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP DISCUSSION ON POSSIBLE INVOLVEMENT IN PARK. RX PubMed=27270108; DOI=10.1038/ng.3589; RA Deng H.X., Shi Y., Yang Y., Ahmeti K.B., Miller N., Huang C., Cheng L., RA Zhai H., Deng S., Nuytemans K., Corbett N.J., Kim M.J., Deng H., Tang B., RA Yang Z., Xu Y., Chan P., Huang B., Gao X.P., Song Z., Liu Z., Fecto F., RA Siddique N., Foroud T., Jankovic J., Ghetti B., Nicholson D.A., Krainc D., RA Melen O., Vance J.M., Pericak-Vance M.A., Ma Y.C., Rajput A.H., RA Siddique T.; RT "Identification of TMEM230 mutations in familial Parkinson's disease."; RL Nat. Genet. 48:733-739(2016). CC -!- FUNCTION: Involved in membrane trafficking through early endosomes, CC such as the early endosome to recycling endosome transport implicated CC in the recycling of transferrin and the early endosome to late endosome CC transport implicated in degradation of EGF and EGFR (PubMed:18256511, CC PubMed:18307993). Involved in the regulation of endosomal membrane CC tubulation and regulates the dynamics of SNX1 on the endosomal CC membrane; via association with WASHC2 may link the WASH complex to the CC retromer SNX-BAR subcomplex (PubMed:24643499). CC {ECO:0000269|PubMed:18256511, ECO:0000269|PubMed:18307993, CC ECO:0000269|PubMed:24643499}. CC -!- SUBUNIT: Interacts with WASHC2C; mediates the association with the WASH CC complex (PubMed:24643499). {ECO:0000269|PubMed:24643499}. CC -!- INTERACTION: CC O75165; O15126: SCAMP1; NbExp=3; IntAct=EBI-4324603, EBI-954338; CC -!- SUBCELLULAR LOCATION: Early endosome {ECO:0000269|PubMed:18256511}. CC Early endosome membrane {ECO:0000305}; Peripheral membrane protein CC {ECO:0000269|PubMed:18256511}. Endosome membrane CC {ECO:0000269|PubMed:24643499}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:24218364, CC ECO:0000269|PubMed:25393719}. Note=The gene represented in this entry CC may be involved in disease pathogenesis. Genetic variants in DNAJC13 CC (PubMed:24218364, PubMed:25393719) and TMEM230 (PubMed:27270108) have CC been found in the same large multigenerational family with adult-onset CC Parkinson disease. The pathological role of each gene and therefore the CC exact molecular basis of the disease is unclear. CC {ECO:0000305|PubMed:27270108}. CC -!- CAUTION: In human, WASHC2 has undergone evolutionary duplication giving CC rise to highly homologous family members. A WASHC2C construct with CC WASHC2A-specific sequence insertions (of 2 aa and 21 aa length CC resulting in a construct length of 1341 aa similar to WASHC2A length) CC has been used to demonstrate the interaction with WASHC2 CC (PubMed:24643499). {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH43583.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305}; CC Sequence=BAA31653.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86133.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86835.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAC86835.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY779857; AAV41096.1; -; mRNA. DR EMBL; AB014578; BAA31653.2; ALT_INIT; mRNA. DR EMBL; AC020632; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC020633; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC026374; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000164; AAH00164.2; -; mRNA. DR EMBL; BC009630; AAH09630.1; -; mRNA. DR EMBL; BC040638; AAH40638.1; -; mRNA. DR EMBL; BC043583; AAH43583.1; ALT_SEQ; mRNA. DR EMBL; AK125330; BAC86133.1; ALT_INIT; mRNA. DR EMBL; AK127112; BAC86835.1; ALT_SEQ; mRNA. DR EMBL; AY369172; AAQ57271.1; -; mRNA. DR CCDS; CCDS33857.1; -. DR PIR; T00361; T00361. DR RefSeq; NP_056083.3; NM_015268.4. DR RefSeq; XP_047303776.1; XM_047447820.1. DR AlphaFoldDB; O75165; -. DR SMR; O75165; -. DR BioGRID; 116908; 171. DR FunCoup; O75165; 4068. DR IntAct; O75165; 105. DR MINT; O75165; -. DR STRING; 9606.ENSP00000260818; -. DR GlyGen; O75165; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site). DR iPTMnet; O75165; -. DR MetOSite; O75165; -. DR PhosphoSitePlus; O75165; -. DR SwissPalm; O75165; -. DR BioMuta; DNAJC13; -. DR jPOST; O75165; -. DR MassIVE; O75165; -. DR PaxDb; 9606-ENSP00000260818; -. DR PeptideAtlas; O75165; -. DR ProteomicsDB; 49830; -. DR Pumba; O75165; -. DR Antibodypedia; 51566; 43 antibodies from 19 providers. DR Ensembl; ENST00000260818.11; ENSP00000260818.6; ENSG00000138246.17. DR GeneID; 23317; -. DR KEGG; hsa:23317; -. DR MANE-Select; ENST00000260818.11; ENSP00000260818.6; NM_015268.4; NP_056083.3. DR UCSC; uc003eor.4; human. DR AGR; HGNC:30343; -. DR ClinPGx; PA134947358; -. DR CTD; 23317; -. DR DisGeNET; 23317; -. DR GeneCards; DNAJC13; -. DR HGNC; HGNC:30343; DNAJC13. DR HPA; ENSG00000138246; Low tissue specificity. DR MalaCards; DNAJC13; -. DR MIM; 168600; phenotype. DR MIM; 614334; gene. DR OpenTargets; ENSG00000138246; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000138246; -. DR eggNOG; KOG1789; Eukaryota. DR GeneTree; ENSGT00390000017582; -. DR HOGENOM; CLU_001238_1_0_1; -. DR InParanoid; O75165; -. DR OMA; PQTYSIC; -. DR OrthoDB; 69656at2759; -. DR PAN-GO; O75165; 2 GO annotations based on evolutionary models. DR PhylomeDB; O75165; -. DR PathwayCommons; O75165; -. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; O75165; -. DR Agora; ENSG00000138246; -. DR BioGRID-ORCS; 23317; 78 hits in 1161 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DNAJC13; human. DR GeneWiki; DNAJC13; -. DR GenomeRNAi; 23317; -. DR Pharos; O75165; Tbio. DR PRO; PR:O75165; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; O75165; protein. DR Bgee; ENSG00000138246; Expressed in calcaneal tendon and 209 other cell types or tissues. DR ExpressionAtlas; O75165; baseline and differential. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome. DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB. DR GO; GO:0001649; P:osteoblast differentiation; HDA:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0006898; P:receptor-mediated endocytosis; IBA:GO_Central. DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; IMP:UniProtKB. DR GO; GO:1902954; P:regulation of early endosome to recycling endosome transport; IMP:UniProtKB. DR CDD; cd06257; DnaJ; 1. DR FunFam; 1.10.287.110:FF:000007; DnaJ (Hsp40) homolog, subfamily C, member 13; 1. DR FunFam; 1.25.10.10:FF:000133; DnaJ heat shock protein family (Hsp40) member C13; 1. DR FunFam; 1.25.10.10:FF:000072; dnaJ homolog subfamily C member 13 isoform X2; 1. DR Gene3D; 1.10.287.110; DnaJ domain; 1. DR Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 2. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR001623; DnaJ_domain. DR InterPro; IPR044978; GRV2/DNAJC13. DR InterPro; IPR045802; GRV2/DNAJC13_N. DR InterPro; IPR035445; GYF-like_dom_sf. DR InterPro; IPR025640; GYF_2. DR InterPro; IPR036869; J_dom_sf. DR PANTHER; PTHR36983; DNAJ HOMOLOG SUBFAMILY C MEMBER 13; 1. DR PANTHER; PTHR36983:SF2; DNAJ HOMOLOG SUBFAMILY C MEMBER 13; 1. DR Pfam; PF00226; DnaJ; 1. DR Pfam; PF14237; GYF_2; 1. DR Pfam; PF19432; RME-8_N; 1. DR SMART; SM00271; DnaJ; 1. DR SUPFAM; SSF48371; ARM repeat; 3. DR SUPFAM; SSF46565; Chaperone J-domain; 1. DR SUPFAM; SSF55277; GYF domain; 1. DR PROSITE; PS50076; DNAJ_2; 1. PE 1: Evidence at protein level; KW Acetylation; Chaperone; Disease variant; Endosome; Membrane; KW Neurodegeneration; Parkinson disease; Parkinsonism; Protein transport; KW Proteomics identification; Reference proteome; Transport. FT CHAIN 1..2243 FT /note="DnaJ homolog subfamily C member 13" FT /id="PRO_0000071072" FT DOMAIN 1301..1366 FT /note="J" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00286" FT REGION 1..453 FT /note="Involved in membrane association" FT /evidence="ECO:0000269|PubMed:18256511" FT MOD_RES 84 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT VARIANT 264 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073784" FT VARIANT 556 FT /note="L -> S (in dbSNP:rs749000301)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076716" FT VARIANT 674 FT /note="D -> A (in dbSNP:rs199541720)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076717" FT VARIANT 722 FT /note="V -> L (in PARK; uncertain significance; FT dbSNP:rs146930051)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076718" FT VARIANT 855 FT /note="N -> S (in PARK; uncertain significance; affects FT regulation of endosomal membrane trafficking as indicated FT by accumulation of transferrin in endosomal compartments; FT dbSNP:rs387907571)" FT /evidence="ECO:0000269|PubMed:24218364, FT ECO:0000269|PubMed:25393719" FT /id="VAR_073785" FT VARIANT 903 FT /note="R -> K (in dbSNP:rs141952333)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076719" FT VARIANT 997 FT /note="L -> F (in dbSNP:rs752189478)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076720" FT VARIANT 1082 FT /note="T -> I (in dbSNP:rs202127368)" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073786" FT VARIANT 1135 FT /note="N -> S (in dbSNP:rs751747947)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076721" FT VARIANT 1266 FT /note="R -> Q (in PARK; uncertain significance; FT dbSNP:rs766013346)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076722" FT VARIANT 1291 FT /note="E -> G (in dbSNP:rs61748101)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076723" FT VARIANT 1463 FT /note="A -> S (in dbSNP:rs3762672)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:9734811" FT /id="VAR_047458" FT VARIANT 1487 FT /note="F -> C (in dbSNP:rs4405917)" FT /id="VAR_047459" FT VARIANT 1515 FT /note="P -> S (in dbSNP:rs55825559)" FT /id="VAR_061144" FT VARIANT 1516 FT /note="R -> H (in dbSNP:rs139620588)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076724" FT VARIANT 1740 FT /note="E -> Q (in dbSNP:rs142160751)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076725" FT VARIANT 1895 FT /note="T -> M (in PARK; uncertain significance; FT dbSNP:rs145242123)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076726" FT VARIANT 1995 FT /note="V -> I (in dbSNP:rs10935014)" FT /id="VAR_047460" FT VARIANT 2057 FT /note="A -> S (in dbSNP:rs138693725)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076727" FT VARIANT 2115 FT /note="R -> L (in dbSNP:rs770715465)" FT /evidence="ECO:0000269|PubMed:24218364" FT /id="VAR_073787" FT VARIANT 2170 FT /note="L -> W (in dbSNP:rs140537885)" FT /evidence="ECO:0000269|PubMed:25393719" FT /id="VAR_076728" FT CONFLICT 476 FT /note="D -> E (in Ref. 2; BAA31653)" FT /evidence="ECO:0000305" FT CONFLICT 562 FT /note="N -> D (in Ref. 5; AAH43583)" FT /evidence="ECO:0000305" FT CONFLICT 1097 FT /note="I -> T (in Ref. 6; BAC86133)" FT /evidence="ECO:0000305" FT CONFLICT 1148 FT /note="T -> I (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 1227 FT /note="Q -> H (in Ref. 2; BAA31653)" FT /evidence="ECO:0000305" FT CONFLICT 1230 FT /note="T -> A (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 1269 FT /note="D -> N (in Ref. 6; BAC86133)" FT /evidence="ECO:0000305" FT CONFLICT 2041 FT /note="L -> P (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" FT CONFLICT 2091 FT /note="T -> A (in Ref. 6; BAC86835)" FT /evidence="ECO:0000305" SQ SEQUENCE 2243 AA; 254415 MW; C6D292837DE1F170 CRC64; MNIIRENKDL ACFYTTKHSW RGKYKRVFSV GTHAITTYNP NTLEVTNQWP YGDICSISPV GKGQGTEFNL TFRKGSGKKS ETLKFSTEHR TELLTEALRF RTDFSEGKIT GRRYNCYKHH WSDSRKPVIL EVTPGGFDQI NPATNRVLCS YDYRNIEGFV DLSDYQGGFC ILYGGFSRLH LFASEQREEI IKSAIDHAGN YIGISLRIRK EPLEFEQYLN LRFGKYSTDE SITSLAEFVV QKISPRHSEP VKRVLALTET CLVERDPATY NIATLKPLGE VFALVCDSEN PQLFTIEFIK GQVRKYSSTE RDSLLASLLD GVRASGNRDV CVKMTPTHKG QRWGLLSMPV DEEVESLHLR FLATPPNGNF ADAVFRFNAN ISYSGVLHAV TQDGLFSENK EKLINNAITA LLSQEGDVVA SNAELESQFQ AVRRLVASKA GFLAFTQLPK FRERLGVKVV KALKRSNNGI IHAAVDMLCA LMCPMHDDYD LRQEQLNKAS LLSSKKFLEN LLEKFNSHVD HGTGALVISS LLDFLTFALC APYSETTEGQ QFDMLLEMVA SNGRTLFKLF QHPSMAIIKG AGLVMKAIIE EGDKEIATKM QELALSEGAL PRHLHTAMFT ISSDQRMLTN RQLSRHLVGL WTADNATATN LLKRILPPGL LAYLESSDLV PEKDADRMHV RDNVKIAMDQ YGKFNKVPEW QRLAGKAAKE VEKFAKEKVD LVLMHWRDRM GIAQKENINQ KPVVLRKRRQ RIKIEANWDL FYYRFGQDHA RSNLIWNFKT REELKDTLES EMRAFNIDRE LGSANVISWN HHEFEVKYEC LAEEIKIGDY YLRLLLEEDE NEESGSIKRS YEFFNELYHR FLLTPKVNMK CLCLQALAIV YGRCHEEIGP FTDTRYIIGM LERCTDKLER DRLILFLNKL ILNKKNVKDL MDSNGIRILV DLLTLAHLHV SRATVPLQSN VIEAAPDMKR ESEKEWYFGN ADKERSGPYG FHEMQELWTK GMLNAKTRCW AQGMDGWRPL QSIPQLKWCL LASGQAVLNE TDLATLILNM LITMCGYFPS RDQDNAIIRP LPKVKRLLSD STCLPHIIQL LLTFDPILVE KVAILLYHIM QDNPQLPRLY LSGVFFFIMM YTGSNVLPVA RFLKYTHTKQ AFKSEETKGQ DIFQRSILGH ILPEAMVCYL ENYEPEKFSE IFLGEFDTPE AIWSSEMRRL MIEKIAAHLA DFTPRLQSNT RALYQYCPIP IINYPQLENE LFCNIYYLKQ LCDTLRFPDW PIKDPVKLLK DTLDAWKKEV EKKPPMMSID DAYEVLNLPQ GQGPHDESKI RKAYFRLAQK YHPDKNPEGR DMFEKVNKAY EFLCTKSAKI VDGPDPENII LILKTQSILF NRHKEDLQPY KYAGYPMLIR TITMETSDDL LFSKESPLLP AATELAFHTV NCSALNAEEL RRENGLEVLQ EAFSRCVAVL TRASKPSDMS VQVCGYISKC YSVAAQFEEC REKITEMPSI IKDLCRVLYF GKSIPRVAAL GVECVSSFAV DFWLQTHLFQ AGILWYLLGF LFNYDYTLEE SGIQKSEETN QQEVANSLAK LSVHALSRLG GYLAEEQATP ENPTIRKSLA GMLTPYVARK LAVASVTEIL KMLNSNTESP YLIWNNSTRA ELLEFLESQQ ENMIKKGDCD KTYGSEFVYS DHAKELIVGE IFVRVYNEVP TFQLEVPKAF AASLLDYIGS QAQYLHTFMA ITHAAKVESE QHGDRLPRVE MALEALRNVI KYNPGSESEC IGHFKLIFSL LRVHGAGQVQ QLALEVVNIV TSNQDCVNNI AESMVLSSLL ALLHSLPSSR QLVLETLYAL TSSTKIIKEA MAKGALIYLL DMFCNSTHPQ VRAQTAELFA KMTADKLIGP KVRITLMKFL PSVFMDAMRD NPEAAVHIFE GTHENPELIW NDNSRDKVST TVREMMLEHF KNQQDNPEAN WKLPEDFAVV FGEAEGELAV GGVFLRIFIA QPAWVLRKPR EFLIALLEKL TELLEKNNPH GETLETLTMA TVCLFSAQPQ LADQVPPLGH LPKVIQAMNH RNNAIPKSAI RVIHALSENE LCVRAMASLE TIGPLMNGMK KRADTVGLAC EAINRMFQKE QSELVAQALK ADLVPYLLKL LEGIGLENLD SPAATKAQIV KALKAMTRSL QYGEQVNEIL CRSSVWSAFK DQKHDLFISE SQTAGYLTGP GVAGYLTAGT STSVMSNLPP PVDHEAGDLG YQT // ID GBA1_HUMAN Reviewed; 536 AA. AC P04062; A8K796; B7Z5G2; B7Z6S1; J3KQG4; J3KQK9; Q16545; Q4VX22; Q6I9R6; AC Q9UMJ8; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 09-NOV-2004, sequence version 3. DT 28-JAN-2026, entry version 274. DE RecName: Full=Lysosomal acid glucosylceramidase {ECO:0000305}; DE Short=Lysosomal acid GCase {ECO:0000303|PubMed:24211208}; DE EC=3.2.1.45 {ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204, ECO:0000269|PubMed:9201993}; DE AltName: Full=Acid beta-glucosidase; DE AltName: Full=Alglucerase; DE AltName: Full=Beta-glucocerebrosidase; DE Short=Beta-GC; DE AltName: Full=Beta-glucosylceramidase 1; DE AltName: Full=Cholesterol glucosyltransferase {ECO:0000305|PubMed:24211208}; DE Short=SGTase {ECO:0000303|PubMed:24211208}; DE EC=2.4.1.- {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:32144204}; DE AltName: Full=Cholesteryl-beta-glucosidase {ECO:0000305|PubMed:24211208}; DE EC=3.2.1.- {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:32144204}; DE AltName: Full=D-glucosyl-N-acylsphingosine glucohydrolase; DE AltName: Full=Glucosylceramidase beta 1 {ECO:0000312|HGNC:HGNC:4177}; DE AltName: Full=Imiglucerase; DE AltName: Full=Lysosomal cholesterol glycosyltransferase {ECO:0000305}; DE AltName: Full=Lysosomal galactosylceramidase {ECO:0000305}; DE EC=3.2.1.46 {ECO:0000269|PubMed:32144204}; DE AltName: Full=Lysosomal glycosylceramidase {ECO:0000305}; DE Flags: Precursor; GN Name=GBA1 {ECO:0000312|HGNC:HGNC:4177}; Synonyms=GBA, GC, GLUC; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT). RC TISSUE=Placenta; RX PubMed=3864160; DOI=10.1073/pnas.82.21.7289; RA Sorge J., West C., Westwood B., Beutler E.; RT "Molecular cloning and nucleotide sequence of human glucocerebrosidase RT cDNA."; RL Proc. Natl. Acad. Sci. U.S.A. 82:7289-7293(1985). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), AND VARIANT LEU-298. RC TISSUE=Hepatoma; RX PubMed=3001061; DOI=10.1016/s0021-9258(17)42428-8; RA Tsuji S., Choudary P.V., Martin B.M., Winfield S., Barranger J.A., RA Ginns E.I.; RT "Nucleotide sequence of cDNA containing the complete coding sequence for RT human lysosomal glucocerebrosidase."; RL J. Biol. Chem. 261:50-53(1986). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Liver; RX PubMed=2914709; DOI=10.1016/0888-7543(89)90319-4; RA Horowitz M., Wilder S., Horowitz Z., Reiner O., Gelbart T., Beutler E.; RT "The human glucocerebrosidase gene and pseudogene: structure and RT evolution."; RL Genomics 4:87-96(1989). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Liver; RX PubMed=1572652; DOI=10.1016/0888-7543(92)90311-f; RA Beutler E., West C., Gelbart T.; RT "Polymorphisms in the human glucocerebrosidase gene."; RL Genomics 12:795-800(1992). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND 3), VARIANTS GD ARG-223; RP GLY-230; PRO-235; ARG-241; ILE-252 AND ARG-364, AND VARIANTS GLY-310 AND RP HIS-368. RX PubMed=8294033; DOI=10.1016/0378-1119(93)90497-q; RA Imai K., Nakamura M., Yamada M., Asano A., Yokoyama S., Tsuji S., RA Ginns E.I.; RT "A novel transcript from a pseudogene for human glucocerebrosidase in non- RT Gaucher disease cells."; RL Gene 136:365-368(1993). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9331372; DOI=10.1101/gr.7.10.1020; RA Winfield S.L., Tayebi N., Martin B.M., Ginns E.I., Sidransky E.; RT "Identification of three additional genes contiguous to the RT glucocerebrosidase locus on chromosome 1q21: implications for Gaucher RT disease."; RL Genome Res. 7:1020-1026(1997). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG; 4 AND 5), AND RP VARIANT MET-408. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-11. RX PubMed=3359914; DOI=10.1089/dna.1988.7.107; RA Reiner O., Wigderson M., Horowitz M.; RT "Structural analysis of the human glucocerebrosidase genes."; RL DNA 7:107-116(1988). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-45, AND ALTERNATIVE INITIATION. RX PubMed=3687939; RA Sorge J.A., West C., Kuhl W., Treger L., Beutler E.; RT "The human glucocerebrosidase gene has two functional ATG initiator RT codons."; RL Am. J. Hum. Genet. 41:1016-1024(1987). RN [12] RP PROTEIN SEQUENCE OF 40-44, AND CLEAVAGE OF SIGNAL PEPTIDE AFTER GLY-39. RC TISSUE=Placenta; RA Martin B.M., Murray G.J., Coligan J.E., Raum M., Brady R.O., RA Barranger J.A.; RT "Structural studies of human placental glucocerebrosidase."; RL Fed. Proc. 43:1869-1869(1984). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 403-416. RX PubMed=6091633; DOI=10.1016/0006-291x(84)90268-7; RA Ginns E.I., Choudary P.V., Martin B.M., Winfield S., Stubblefield B., RA Mayor J., Merkle-Lehman D., Murray G.J., Bowers L.A., Barranger J.A.; RT "Isolation of cDNA clones for human beta-glucocerebrosidase using the RT lambda gt11 expression system."; RL Biochem. Biophys. Res. Commun. 123:574-580(1984). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 409-462, AND VARIANT GD1 SER-409. RC TISSUE=Skin; RA Tsuji S., Martin B.M., Barranger J.A., Stubblefield B.K., LaMarca M.E., RA Ginns E.I.; RT "Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in RT Ashkenazic and non-Ashkenazic individuals."; RL Proc. Natl. Acad. Sci. U.S.A. 85:2349-2352(1988). RN [15] RP PROTEIN SEQUENCE OF 469-520. RC TISSUE=Placenta; RX PubMed=3456607; DOI=10.1073/pnas.83.6.1660; RA Dinur T., Osiecki K.M., Legler G., Gatt S., Desnick R.J., Grabowski G.A.; RT "Human acid beta-glucosidase: isolation and amino acid sequence of a RT peptide containing the catalytic site."; RL Proc. Natl. Acad. Sci. U.S.A. 83:1660-1664(1986). RN [16] RP TOPOLOGY. RX PubMed=1848227; DOI=10.1016/s0021-9258(19)67728-8; RA Rijnboutt S., Aerts H.M., Geuze H.J., Tager J.M., Strous G.J.; RT "Mannose 6-phosphate-independent membrane association of cathepsin D, RT glucocerebrosidase, and sphingolipid-activating protein in HepG2 cells."; RL J. Biol. Chem. 266:4862-4868(1991). RN [17] RP MUTAGENESIS OF GLU-379, ACTIVE SITE, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=7908905; DOI=10.1016/s0021-9258(19)78077-6; RA Miao S., McCarter J.D., Grace M.E., Grabowski G.A., Aebersold R., RA Withers S.G.; RT "Identification of Glu340 as the active-site nucleophile in human RT glucocerebrosidase by use of electrospray tandem mass spectrometry."; RL J. Biol. Chem. 269:10975-10978(1994). RN [18] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND ACTIVITY REGULATION. RX PubMed=9201993; DOI=10.1074/jbc.272.27.16862; RA Vaccaro A.M., Tatti M., Ciaffoni F., Salvioli R., Barca A., Scerch C.; RT "Effect of saposins A and C on the enzymatic hydrolysis of liposomal RT glucosylceramide."; RL J. Biol. Chem. 272:16862-16867(1997). RN [19] RP INTERACTION WITH SAPOSIN-C, ACTIVITY REGULATION, AND TOPOLOGY. RX PubMed=10781797; DOI=10.1016/s0014-5793(00)01417-4; RA Salvioli R., Tatti M., Ciaffoni F., Vaccaro A.M.; RT "Further studies on the reconstitution of glucosylceramidase activity by RT Sap C and anionic phospholipids."; RL FEBS Lett. 472:17-21(2000). RN [20] RP GLYCOSYLATION AT ASN-98; ASN-185 AND ASN-309. RX PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [21] RP SUBCELLULAR LOCATION, TOPOLOGY, AND INTERACTION WITH SCARB2. RX PubMed=18022370; DOI=10.1016/j.cell.2007.10.018; RA Reczek D., Schwake M., Schroder J., Hughes H., Blanz J., Jin X., RA Brondyk W., Van Patten S., Edmunds T., Saftig P.; RT "LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent RT targeting of beta-glucocerebrosidase."; RL Cell 131:770-783(2007). RN [22] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Placenta; RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x; RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H., RA Elsaesser H.-P., Mann M., Hasilik A.; RT "Integral and associated lysosomal membrane proteins."; RL Traffic 8:1676-1686(2007). RN [23] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=19279011; DOI=10.1074/jbc.m802790200; RA Kitatani K., Sheldon K., Rajagopalan V., Anelli V., Jenkins R.W., Sun Y., RA Grabowski G.A., Obeid L.M., Hannun Y.A.; RT "Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide RT formation."; RL J. Biol. Chem. 284:12972-12978(2009). RN [24] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-98 AND ASN-309. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [25] RP INTERACTION WITH TCP1, CHARACTERIZATION OF VARIANT GD1 SER-409, AND RP CHARACTERIZATION OF VARIANT GD2 SER-409 AND PRO-483. RX PubMed=21098288; DOI=10.1073/pnas.1014376107; RA Lu J., Chiang J., Iyer R.R., Thompson E., Kaneski C.R., Xu D.S., Yang C., RA Chen M., Hodes R.J., Lonser R.R., Brady R.O., Zhuang Z.; RT "Decreased glucocerebrosidase activity in Gaucher disease parallels RT quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl."; RL Proc. Natl. Acad. Sci. U.S.A. 107:21665-21670(2010). RN [26] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, SUBSTRATE RP SPECIFICITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=24211208; DOI=10.1016/j.bbrc.2013.10.145; RA Akiyama H., Kobayashi S., Hirabayashi Y., Murakami-Murofushi K.; RT "Cholesterol glucosylation is catalyzed by transglucosylation reaction of RT beta-glucosidase 1."; RL Biochem. Biophys. Res. Commun. 441:838-843(2013). RN [28] RP INTERACTION WITH SNCA. RX PubMed=23266198; DOI=10.1016/j.ymgme.2012.11.010; RA Yap T.L., Velayati A., Sidransky E., Lee J.C.; RT "Membrane-bound alpha-synuclein interacts with glucocerebrosidase and RT inhibits enzyme activity."; RL Mol. Genet. Metab. 108:56-64(2013). RN [29] RP INTERACTION WITH GRN. RX PubMed=27789271; DOI=10.1016/j.ebiom.2016.10.010; RA Jian J., Tian Q.Y., Hettinghouse A., Zhao S., Liu H., Wei J., Grunig G., RA Zhang W., Setchell K.D.R., Sun Y., Overkleeft H.S., Chan G.L., Liu C.J.; RT "Progranulin Recruits HSP70 to beta-Glucocerebrosidase and Is Therapeutic RT Against Gaucher Disease."; RL EBioMedicine 13:212-224(2016). RN [30] RP FUNCTION. RX PubMed=27378698; DOI=10.1093/hmg/ddw185; RA Magalhaes J., Gegg M.E., Migdalska-Richards A., Doherty M.K., RA Whitfield P.D., Schapira A.H.; RT "Autophagic lysosome reformation dysfunction in glucocerebrosidase RT deficient cells: relevance to Parkinson disease."; RL Hum. Mol. Genet. 25:3432-3445(2016). RN [31] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND ACTIVITY REGULATION. RX PubMed=26724485; DOI=10.1194/jlr.m064923; RA Marques A.R., Mirzaian M., Akiyama H., Wisse P., Ferraz M.J., Gaspar P., RA Ghauharali-van der Vlugt K., Meijer R., Giraldo P., Alfonso P., Irun P., RA Dahl M., Karlsson S., Pavlova E.V., Cox T.M., Scheij S., Verhoek M., RA Ottenhoff R., van Roomen C.P., Pannu N.S., van Eijk M., Dekker N., RA Boot R.G., Overkleeft H.S., Blommaart E., Hirabayashi Y., Aerts J.M.; RT "Glucosylated cholesterol in mammalian cells and tissues: formation and RT degradation by multiple cellular beta-glucosidases."; RL J. Lipid Res. 57:451-463(2016). RN [32] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=32144204; DOI=10.1074/jbc.ra119.012502; RA Akiyama H., Ide M., Nagatsuka Y., Sayano T., Nakanishi E., Uemura N., RA Yuyama K., Yamaguchi Y., Kamiguchi H., Takahashi R., Aerts J.M.F.G., RA Greimel P., Hirabayashi Y.; RT "Glucocerebrosidases catalyze a transgalactosylation reaction that yields a RT newly-identified brain sterol metabolite, galactosylated cholesterol."; RL J. Biol. Chem. 295:5257-5277(2020). RN [33] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=33361282; DOI=10.1194/jlr.ra120001043; RA Boer D.E., Mirzaian M., Ferraz M.J., Zwiers K.C., Baks M.V., Hazeu M.D., RA Ottenhoff R., Marques A.R.A., Meijer R., Roos J.C.P., Cox T.M., Boot R.G., RA Pannu N., Overkleeft H.S., Artola M., Aerts J.M.; RT "Human glucocerebrosidase mediates formation of xylosyl-cholesterol by RT beta-xylosidase and transxylosidase reactions."; RL J. Lipid Res. 62:100018-100018(2021). RN [34] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=39395789; DOI=10.1016/j.jlr.2024.100670; RA Bannink S., Bila K.O., van Weperen J., Ligthart N.A.M., Ferraz M.J., RA Boot R.G., van der Vliet D., Boer D.E.C., Overkleeft H.S., Artola M., RA Aerts J.M.F.G.; RT "6-O-alkyl 4-methylumbelliferyl-beta-D-glucosides as selective substrates RT for GBA1 in the discovery of glycosylated sterols."; RL J. Lipid Res. 65:100670-100670(2024). RN [35] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 40-536, GLYCOSYLATION AT ASN-58, RP AND DISULFIDE BONDS. RX PubMed=12792654; DOI=10.1038/sj.embor.embor873; RA Dvir H., Harel M., McCarthy A.A., Toker L., Silman I., Futerman A.H., RA Sussman J.L.; RT "X-ray structure of human acid-beta-glucosidase, the defective enzyme in RT Gaucher disease."; RL EMBO Rep. 4:704-709(2003). RN [36] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 40-536 IN COMPLEX WITH SYNTHETIC RP INHIBITOR, AND ACTIVE SITE. RX PubMed=15817452; DOI=10.1074/jbc.m502799200; RA Premkumar L., Sawkar A.R., Boldin-Adamsky S., Toker L., Silman I., RA Kelly J.W., Futerman A.H., Sussman J.L.; RT "X-ray structure of human acid-beta-glucosidase covalently bound to RT conduritol-B-epoxide. Implications for Gaucher disease."; RL J. Biol. Chem. 280:23815-23819(2005). RN [37] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 40-536, CATALYTIC ACTIVITY, RP PATHWAY, CHARACTERIZATION OF VARIANTS GD SER-55; GLN-87; ASN-118; LEU-161; RP VAL-162; VAL-166; ASN-200; PHE-213; PHE-224; GLU-232; GLU-237; LEU-298; RP ILE-303; CYS-343; ILE-362; LYS-365; GLY-381; LYS-388; TRP-392; CYS-402; RP SER-409; VAL-410; HIS-419; LYS-421; ARG-429; LEU-433; SER-436; ASN-438; RP HIS-448; VAL-455; PRO-483; PRO-500; CYS-502 AND PRO-502, CHARACTERIZATION RP OF VARIANT GD2 GLN-159, AND MUTAGENESIS OF CYS-43; CYS-57 AND CYS-62. RX PubMed=16293621; DOI=10.1074/jbc.m511110200; RA Liou B., Kazimierczuk A., Zhang M., Scott C.R., Hegde R.S., Grabowski G.A.; RT "Analyses of variant acid beta-glucosidases: effects of Gaucher disease RT mutations."; RL J. Biol. Chem. 281:4242-4253(2006). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 40-536, AND GLYCOSYLATION AT RP ASN-58; ASN-98 AND ASN-185. RX PubMed=17139081; DOI=10.1107/s0907444906038303; RA Brumshtein B., Wormald M.R., Silman I., Futerman A.H., Sussman J.L.; RT "Structural comparison of differently glycosylated forms of acid-beta- RT glucosidase, the defective enzyme in Gaucher disease."; RL Acta Crystallogr. D 62:1458-1465(2006). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 40-536 IN COMPLEXES WITH RP ISOFAGOMINE, AND SUBCELLULAR LOCATION. RX PubMed=17187079; DOI=10.1038/nchembio850; RA Lieberman R.L., Wustman B.A., Huertas P., Powe A.C. Jr., Pine C.W., RA Khanna R., Schlossmacher M.G., Ringe D., Petsko G.A.; RT "Structure of acid beta-glucosidase with pharmacological chaperone provides RT insight into Gaucher disease."; RL Nat. Chem. Biol. 3:101-107(2007). RN [40] RP REVIEW ON GD VARIANTS. RX PubMed=8118460; DOI=10.1002/humu.1380030102; RA Horowitz M., Zimran A.; RT "Mutations causing Gaucher disease."; RL Hum. Mutat. 3:1-11(1994). RN [41] RP REVIEW ON GD VARIANTS. RX PubMed=8889578; RX DOI=10.1002/(sici)1098-1004(1996)8:3<207::aid-humu2>3.0.co;2-6; RA Beutler E., Gelbart T.; RT "Glucocerebrosidase (Gaucher disease)."; RL Hum. Mutat. 8:207-213(1996). RN [42] RP REVIEW ON GD VARIANTS. RX PubMed=10527671; DOI=10.1006/mgme.1999.2918; RA Tayebi N., Stone D.L., Sidransky E.; RT "Type 2 Gaucher disease: an expanding phenotype."; RL Mol. Genet. Metab. 68:209-219(1999). RN [43] RP VARIANTS GD2 ARG-454 AND PRO-483, AND CHARACTERIZATION OF VARIANTS GD2 RP ARG-454 AND PRO-483. RX PubMed=2464926; RA Wigderson M., Firon N., Horowitz Z., Wilder S., Frishberg Y., Reiner O., RA Horowitz M.; RT "Characterization of mutations in Gaucher patients by cDNA cloning."; RL Am. J. Hum. Genet. 44:365-377(1989). RN [44] RP VARIANTS GD1 LEU-433 AND HIS-448, AND VARIANTS GD3 LEU-433; HIS-448 AND RP VAL-448. RX PubMed=2508065; DOI=10.1093/nar/17.19.7707; RA Theophilus B.D., Latham T., Grabowski G.A., Smith F.I.; RT "Comparison of RNase A, a chemical cleavage and GC-clamped denaturing RT gradient gel electrophoresis for the detection of mutations in exon 9 of RT the human acid beta-glucosidase gene."; RL Nucleic Acids Res. 17:7707-7722(1989). RN [45] RP VARIANT GD TYR-255. RX PubMed=1974409; DOI=10.1111/j.1469-1809.1990.tb00371.x; RA Beutler E., Gelbart T.; RT "Gaucher disease associated with a unique KpnI restriction site: RT identification of the amino-acid substitution."; RL Ann. Hum. Genet. 54:149-153(1990). RN [46] RP VARIANT GD CYS-502, AND CHARACTERIZATION OF VARIANT GD CYS-502. RX PubMed=1972019; DOI=10.1089/dna.1990.9.233; RA Hong C.M., Ohashi T., Yu X.J., Weiler S., Barranger J.A.; RT "Sequence of two alleles responsible for Gaucher disease."; RL DNA Cell Biol. 9:233-241(1990). RN [47] RP VARIANTS GD2 ARG-364 AND GLY-381, AND VARIANT GD1 HIS-448. RX PubMed=2269438; DOI=10.1016/0378-1119(90)90264-r; RA Eyal N., Wilder S., Horowitz M.; RT "Prevalent and rare mutations among Gaucher patients."; RL Gene 96:277-283(1990). RN [48] RP VARIANTS GD1 GLN-196; VAL-348; CYS-351 AND THR-403. RX PubMed=1899336; DOI=10.1089/dna.1991.10.15; RA Latham T.E., Theophilus B.D., Grabowski G.A., Smith F.I.; RT "Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher RT disease patients."; RL DNA Cell Biol. 10:15-21(1991). RN [49] RP VARIANTS GD1 HIS-179; GLN-196 AND LYS-365. RX PubMed=1864608; DOI=10.1007/bf00200914; RA Eyal N., Firon N., Wilder S., Kolodny E.H., Horowitz M.; RT "Three unique base pair changes in a family with Gaucher disease."; RL Hum. Genet. 87:328-332(1991). RN [50] RP VARIANTS GD1 GLN-398 AND CYS-535, AND VARIANT GD3 GLU-464. RX PubMed=1487244; DOI=10.1007/bf00220082; RA Kawame H., Hasegawa Y., Eto Y., Maekawa K.; RT "Rapid identification of mutations in the glucocerebrosidase gene of RT Gaucher disease patients by analysis of single-strand conformation RT polymorphisms."; RL Hum. Genet. 90:294-296(1992). RN [51] RP VARIANTS GD1 ILE-252; LEU-328; ILE-362 AND CYS-502, AND CHARACTERIZATION OF RP VARIANTS GD1 LEU-328; ILE-362 AND CYS-502. RX PubMed=1301953; DOI=10.1002/humu.1380010513; RA He G.S., Grace M.E., Grabowski G.A.; RT "Gaucher disease: four rare alleles encoding F213I, P289L, T323I, and R463C RT in type 1 variants."; RL Hum. Mutat. 1:423-427(1992). RN [52] RP VARIANTS GD HIS-251 AND SER-517, AND VARIANTS GD1 SER-161 AND HIS-535. RX PubMed=8432537; DOI=10.1006/geno.1993.1035; RA Beutler E., Gelbart T., West C.; RT "Identification of six new Gaucher disease mutations."; RL Genomics 15:203-205(1993). RN [53] RP VARIANT GD1 HIS-535. RX PubMed=7916532; DOI=10.1002/ajmg.1320510216; RA Choy F.Y.M., Wei C., Applegarth D.A., McGillivray B.C.; RT "DNA analysis of an uncommon missense mutation in a Gaucher disease patient RT of Jewish-Polish-Russian descent."; RL Am. J. Med. Genet. 51:156-160(1994). RN [54] RP VARIANT GD2 ASN-438. RX PubMed=8112750; DOI=10.1007/bf00210614; RA Beutler E., Gelbart T.; RT "Two new Gaucher disease mutations."; RL Hum. Genet. 93:209-210(1994). RN [55] RP VARIANTS GD SER-409 AND CYS-457. RX PubMed=8076951; DOI=10.1007/bf00208292; RA Tuteja R., Tuteja N., Lilliu F., Bembi B., Galanello R., Cao A., RA Baralle F.E.; RT "Y418C: a novel mutation in exon 9 of the glucocerebrosidase gene of a RT patient with Gaucher disease creates a new Bgl I site."; RL Hum. Genet. 94:314-315(1994). RN [56] RP VARIANTS GD1 SER-409 AND VAL-456. RX PubMed=7915932; DOI=10.1093/hmg/3.5.821; RA Choy F.Y., Wei C., Applegarth D.A., Yong S.L.; RT "A new missense mutation in glucocerebrosidase exon 9 of a non-Jewish RT Caucasian type 1 Gaucher disease patient."; RL Hum. Mol. Genet. 3:821-823(1994). RN [57] RP VARIANT GD2 ARG-483. RX PubMed=7981693; DOI=10.1093/hmg/3.7.1183; RA Uchiyama A., Tomatsu S., Kondo N., Suzuki Y., Shimozawa N., Fukuda S., RA Sukegawa K., Taki N., Inamori H., Orii T.; RT "New Gaucher disease mutations in exon 10: a novel L444R mutation produces RT a new NciI site the same as L444P."; RL Hum. Mol. Genet. 3:1183-1184(1994). RN [58] RP CHARACTERIZATION OF VARIANT GD TYR-255, CHARACTERIZATION OF VARIANTS GD1 RP LEU-328; ILE-362; THR-403; SER-409; LEU-433; HIS-448; PRO-483; PRO-495 AND RP CYS-502, CHARACTERIZATION OF VARIANT GD2 ARG-454, CHARACTERIZATION OF RP VARIANT GD3 VAL-448, AND MUTAGENESIS OF ASP-482 AND ASN-501. RX PubMed=8294487; DOI=10.1016/s0021-9258(17)42166-1; RA Grace M.E., Newman K.M., Scheinker V., Berg-Fussman A., Grabowski G.A.; RT "Analysis of human acid beta-glucosidase by site-directed mutagenesis and RT heterologous expression."; RL J. Biol. Chem. 269:2283-2291(1994). RN [59] RP VARIANTS GD1 ASP-215; THR-221; ARG-241; GLN-296; CYS-324; GLY-417 AND RP ASN-419. RX PubMed=8790604; DOI=10.1007/bf03403534; RA Beutler E., Demina A., Gelbart T.; RT "Glucocerebrosidase mutations in Gaucher disease."; RL Mol. Med. 1:82-92(1994). RN [60] RP VARIANTS GD1 ILE-82 AND TRP-87. RX PubMed=7655857; DOI=10.1006/bcmd.1995.0004; RA Beutler E., Gelbart T., Demina A., Zimran A., LeCoutre P.; RT "Five new Gaucher disease mutations."; RL Blood Cells Mol. Dis. 21:20-24(1995). RN [61] RP VARIANTS GD1 ARG-305; HIS-354 AND ASP-357. RX PubMed=8547070; DOI=10.1111/j.1365-2141.1995.tb05298.x; RA Walley A.J., Ellis I., Harris A.; RT "Three unrelated Gaucher's disease patients with three novel point RT mutations in the glucocerebrosidase gene (P266R, D315H and A318D)."; RL Br. J. Haematol. 91:330-332(1995). RN [62] RP VARIANTS GD SER-409; HIS-448; PRO-483 AND CYS-502. RX PubMed=7627184; DOI=10.1002/humu.1380050406; RA Cormand B., Vilageliu L., Burguera J.M., Balcells S., Gonzalez-Duarte R., RA Grinberg D., Chabas A.; RT "Gaucher disease in Spanish patients: analysis of eight mutations."; RL Hum. Mutat. 5:303-309(1995). RN [63] RP VARIANT GD2 SER-217. RX PubMed=7627192; DOI=10.1002/humu.1380050414; RA Choy F.Y.M., Wei C.; RT "Identification of a new mutation (P178S) in an African-American patient RT with type 2 Gaucher disease."; RL Hum. Mutat. 5:345-347(1995). RN [64] RP VARIANTS GD1 SER-409 AND PRO-483, VARIANTS GD2 HIS-448; PRO-483 AND RP CYS-502, AND VARIANTS GD3 HIS-448 AND PRO-483. RX PubMed=8598642; DOI=10.1007/bf02436006; RA Michelakakis H., Dimitriou E., Van Weely S., Boot R.G., Mavridou I., RA Verhoek M., Aerts J.M.; RT "Characterization of glucocerebrosidase in Greek Gaucher disease patients: RT mutation analysis and biochemical studies."; RL J. Inherit. Metab. Dis. 18:609-615(1995). RN [65] RP VARIANT GD HIS-448. RX PubMed=7475546; DOI=10.1016/s0140-6736(95)91688-1; RA Abrahamov A., Elstein D., Gross-Tsur V., Farber B., Glaser Y., RA Hadas-Halpern I., Ronen S., Tafakjdi M., Horowitz M., Zimran A.; RT "Gaucher's disease variant characterised by progressive calcification of RT heart valves and unique genotype."; RL Lancet 346:1000-1003(1995). RN [66] RP CHARACTERIZATION OF VARIANTS GD1 SER-409; VAL-456 AND HIS-535, AND RP CHARACTERIZATION OF VARIANT GD2 PRO-483. RX PubMed=9240741; RX DOI=10.1002/(sici)1096-8628(19961028)65:3<184::aid-ajmg3>3.0.co;2-q; RA Choy F.Y., Wei C., Levin D.; RT "Gaucher disease: functional expression of the normal glucocerebrosidase RT and Gaucher T1366G and G1604A alleles in Baculovirus-transfected Spodoptera RT frugiperda cells."; RL Am. J. Med. Genet. 65:184-189(1996). RN [67] RP VARIANTS GD SER-409; LEU-426; LEU-433 AND PRO-483. RX PubMed=8937765; DOI=10.1111/j.1399-0004.1996.tb02352.x; RA Morar B., Lane A.B.; RT "The molecular characterization of Gaucher disease in South Africa."; RL Clin. Genet. 50:78-84(1996). RN [68] RP VARIANTS GD LEU-54; GLU-85 AND SER-227. RX PubMed=8829654; RX DOI=10.1002/(sici)1098-1004(1996)7:3<214::aid-humu5>3.0.co;2-a; RA Kim J.-W., Liou B.B., Lai M.-Y., Ponce E., Grabowski G.A.; RT "Gaucher disease: identification of three new mutations in the Korean and RT Chinese (Taiwanese) populations."; RL Hum. Mutat. 7:214-218(1996). RN [69] RP VARIANTS GD HIS-352 AND GLN-398. RX PubMed=8829663; RX DOI=10.1002/(sici)1098-1004(1996)7:3<272::aid-humu14>3.0.co;2-#; RA Cormand B., Vilageliu L., Balcells S., Gonzalez-Duatre R., Chabas A., RA Grinberg D.; RT "Two novel (1098insA and Y313H) and one rare (R359Q) mutations detected in RT exon 8 of the beta-glucocerebrosidase gene in Gaucher's disease patients."; RL Hum. Mutat. 7:272-274(1996). RN [70] RP VARIANT GD1 THR-435. RX PubMed=8889591; RX DOI=10.1002/(sici)1098-1004(1996)8:3<280::aid-humu15>3.0.co;2-z; RA Amaral O., Pinto E., Fortuna M., Lacerda L., Sa Miranda M.C.; RT "Type 1 Gaucher disease: identification of N396T and prevalence of RT glucocerebrosidase mutations in the Portuguese."; RL Hum. Mutat. 8:280-281(1996). RN [71] RP VARIANTS GD3 LEU-437 AND ILE-530. RX PubMed=8780099; DOI=10.1212/wnl.46.4.1102; RA Seeman P.J.V., Finckh U., Hoeppner J., Lakner V., Liebisch I., Grau G., RA Rolfs A.; RT "Two new missense mutations in a non-Jewish Caucasian family with type 3 RT Gaucher disease."; RL Neurology 46:1102-1107(1996). RN [72] RP VARIANTS GD LEU-414 AND THR-441. RX PubMed=9182788; RX DOI=10.1002/(sici)1096-8628(19970627)70:4<437::aid-ajmg19>3.0.co;2-i; RA Cormand B., Grinberg D., Gort L., Fiumara A., Barone R., Vilageliu L., RA Chabas A.; RT "Two new mild homozygous mutations in Gaucher disease patients: clinical RT signs and biochemical analyses."; RL Am. J. Med. Genet. 70:437-443(1997). RN [73] RP VARIANTS GD VAL-76; GLU-85; TRP-87; TRP-159; SER-227; ILE-252 AND PRO-483. RX PubMed=9217217; RX DOI=10.1002/(sici)1096-8628(19970808)71:2<172::aid-ajmg10>3.0.co;2-b; RA Choy F.Y.M., Humphries M.L., Shi H.; RT "Identification of two novel and four uncommon missense mutations among RT Chinese Gaucher disease patients."; RL Am. J. Med. Genet. 71:172-178(1997). RN [74] RP VARIANT GD1 TRP-87. RX PubMed=9295080; RX DOI=10.1002/(sici)1096-8628(19971003)72:1<77::aid-ajmg16>3.0.co;2-r; RA Rockah R., Narinsky R., Hatskelzon L., Frisch A.; RT "Type I Gaucher disease due to homozygosity for the 259T mutation in a RT Bedouin patient."; RL Am. J. Med. Genet. 72:77-78(1997). RN [75] RP VARIANT GD2 LYS-501. RX PubMed=9279145; DOI=10.1136/adc.77.1.17; RA Hatton C.E., Cooper A., Whitehouse C., Wraith J.E.; RT "Mutation analysis in 46 British and Irish patients with Gaucher's RT disease."; RL Arch. Dis. Child. 77:17-22(1997). RN [76] RP VARIANTS GD1 TRP-87; GLU-234; ASN-310; LEU-391 AND SER-409, VARIANTS GD2 RP ARG-241 AND ILE-252, CHARACTERIZATION OF VARIANTS GD1 TRP-87; GLU-234; RP ASN-310; LEU-391 AND SER-409, AND CHARACTERIZATION OF VARIANT GD2 ARG-241. RX PubMed=9153297; DOI=10.1172/jci119437; RA Grace M.E., Desnick R.J., Pastores G.M.; RT "Identification and expression of acid beta-glucosidase mutations causing RT severe type 1 and neurologic type 2 Gaucher disease in non-Jewish RT patients."; RL J. Clin. Invest. 99:2530-2537(1997). RN [77] RP VARIANTS GD VAL-228; ILE-252; GLY-405; HIS-448; GLN-452; PRO-483 AND RP CYS-535. RX PubMed=9061570; DOI=10.1023/a:1005313724361; RA Ida H., Rennert O.M., Kawame H., Maekawa K., Eto Y.; RT "Mutation prevalence among 47 unrelated Japanese patients with Gaucher RT disease: identification of four novel mutations."; RL J. Inherit. Metab. Dis. 20:67-73(1997). RN [78] RP VARIANT GD3C HIS-448. RX PubMed=9040001; DOI=10.1136/jmg.34.2.175; RA Uyama E., Uchino M., Ida H., Eto Y., Owada M.; RT "D409H/D409H genotype in Gaucher-like disease."; RL J. Med. Genet. 34:175-175(1997). RN [79] RP VARIANTS GD LEU-198; THR-380; ASN-405 AND ARG-432, AND VARIANT GD2 LEU-146. RX PubMed=9554454; DOI=10.1159/000040815; RA Demina A., Beutler E.; RT "Six new Gaucher disease mutations."; RL Acta Haematol. 99:80-82(1998). RN [80] RP VARIANTS GD1 TRP-87; THR-158; TRP-159; PRO-209; LYS-227; PRO-276; ILE-342; RP PRO-363; SER-409; SER-416; PRO-483; PRO-485 AND CYS-502, AND VARIANTS GD3 RP LEU-433 AND PRO-483. RX PubMed=9683600; DOI=10.1086/301969; RA Germain D.P., Puech J.-P., Caillaud C., Kahn A., Poenaru L.; RT "Exhaustive screening of the acid beta-glucosidase gene, by fluorescence- RT assisted mismatch analysis using universal primers: mutation profile and RT genotype/phenotype correlations in Gaucher disease."; RL Am. J. Hum. Genet. 63:415-427(1998). RN [81] RP VARIANT GD2 TYR-513. RX PubMed=9637431; RX DOI=10.1002/(sici)1096-8628(19980616)78:1<92::aid-ajmg19>3.3.co;2-8; RA Choy F.Y.M., Humphries M.L., Ben-Yoseph Y.; RT "Gaucher type 2 disease: identification of a novel transversion mutation in RT a French-Irish patient."; RL Am. J. Med. Genet. 78:92-93(1998). RN [82] RP VARIANTS GD1 TRP-87; TRP-159; SER-200; ARG-241; ASP-304; CYS-324; SER-409; RP ASN-438; ILE-450 AND PRO-483, AND VARIANT GD2 HIS-448. RX PubMed=9856561; RX DOI=10.1002/(sici)1096-8628(19981204)80:4<343::aid-ajmg8>3.0.co;2-w; RA Cormand B., Harboe T.L., Gort L., Campoy C., Blanco M., Chamoles N., RA Chabas A., Vilageliu L., Grinberg D.; RT "Mutation analysis of Gaucher disease patients from Argentina: high RT prevalence of the RecNciI mutation."; RL Am. J. Med. Genet. 80:343-351(1998). RN [83] RP VARIANTS GD. RX PubMed=9516376; DOI=10.1006/bcmd.1998.0165; RA Beutler E., Gelbart T.; RT "Hematologically important mutations: Gaucher disease."; RL Blood Cells Mol. Dis. 24:2-8(1998). RN [84] RP VARIANTS GD2 LYS-80; CYS-170 AND PRO-483. RX PubMed=9851895; DOI=10.1006/bcmd.1998.0210; RA Sinclair G., Choy F.Y.M., Humphries L.; RT "A novel complex allele and two new point mutations in type 2 (acute RT neuronopathic) Gaucher disease."; RL Blood Cells Mol. Dis. 24:420-427(1998). RN [85] RP VARIANT GD GLY-392. RX PubMed=9650766; DOI=10.1111/j.1399-0004.1998.tb02697.x; RA Parenti G., Filocamo M., Titomanlio L., Rizzolo G., Silvestro E., RA Perretti A., Gatti R., Andria G.; RT "A novel mutation of the beta-glucocerebrosidase gene associated with RT neurologic manifestations in three sibs."; RL Clin. Genet. 53:281-285(1998). RN [86] RP VARIANTS GD1 GLU-152; PRO-173; LEU-430 AND HIS-451, AND VARIANTS GD2 RP GLU-428 AND ILE-431. RX PubMed=9554746; RX DOI=10.1002/(sici)1098-1004(1998)11:4<295::aid-humu7>3.0.co;2-6; RA Cormand B., Grinberg D., Gort L., Chabas A., Vilageliu L.; RT "Molecular analysis and clinical findings in the Spanish Gaucher disease RT population: putative haplotype of the N370S ancestral chromosome."; RL Hum. Mutat. 11:295-305(1998). RN [87] RP VARIANTS GD1 GLY-230 AND SER-409. RX PubMed=10206680; RX DOI=10.1002/(sici)1098-1004(1998)11:5<411::aid-humu11>3.0.co;2-2; RA Choy F.Y.M., Humphries M.L., Ben-Yoseph Y.; RT "A novel mutation (V191G) in a German-British type 1 Gaucher disease RT patient."; RL Hum. Mutat. 11:411-412(1998). RN [88] RP VARIANTS GD1 SER-409 AND LEU-440. RX PubMed=10340647; RX DOI=10.1002/(sici)1096-8628(19990604)84:4<334::aid-ajmg5>3.3.co;2-g; RA Wasserstein M.P., Martignetti J.A., Zeitlin R., Lumerman H., Solomon M., RA Grace M.E., Desnick R.J.; RT "Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: RT identification and expression of a novel acid beta-glucosidase mutation."; RL Am. J. Med. Genet. 84:334-339(1999). RN [89] RP VARIANT GD1 CYS-244, VARIANTS GD2 ILE-252 AND PRO-483, AND VARIANTS GD3 RP ARG-241; HIS-448 AND PRO-483. RX PubMed=10360404; RX DOI=10.1002/(sici)1096-8628(19990611)84:5<484::aid-ajmg14>3.0.co;2-w; RA Choy F.Y.M., Wong K., Shi H.P.; RT "Glucocerebrosidase mutations among Chinese neuronopathic and non- RT neuronopathic Gaucher disease patients."; RL Am. J. Med. Genet. 84:484-486(1999). RN [90] RP VARIANTS GD. RX PubMed=10744424; RA Hodanov K., Hrebicek M., Cervenkov M., Mrzov L., Veprekov L., Zemen J.; RT "Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher RT patients: mutation profile and description of six novel mutant alleles."; RL Blood Cells Mol. Dis. 25:287-298(1999). RN [91] RP VARIANTS GDPL ARG-350 AND PHE-437. RX PubMed=10352942; DOI=10.1038/sj.ejhg.5200315; RA Stone D.L., van Diggelen O.P., de Klerk J.B.C., Gaillard J.L.J., RA Niermeijer M.F., Willemsen R., Tayebi N., Sidransky E.; RT "Is the perinatal lethal form of Gaucher disease more common than classic RT type 2 Gaucher disease?"; RL Eur. J. Hum. Genet. 7:505-509(1999). RN [92] RP VARIANTS GD PRO-173; TRP-234; SER-409; SER-416; HIS-448 AND PRO-483. RX PubMed=10447266; RX DOI=10.1002/(sici)1098-1004(1999)14:1<88::aid-humu16>3.0.co;2-e; RA Sarria A.J., Giraldo P., Perez-Calvo J.I., Pocovi M.; RT "Detection of three rare (G377S, T134P and 1451delAC), and two novel RT mutations (G195W and Rec[1263del55;1342G>C]] in Spanish Gaucher disease RT patients."; RL Hum. Mutat. 14:88-88(1999). RN [93] RP VARIANTS GD1 TRP-87; ASN-118; THR-129; ASP-156; GLN-159; TRP-159; LEU-170; RP ILE-173; CYS-209; PRO-209; SER-227; PRO-235; ARG-241; ILE-252; GLN-296; RP CYS-324; LYS-365; THR-380; MET-408; SER-409; SER-416; LEU-433; TYR-438; RP HIS-448; PRO-483 AND CYS-502, VARIANT GD2 GLN-159, AND VARIANTS GD3 RP THR-229; HIS-448; PRO-483 AND CYS-502. RX PubMed=10796875; DOI=10.1086/302925; RA Koprivica V., Stone D.L., Park J.K., Callahan M., Frisch A., Cohen I.J., RA Tayebi N., Sidransky E.; RT "Analysis and classification of 304 mutant alleles in patients with type 1 RT and type 3 Gaucher disease."; RL Am. J. Hum. Genet. 66:1777-1786(2000). RN [94] RP VARIANTS GD2 LEU-170; LYS-227; GLU-229; PRO-235; GLN-294; GLN-296; LEU-298; RP HIS-324 AND CYS-343. RX PubMed=10649495; RX DOI=10.1002/(sici)1098-1004(200002)15:2<181::aid-humu7>3.0.co;2-s; RA Stone D.L., Tayebi N., Orvisky E., Stubblefield B., Madike V., RA Sidransky E.; RT "Glucocerebrosidase gene mutations in patients with type 2 Gaucher RT disease."; RL Hum. Mutat. 15:181-188(2000). RN [95] RP VARIANTS GD2 ARG-223 AND PRO-483. RX PubMed=10679038; DOI=10.1007/s100240050023; RA Choy F.Y., Wong K., Vallance H.D., Baldwin V.; RT "Novel point mutation (W184R) in neonatal type 2 Gaucher disease."; RL Pediatr. Dev. Pathol. 3:180-183(2000). RN [96] RP VARIANTS GD SER-55 AND HIS-448. RX PubMed=11992489; DOI=10.1002/ajmg.10385; RA Bodamer O.A.F., Church H.J., Cooper A., Wraith J.E., Scott C.R., RA Scaglia F.; RT "Variant Gaucher disease characterized by dysmorphic features, absence of RT cardiovascular involvement, laryngospasm, and compound heterozygosity for a RT novel mutation (D409H/C16S)."; RL Am. J. Med. Genet. 109:328-331(2002). RN [97] RP VARIANT LYS-365. RX PubMed=11903352; DOI=10.1034/j.1399-0004.2002.610106.x; RA Park J.K., Tayebi N., Stubblefield B.K., LaMarca M.E., MacKenzie J.J., RA Stone D.L., Sidransky E.; RT "The E326K mutation and Gaucher disease: mutation or polymorphism?"; RL Clin. Genet. 61:32-34(2002). RN [98] RP VARIANT GD GLU-175, VARIANT GDPL LEU-290, VARIANTS GD1 PRO-201 AND SER-409, RP VARIANT GD2 GLU-237, AND VARIANTS GD3 CYS-244; SER-416; PHE-441 AND RP HIS-448. RX PubMed=11933202; DOI=10.1002/humu.9024; RA Orvisky E., Park J.K., Parker A., Walker J.M., Martin B.M., RA Stubblefield B.K., Uyama E., Tayebi N., Sidransky E.; RT "The identification of eight novel glucocerebrosidase (GBA) mutations in RT patients with Gaucher disease."; RL Hum. Mutat. 19:458-459(2002). RN [99] RP VARIANTS GD1 THR-198; CYS-209; PRO-209; ARG-241; ILE-252; CYS-324; HIS-324; RP CYS-351; ASN-438; HIS-448; CYS-457; PRO-485 AND ARG-490, VARIANTS GD2 RP CYS-170; PRO-235; ARG-241; ARG-270 AND ILE-400, AND VARIANTS GD3 LEU-146; RP SER-227; ARG-241; ILE-252; CYS-324; GLY-392 AND HIS-448. RX PubMed=12204005; DOI=10.1002/humu.9058; RA Filocamo M., Mazzotti R., Stroppiano M., Seri M., Giona F., Parenti G., RA Regis S., Corsolini F., Zoboli S., Gatti R.; RT "Analysis of the glucocerebrosidase gene and mutation profile in 144 RT Italian Gaucher patients."; RL Hum. Mutat. 20:234-235(2002). RN [100] RP VARIANT MET-408. RX PubMed=12694238; DOI=10.1034/j.1399-0004.2003.00055.x; RA Walker J.M., Lwin A., Tayebi N., LaMarca M.E., Orvisky E., Sidransky E.; RT "Glucocerebrosidase mutation T369M appears to be another polymorphism."; RL Clin. Genet. 63:237-238(2003). RN [101] RP POSSIBLE INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=12847165; DOI=10.1212/01.wnl.0000072482.70963.d7; RA Bembi B., Zambito Marsala S., Sidransky E., Ciana G., Carrozzi M., RA Zorzon M., Martini C., Gioulis M., Pittis M.G., Capus L.; RT "Gaucher's disease with Parkinson's disease: clinical and pathological RT aspects."; RL Neurology 61:99-101(2003). RN [102] RP VARIANT GD SER-55. RX PubMed=15292921; DOI=10.1038/sj.ejhg.5201251; RA Church H.J., Cooper A., Stewart F., Thornton C.M., Wraith J.E.; RT "Homozygous loss of a cysteine residue in the glucocerebrosidase gene RT results in Gaucher's disease with a hydropic phenotype."; RL Eur. J. Hum. Genet. 12:975-978(2004). RN [103] RP VARIANTS GD2 GLN-294 AND HIS-448. RX PubMed=15690354; DOI=10.1002/ajmg.a.30316; RA Filocamo M., Grossi S., Stroppiano M., Tortori-Donati P., Regis S., RA Allegri A., Di Rocco M.; RT "Homozygosity for a non-pseudogene complex glucocerebrosidase allele as RT cause of an atypical neuronopathic form of Gaucher disease."; RL Am. J. Med. Genet. A 134A:95-96(2005). RN [104] RP CHARACTERIZATION OF VARIANT GD SER-409. RX PubMed=15826241; DOI=10.1042/bj20050325; RA Salvioli R., Tatti M., Scarpa S., Moavero S.M., Ciaffoni F., Felicetti F., RA Kaneski C.R., Brady R.O., Vaccaro A.M.; RT "The N370S (Asn370->Ser) mutation affects the capacity of RT glucosylceramidase to interact with anionic phospholipid-containing RT membranes and saposin C."; RL Biochem. J. 390:95-103(2005). RN [105] RP CHARACTERIZATION OF VARIANTS GD HIS-179 AND GLN-196, CATALYTIC ACTIVITY, RP AND FUNCTION. RX PubMed=15916907; DOI=10.1016/j.bcmd.2005.03.006; RA Ron I., Dagan A., Gatt S., Pasmanik-Chor M., Horowitz M.; RT "Use of fluorescent substrates for characterization of Gaucher disease RT mutations."; RL Blood Cells Mol. Dis. 35:57-65(2005). RN [106] RP VARIANTS GD1 ASN-63; SER-158; TRP-159; CYS-170; LEU-221; GLU-230; ARG-241; RP CYS-324; SER-409; ASN-438; LEU-440; HIS-448; CYS-457; ASP-460; PRO-483 AND RP ARG-490, AND CHARACTERIZATION OF VARIANTS GD1 ASN-63; SER-158; LEU-221; RP GLU-230; ASP-460 AND ARG-490. RX PubMed=15605411; DOI=10.1002/humu.9301; RA Miocic S., Filocamo M., Dominissini S., Montalvo A.L., Vlahovicek K., RA Deganuto M., Mazzotti R., Cariati R., Bembi B., Pittis M.G.; RT "Identification and functional characterization of five novel mutant RT alleles in 58 Italian patients with Gaucher disease type 1."; RL Hum. Mutat. 25:100-100(2005). RN [107] RP POSSIBLE INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=16148263; DOI=10.1212/01.wnl.0000176987.47875.28; RA Aharon-Peretz J., Badarny S., Rosenbaum H., Gershoni-Baruch R.; RT "Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype- RT genotype correlation."; RL Neurology 65:1460-1461(2005). RN [108] RP INVOLVEMENT OF VARIANT GD PRO-483 IN SUSCEPTIBILITY TO PARKINSON DISEASE. RX PubMed=17620502; DOI=10.1001/archneur.64.7.1056; RA Tan E.K., Tong J., Fook-Chong S., Yih Y., Wong M.C., Pavanni R., Zhao Y.; RT "Glucocerebrosidase mutations and risk of Parkinson disease in Chinese RT patients."; RL Arch. Neurol. 64:1056-1058(2007). RN [109] RP INVOLVEMENT OF VARIANTS GD SER-409 AND PRO-483 IN SUSCEPTIBILITY TO RP PARKINSON DISEASE. RX PubMed=18332251; DOI=10.1001/archneurol.2007.68; RA Mata I.F., Samii A., Schneer S.H., Roberts J.W., Griffith A., Leis B.C., RA Schellenberg G.D., Sidransky E., Bird T.D., Leverenz J.B., Tsuang D., RA Zabetian C.P.; RT "Glucocerebrosidase gene mutations: a risk factor for Lewy body RT disorders."; RL Arch. Neurol. 65:379-382(2008). RN [110] RP INVOLVEMENT IN PARKINSON DISEASE, AND VARIANTS GLU-46; CYS-170; GLU-232; RP GLN-296; SER-409; ALA-419; HIS-448; ASN-482; PRO-483; PRO-495; LEU-497 AND RP CYS-502. RX PubMed=19286695; DOI=10.1093/brain/awp044; RA Neumann J., Bras J., Deas E., O'Sullivan S.S., Parkkinen L., Lachmann R.H., RA Li A., Holton J., Guerreiro R., Paudel R., Segarane B., Singleton A., RA Lees A., Hardy J., Houlden H., Revesz T., Wood N.W.; RT "Glucocerebrosidase mutations in clinical and pathologically proven RT Parkinson's disease."; RL Brain 132:1783-1794(2009). RN [111] RP INVOLVEMENT OF VARIANTS GD SER-409 AND PRO-483 IN SUSCEPTIBILITY TO RP PARKINSON DISEASE. RX PubMed=19846850; DOI=10.1056/nejmoa0901281; RA Sidransky E., Nalls M.A., Aasly J.O., Aharon-Peretz J., Annesi G., RA Barbosa E.R., Bar-Shira A., Berg D., Bras J., Brice A., Chen C.M., RA Clark L.N., Condroyer C., De Marco E.V., Durr A., Eblan M.J., Fahn S., RA Farrer M.J., Fung H.C., Gan-Or Z., Gasser T., Gershoni-Baruch R., RA Giladi N., Griffith A., Gurevich T., Januario C., Kropp P., Lang A.E., RA Lee-Chen G.J., Lesage S., Marder K., Mata I.F., Mirelman A., Mitsui J., RA Mizuta I., Nicoletti G., Oliveira C., Ottman R., Orr-Urtreger A., RA Pereira L.V., Quattrone A., Rogaeva E., Rolfs A., Rosenbaum H., RA Rozenberg R., Samii A., Samaddar T., Schulte C., Sharma M., Singleton A., RA Spitz M., Tan E.K., Tayebi N., Toda T., Troiano A.R., Tsuji S., RA Wittstock M., Wolfsberg T.G., Wu Y.R., Zabetian C.P., Zhao Y., RA Ziegler S.G.; RT "Multicenter analysis of glucocerebrosidase mutations in Parkinson's RT disease."; RL N. Engl. J. Med. 361:1651-1661(2009). RN [112] RP VARIANTS GD1 VAL-289; GLY-301 AND GLU-486. RX PubMed=22658918; DOI=10.1016/j.ymgme.2012.05.006; RA Duran R., McNeill A., Mehta A., Hughes D., Cox T., Deegan P., RA Schapira A.H., Hardy J.; RT "Novel pathogenic mutations in the glucocerebrosidase locus."; RL Mol. Genet. Metab. 106:495-497(2012). RN [113] RP VARIANTS GD1 LEU-266 AND SER-347. RX PubMed=24577513; DOI=10.1007/s00277-014-2036-x; RA Machaczka M., Klimkowska M.; RT "Novel heterozygous c.798C>G and c.1040T>G mutations in the GBA1 gene are RT associated with a severe phenotype of Gaucher disease type 1."; RL Ann. Hematol. 93:1787-1789(2014). RN [114] RP VARIANTS GD1 SER-198; THR-284; SER-351; LYS-365; ARG-405; ASN-419 AND RP CYS-420, CHARACTERIZATION OF VARIANTS GD1 SER-198; THR-284; SER-351; RP LYS-365; ARG-405; SER-409; ASN-419 AND CYS-420, VARIANTS GD2 ILE-227 AND RP LYS-274, CHARACTERIZATION OF VARIANTS GD2 ILE-227 AND LYS-274, VARIANTS GD3 RP SER-227 AND ARG-304, AND CHARACTERIZATION OF VARIANTS GD3 SER-227 AND RP ARG-304. RX PubMed=24022302; DOI=10.1038/ejhg.2013.182; RA Malini E., Grossi S., Deganuto M., Rosano C., Parini R., Dominisini S., RA Cariati R., Zampieri S., Bembi B., Filocamo M., Dardis A.; RT "Functional analysis of 11 novel GBA alleles."; RL Eur. J. Hum. Genet. 22:511-516(2014). RN [115] RP VARIANT GD1 TRP-62. RX PubMed=24434810; DOI=10.1016/j.gene.2014.01.015; RA Jack A., Amato D., Morris G., Choy F.Y.; RT "Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified RT in Type 1 Gaucher patients heterozygous for N370S."; RL Gene 538:84-87(2014). RN [116] RP VARIANT PRO-363. RX PubMed=26528954; DOI=10.1002/ana.24553; RG International Parkinsonism Genetics Network; RA Olgiati S., Quadri M., Fang M., Rood J.P., Saute J.A., Chien H.F., RA Bouwkamp C.G., Graafland J., Minneboo M., Breedveld G.J., Zhang J., RA Verheijen F.W., Boon A.J., Kievit A.J., Jardim L.B., Mandemakers W., RA Barbosa E.R., Rieder C.R., Leenders K.L., Wang J., Bonifati V.; RT "DNAJC6 mutations associated with early-onset Parkinson's disease."; RL Ann. Neurol. 79:244-256(2016). RN [117] RP VARIANT GD2 ARG-350, AND VARIANTS GD1 SER-409; SER-416; ARG-483; PRO-483 RP AND PRO-495. RX PubMed=27825739; DOI=10.1016/j.bcmd.2016.10.013; RA Basgalupp S.P., Siebert M., Vairo F.P.E., Chami A.M., Pinto L.L.C., RA Carvalho G.D.S., Schwartz I.V.D.; RT "Use of a multiplex ligation-dependent probe amplification method for the RT detection of deletions/duplications in the GBA1 gene in Gaucher disease RT patients."; RL Blood Cells Mol. Dis. 68:17-20(2018). RN [118] RP VARIANTS GD1 GLN-87; LEU-120; HIS-155; TRP-159; SER-174; PRO-214; ARG-223; RP ARG-241; ILE-252; ILE-270; GLN-294; ASN-322; VAL-348; ARG-350; SER-409; RP HIS-448; PRO-483; TYR-501; LYS-521 AND CYS-535, VARIANTS GD2 TRP-159; RP ARG-241; GLN-294; HIS-448 AND PRO-483, AND VARIANTS GD3 CYS-147; GLN-294; RP HIS-448 AND PRO-483. RX PubMed=32547927; DOI=10.1016/j.ymgmr.2020.100614; RA Dimitriou E., Moraitou M., Cozar M., Serra-Vinardell J., Vilageliu L., RA Grinberg D., Mavridou I., Michelakakis H.; RT "Gaucher disease: Biochemical and molecular findings in 141 patients RT diagnosed in Greece."; RL Mol. Genet. Metab. Rep. 24:100614-100614(2020). RN [119] RP CHARACTERIZATION OF VARIANT GD3 VAL-448. RX PubMed=34106956; DOI=10.1371/journal.pone.0252325; RA Polinski N.K., Martinez T.N., Gorodinsky A., Gareus R., Sasner M., RA Herberth M., Switzer R., Ahmad S.O., Cosden M., Kandebo M., Drolet R.E., RA Buckett P.D., Shan W., Chen Y., Pellegrino L.J., Ellsworth G.D., RA Dungan L.B., Hirst W.D., Clark S.W., Dave K.D.; RT "Decreased glucocerebrosidase activity and substrate accumulation of RT glycosphingolipids in a novel GBA1 D409V knock-in mouse model."; RL PLoS ONE 16:e0252325-e0252325(2021). RN [120] RP VARIANTS GD1 LEU-414 AND HIS-448. RX PubMed=36776904; DOI=10.3389/fped.2023.1092645; RA Liu Q., Shen Z., Pan H., Ma S., Xiong F., He F.; RT "The molecular mechanism of Gaucher disease caused by compound heterozygous RT mutations in GBA1 gene."; RL Front. Pediatr. 11:1092645-1092645(2023). CC -!- FUNCTION: Glucosylceramidase that catalyzes, within the lysosomal CC compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta- CC D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as CC N-acylsphing-4-enine) and glucose (PubMed:15916907, PubMed:24211208, CC PubMed:32144204, PubMed:39395789, PubMed:9201993). Plays a central role CC in the degradation of complex lipids and the turnover of cellular CC membranes (PubMed:27378698). Through the production of ceramides, CC participates in the PKC-activated salvage pathway of ceramide formation CC (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through CC a transglucosylation reaction where glucose is transferred from GlcCer CC to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). CC GlcCer containing mono-unsaturated fatty acids (such as beta-D- CC glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose CC donors for cholesterol glucosylation when compared with GlcCer CC containing same chain length of saturated fatty acids (such as beta-D- CC glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under CC specific conditions, may alternatively catalyze the reverse reaction, CC transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide CC (Probable) (PubMed:26724485). Can also hydrolyze cholesteryl 3-beta-D- CC glucoside producing glucose and cholesterol (PubMed:24211208, CC PubMed:26724485, PubMed:39395789). Catalyzes the hydrolysis of CC galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N- CC acylsphing-4-enine), as well as the transfer of galactose between CC GalCers and cholesterol in vitro, but with lower activity than with CC GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, CC xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4- CC enine) is not a good substrate for hydrolysis, however it is a good CC xylose donor for transxylosylation activity to form cholesteryl 3-beta- CC D-xyloside (PubMed:33361282). Can also metabolize plant glycosyl CC phytosterols such as glucosylstigmasterol (PubMed:39395789). CC {ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:19279011, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:27378698, ECO:0000269|PubMed:32144204, CC ECO:0000269|PubMed:33361282, ECO:0000269|PubMed:39395789, CC ECO:0000269|PubMed:9201993, ECO:0000305|PubMed:32144204}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + H2O = an N- CC acylsphing-4-enine + D-glucose; Xref=Rhea:RHEA:13269, CC ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, ChEBI:CHEBI:22801, CC ChEBI:CHEBI:52639; EC=3.2.1.45; CC Evidence={ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204, CC ECO:0000269|PubMed:9201993}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13270; CC Evidence={ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H2O = an CC N-acylsphing-4-enine + D-galactose; Xref=Rhea:RHEA:14297, CC ChEBI:CHEBI:4139, ChEBI:CHEBI:15377, ChEBI:CHEBI:18390, CC ChEBI:CHEBI:52639; EC=3.2.1.46; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14298; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=cholesteryl 3-beta-D-glucoside + H2O = cholesterol + D- CC glucose; Xref=Rhea:RHEA:11956, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:16113, ChEBI:CHEBI:17495; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:33361282, CC ECO:0000269|PubMed:39395789}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11957; CC Evidence={ECO:0000269|PubMed:33361282, ECO:0000269|PubMed:39395789, CC ECO:0000305|PubMed:24211208}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + cholesterol CC = cholesteryl 3-beta-D-glucoside + an N-acylsphing-4-enine; CC Xref=Rhea:RHEA:58264, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:22801, ChEBI:CHEBI:52639; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58265; CC Evidence={ECO:0000269|PubMed:32144204, ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58266; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine + CC cholesterol = N-(9Z-octadecenoyl)-sphing-4-enine + cholesteryl 3- CC beta-D-glucoside; Xref=Rhea:RHEA:58324, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:17495, ChEBI:CHEBI:77996, ChEBI:CHEBI:139140; CC Evidence={ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58325; CC Evidence={ECO:0000269|PubMed:32144204, ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58326; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1')-N-hexadecanoylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-glucoside + N-hexadecanoylsphing- CC 4-enine; Xref=Rhea:RHEA:58316, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72959, ChEBI:CHEBI:84716; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58317; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58318; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-octanoylsphing-4E-enine + cholesterol = N- CC octanoylsphing-4-enine + cholesteryl 3-beta-D-glucoside; CC Xref=Rhea:RHEA:70303, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:45815, ChEBI:CHEBI:65222; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70304; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70305; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-N-dodecanoylsphing-4-enine + cholesterol = N- CC dodecanoylsphing-4-enine + cholesteryl 3-beta-D-glucoside; CC Xref=Rhea:RHEA:70307, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72956, ChEBI:CHEBI:76297; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70308; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70309; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1)-N-octadecanoylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-glucoside + N-octadecanoylsphing- CC 4-enine; Xref=Rhea:RHEA:70311, ChEBI:CHEBI:16113, ChEBI:CHEBI:17495, CC ChEBI:CHEBI:72961, ChEBI:CHEBI:84719; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70312; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70313; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-glucosyl-(1<->1')-N-(15Z-tetracosenoyl)-sphing-4-enine CC + cholesterol = N-(15Z-tetracosenoyl)-sphing-4-enine + cholesteryl 3- CC beta-D-glucoside; Xref=Rhea:RHEA:70315, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:17495, ChEBI:CHEBI:74450, ChEBI:CHEBI:76302; CC Evidence={ECO:0000269|PubMed:24211208}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70316; CC Evidence={ECO:0000305|PubMed:24211208}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70317; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-galactoside + an N-acylsphing-4- CC enine; Xref=Rhea:RHEA:70235, ChEBI:CHEBI:16113, ChEBI:CHEBI:18390, CC ChEBI:CHEBI:52639, ChEBI:CHEBI:189066; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70236; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70237; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol CC = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine; CC Xref=Rhea:RHEA:70255, ChEBI:CHEBI:16113, ChEBI:CHEBI:72956, CC ChEBI:CHEBI:73432, ChEBI:CHEBI:189066; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70256; CC Evidence={ECO:0000269|PubMed:32144204}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70257; CC Evidence={ECO:0000305|PubMed:32144204}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine + cholesterol = CC cholesteryl 3-beta-D-xyloside + an N-acylsphing-4-enine; CC Xref=Rhea:RHEA:70239, ChEBI:CHEBI:16113, ChEBI:CHEBI:52639, CC ChEBI:CHEBI:189067, ChEBI:CHEBI:189068; CC Evidence={ECO:0000269|PubMed:33361282}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70240; CC Evidence={ECO:0000269|PubMed:33361282}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-xylosyl-(1<->1')-N-(9Z-octadecenoyl)-sphing-4-enine + CC cholesterol = cholesteryl 3-beta-D-xyloside + N-(9Z-octadecenoyl)- CC sphing-4-enine; Xref=Rhea:RHEA:70251, ChEBI:CHEBI:16113, CC ChEBI:CHEBI:77996, ChEBI:CHEBI:189067, ChEBI:CHEBI:189081; CC Evidence={ECO:0000269|PubMed:33361282}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70252; CC Evidence={ECO:0000269|PubMed:33361282}; CC -!- CATALYTIC ACTIVITY: CC Reaction=stigmasteryl 3-beta-D-glucoside + H2O = stigmasterol + D- CC glucose; Xref=Rhea:RHEA:62028, ChEBI:CHEBI:4167, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:28824, ChEBI:CHEBI:68383; CC Evidence={ECO:0000269|PubMed:39395789}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62029; CC Evidence={ECO:0000269|PubMed:39395789}; CC -!- ACTIVITY REGULATION: Synergistically activated by saposin-A and CC saposin-C, two saposin peptides produced by proteolytic processing of CC prosaposin/PSAP (PubMed:9201993). Saposin-C activates GBA1 through its CC recruitment to membranes (PubMed:10781797, PubMed:9201993). The CC membrane structure and composition in anionic phospholipids are also CC important for the activation (PubMed:10781797, PubMed:9201993). CC Activated by PKC in the salvage pathway of ceramide formation CC (PubMed:19279011). Inhibited by conduritol B epoxide/CBE CC (PubMed:24211208, PubMed:26724485). {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:19279011, ECO:0000269|PubMed:24211208, CC ECO:0000269|PubMed:26724485, ECO:0000269|PubMed:9201993}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 5.3. {ECO:0000269|PubMed:24211208}; CC Temperature dependence: CC Optimum temperature is 43 degrees Celsius. CC {ECO:0000269|PubMed:24211208}; CC -!- PATHWAY: Steroid metabolism; cholesterol metabolism. CC {ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485}. CC -!- PATHWAY: Sphingolipid metabolism. {ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:24211208, ECO:0000269|PubMed:26724485, CC ECO:0000269|PubMed:9201993}. CC -!- SUBUNIT: Interacts with saposin-C (PubMed:10781797). Interacts with CC SCARB2 (PubMed:18022370). Interacts with TCP1 (PubMed:21098288). May CC interacts with SNCA; this interaction may inhibit the CC glucosylceramidase activity (PubMed:23266198). Interacts with GRN; this CC interaction prevents aggregation of GBA1-SCARB2 complex via interaction CC with HSPA1A upon stress (PubMed:27789271). CC {ECO:0000269|PubMed:10781797, ECO:0000269|PubMed:18022370, CC ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:23266198, CC ECO:0000269|PubMed:27789271}. CC -!- INTERACTION: CC P04062; P17987: TCP1; NbExp=2; IntAct=EBI-1564609, EBI-356553; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17187079, CC ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370}; Peripheral CC membrane protein {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:1848227}; Lumenal side CC {ECO:0000269|PubMed:18022370}. Note=Interaction with saposin-C promotes CC membrane association (PubMed:10781797). Targeting to lysosomes occurs CC through an alternative MPR-independent mechanism via SCARB2 CC (PubMed:18022370). {ECO:0000269|PubMed:10781797, CC ECO:0000269|PubMed:18022370}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=5; CC Name=Long; CC IsoId=P04062-1; Sequence=Displayed; CC Name=Short; CC IsoId=P04062-2; Sequence=VSP_018800; CC Name=3; CC IsoId=P04062-3; Sequence=VSP_025216, VSP_025217, VSP_025218; CC Name=4; CC IsoId=P04062-4; Sequence=VSP_054655; CC Name=5; CC IsoId=P04062-5; Sequence=VSP_054656; CC -!- DISEASE: Gaucher disease (GD) [MIM:230800]: An autosomal recessive CC lysosomal storage disease due to deficient activity of lysosomal beta- CC glucocerebrosidase, and characterized by accumulation of CC glucosylceramide in the reticulo-endothelial system. GD is a CC multisystem disease historically divided into three main subtypes on CC the basis of the presence of neurologic involvement, age at onset and CC progression rate: type 1 is the non-neuropathic form, type 2 is the CC acute neuropathic form with early onset and rapid neurologic CC deterioration, type 3 is the chronic neuropathic form with slow CC progression of neurologic features. GD shows a marked phenotypic CC diversity ranging from adult asymptomatic forms, at the mild end, to CC perinatal lethal forms at the severe end of the disease spectrum. CC Formal diagnosis of Gaucher disease is based on the measurement of CC glucocerebrosidase levels in circulating leukocytes and molecular CC genetic analysis. {ECO:0000269|PubMed:10352942, CC ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10744424, CC ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, CC ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:15826241, CC ECO:0000269|PubMed:15916907, ECO:0000269|PubMed:16293621, CC ECO:0000269|PubMed:17620502, ECO:0000269|PubMed:18332251, CC ECO:0000269|PubMed:1972019, ECO:0000269|PubMed:1974409, CC ECO:0000269|PubMed:19846850, ECO:0000269|PubMed:7475546, CC ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7627192, CC ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8294033, CC ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8432537, CC ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:8829663, CC ECO:0000269|PubMed:8937765, ECO:0000269|PubMed:9061570, CC ECO:0000269|PubMed:9182788, ECO:0000269|PubMed:9217217, CC ECO:0000269|PubMed:9516376, ECO:0000269|PubMed:9554454, CC ECO:0000269|PubMed:9650766}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 1 (GD1) [MIM:230800]: A form of Gaucher CC disease, an autosomal recessive lysosomal storage disease due to CC deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD1 is characterized by hepatosplenomegaly with CC consequent anemia and thrombopenia, and bone involvement. The central CC nervous system is not involved. {ECO:0000269|PubMed:10206680, CC ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:10360404, CC ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, CC ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:1301953, CC ECO:0000269|PubMed:1487244, ECO:0000269|PubMed:15605411, CC ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:1899336, CC ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:22658918, CC ECO:0000269|PubMed:2269438, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:24434810, ECO:0000269|PubMed:24577513, CC ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:27825739, CC ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:36776904, CC ECO:0000269|PubMed:7655857, ECO:0000269|PubMed:7915932, CC ECO:0000269|PubMed:7916532, ECO:0000269|PubMed:8294487, CC ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:8547070, CC ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8790604, CC ECO:0000269|PubMed:8829663, ECO:0000269|PubMed:8889591, CC ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9153297, CC ECO:0000269|PubMed:9240741, ECO:0000269|PubMed:9295080, CC ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9683600, CC ECO:0000269|PubMed:9856561, ECO:0000269|Ref.14}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 2 (GD2) [MIM:230900]: The most severe form of CC Gaucher disease, an autosomal recessive lysosomal storage disease due CC to deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD2 is an acute neuronopathic form that manifests CC soon after birth, with death generally occurring before patients reach CC two years of age. Clinical features include hepatosplenomegaly, CC developmental regression, growth arrest, and rapidly progressing CC neurologic deterioration. {ECO:0000269|PubMed:10360404, CC ECO:0000269|PubMed:10649495, ECO:0000269|PubMed:10679038, CC ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, CC ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15690354, CC ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:21098288, CC ECO:0000269|PubMed:2269438, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:2464926, ECO:0000269|PubMed:27825739, CC ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:7627192, CC ECO:0000269|PubMed:7981693, ECO:0000269|PubMed:8112750, CC ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8598642, CC ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9240741, CC ECO:0000269|PubMed:9279145, ECO:0000269|PubMed:9554454, CC ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9637431, CC ECO:0000269|PubMed:9851895, ECO:0000269|PubMed:9856561}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Gaucher disease 3 (GD3) [MIM:231000]: A form of Gaucher CC disease, an autosomal recessive lysosomal storage disease due to CC deficient activity of lysosomal beta-glucocerebrosidase, and CC characterized by accumulation of glucosylceramide in the reticulo- CC endothelial system. GD3 is a subacute neuronopathic form characterized CC by later onset and slower progression compared to Gaucher disease 2. CC {ECO:0000269|PubMed:10360404, ECO:0000269|PubMed:10796875, CC ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:12204005, CC ECO:0000269|PubMed:1487244, ECO:0000269|PubMed:24022302, CC ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:32547927, CC ECO:0000269|PubMed:34106956, ECO:0000269|PubMed:8294487, CC ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8780099, CC ECO:0000269|PubMed:9683600}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease 3C (GD3C) [MIM:231005]: A variant of subacute CC neuronopathic Gaucher disease 3 associated with cardiovascular CC calcifications. {ECO:0000269|PubMed:9040001}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease perinatal lethal (GDPL) [MIM:608013]: Distinct CC form of Gaucher disease type 2, characterized by fetal onset. Hydrops CC fetalis, in utero fetal death and neonatal distress are prominent CC features. When hydrops is absent, neurologic involvement begins in the CC first week and leads to death within 3 months. Hepatosplenomegaly is a CC major sign, and is associated with ichthyosis, arthrogryposis, and CC facial dysmorphism. {ECO:0000269|PubMed:10352942, CC ECO:0000269|PubMed:11933202}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Perinatal lethal Gaucher CC disease is associated with non-immune hydrops fetalis, a generalized CC edema of the fetus with fluid accumulation in the body cavities due to CC non-immune causes. Non-immune hydrops fetalis is not a diagnosis in CC itself but a symptom, a feature of many genetic disorders, and the end- CC stage of a wide variety of disorders. {ECO:0000269|PubMed:10352942}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12847165, CC ECO:0000269|PubMed:16148263, ECO:0000269|PubMed:17620502, CC ECO:0000269|PubMed:18332251, ECO:0000269|PubMed:19286695, CC ECO:0000269|PubMed:19846850}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC -!- PHARMACEUTICAL: Available under the names Ceredase and Cerenzyme CC (Genzyme). Used to treat Gaucher disease. CC -!- MISCELLANEOUS: [Isoform Long]: Major isoform. CC {ECO:0000269|PubMed:3687939}. CC -!- MISCELLANEOUS: [Isoform Short]: Produced by alternative initiation from CC a downstream AUG. Two to three times less protein is produced from this CC downstream AUG. {ECO:0000269|PubMed:3687939}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 30 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Ceredase; Note=Clinical information on Ceredase; CC URL="https://www.rxlist.com/ceredase-drug.htm"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M16328; AAA35873.1; -; mRNA. DR EMBL; K02920; AAA35877.1; -; mRNA. DR EMBL; J03059; AAC63056.1; -; Genomic_DNA. DR EMBL; D13286; BAA02545.1; -; mRNA. DR EMBL; D13287; BAA02546.1; -; mRNA. DR EMBL; AF023268; AAC51820.1; -; Genomic_DNA. DR EMBL; AK291911; BAF84600.1; -; mRNA. DR EMBL; AK298900; BAH12898.1; -; mRNA. DR EMBL; AK300829; BAH13357.1; -; mRNA. DR EMBL; AL713999; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC003356; AAH03356.1; -; mRNA. DR EMBL; M19285; AAA35880.1; -; mRNA. DR EMBL; M18916; AAA35878.1; ALT_SEQ; Genomic_DNA. DR EMBL; M18917; AAA35879.1; ALT_SEQ; Genomic_DNA. DR EMBL; M20248; AAA35874.1; -; Genomic_DNA. DR EMBL; M20282; AAA35876.1; -; Genomic_DNA. DR CCDS; CCDS1102.1; -. [P04062-1] DR CCDS; CCDS53373.1; -. [P04062-4] DR CCDS; CCDS53374.1; -. [P04062-5] DR PIR; A94068; EUHUGC. DR PIR; I52980; I52980. DR PIR; I67792; I67792. DR RefSeq; NP_000148.2; NM_000157.4. [P04062-1] DR RefSeq; NP_001005741.1; NM_001005741.3. [P04062-1] DR RefSeq; NP_001005742.1; NM_001005742.3. [P04062-1] DR RefSeq; NP_001165282.1; NM_001171811.2. [P04062-4] DR RefSeq; NP_001165283.1; NM_001171812.2. [P04062-5] DR PDB; 1OGS; X-ray; 2.00 A; A/B=40-536. DR PDB; 1Y7V; X-ray; 2.40 A; A/B=40-536. DR PDB; 2F61; X-ray; 2.50 A; A/B=40-536. DR PDB; 2J25; X-ray; 2.90 A; A/B=40-536. DR PDB; 2NSX; X-ray; 2.11 A; A/B/C/D=40-536. DR PDB; 2NT0; X-ray; 1.79 A; A/B/C/D=40-536. DR PDB; 2NT1; X-ray; 2.30 A; A/B/C/D=40-536. DR PDB; 2V3D; X-ray; 1.96 A; A/B=40-536. DR PDB; 2V3E; X-ray; 2.00 A; A/B=40-536. DR PDB; 2V3F; X-ray; 1.95 A; A/B=40-536. DR PDB; 2VT0; X-ray; 2.15 A; A/B=40-536. DR PDB; 2WCG; X-ray; 2.30 A; A/B=40-536. DR PDB; 2WKL; X-ray; 2.70 A; A/B=40-536. DR PDB; 2XWD; X-ray; 2.66 A; A/B=40-536. DR PDB; 2XWE; X-ray; 2.31 A; A/B=40-536. DR PDB; 3GXD; X-ray; 2.50 A; A/B/C/D=40-536. DR PDB; 3GXF; X-ray; 2.40 A; A/B/C/D=40-536. DR PDB; 3GXI; X-ray; 1.84 A; A/B/C/D=40-536. DR PDB; 3GXM; X-ray; 2.20 A; A/B/C/D=40-536. DR PDB; 3KE0; X-ray; 2.70 A; A/B=40-536. DR PDB; 3KEH; X-ray; 2.80 A; A/B=40-536. DR PDB; 3RIK; X-ray; 2.48 A; A/B/C/D=40-536. DR PDB; 3RIL; X-ray; 2.40 A; A/B/C/D=40-536. DR PDB; 5LVX; X-ray; 2.20 A; A/B/C/D=40-536. DR PDB; 6MOZ; X-ray; 2.10 A; A/B=40-536. DR PDB; 6Q1N; X-ray; 2.53 A; A/B=40-536. DR PDB; 6Q1P; X-ray; 2.80 A; A/B=40-536. DR PDB; 6Q6K; X-ray; 1.92 A; A/B=40-536. DR PDB; 6Q6L; X-ray; 1.81 A; A/B=40-536. DR PDB; 6Q6N; X-ray; 1.63 A; A/B=40-536. DR PDB; 6T13; X-ray; 1.85 A; A/B/C/D=1-536. DR PDB; 6TJJ; X-ray; 1.59 A; AAA/BBB=40-536. DR PDB; 6TJK; X-ray; 1.56 A; AAA/BBB=40-536. DR PDB; 6TJQ; X-ray; 1.41 A; BBB=40-536. DR PDB; 6TN1; X-ray; 0.98 A; AAA=40-536. DR PDB; 6YTP; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6YTR; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6YUT; X-ray; 1.76 A; AAA/BBB=40-536. DR PDB; 6YV3; X-ray; 1.80 A; AAA/BBB=40-536. DR PDB; 6Z39; X-ray; 1.70 A; AAA/BBB=40-536. DR PDB; 6Z3I; X-ray; 1.80 A; BBB=40-536. DR PDB; 7NWV; X-ray; 1.86 A; AAA/BBB=40-536. DR PDB; 8AWK; X-ray; 1.58 A; AAA=40-536. DR PDB; 8AWR; X-ray; 1.49 A; AAA=40-536. DR PDB; 8AX3; X-ray; 1.59 A; A/B=40-536. DR PDB; 8P3E; X-ray; 1.75 A; A/B=40-536. DR PDB; 8P41; X-ray; 1.83 A; A/B=40-536. DR PDB; 9ENA; X-ray; 1.70 A; A=40-536. DR PDB; 9F9Z; X-ray; 2.28 A; A=40-536. DR PDB; 9FA3; X-ray; 1.36 A; A=1-536. DR PDB; 9FA6; X-ray; 1.49 A; A=1-536. DR PDB; 9FAD; X-ray; 1.80 A; A=1-536. DR PDB; 9FAL; X-ray; 1.39 A; A=1-536. DR PDB; 9FAY; X-ray; 1.40 A; A=1-536. DR PDB; 9FAZ; X-ray; 1.63 A; A=1-536. DR PDB; 9FB2; X-ray; 1.14 A; A=1-536. DR PDB; 9FDI; X-ray; 1.41 A; A=1-536. DR PDB; 9FJF; EM; 3.70 A; B=40-536. DR PDBsum; 1OGS; -. DR PDBsum; 1Y7V; -. DR PDBsum; 2F61; -. DR PDBsum; 2J25; -. DR PDBsum; 2NSX; -. DR PDBsum; 2NT0; -. DR PDBsum; 2NT1; -. DR PDBsum; 2V3D; -. DR PDBsum; 2V3E; -. DR PDBsum; 2V3F; -. DR PDBsum; 2VT0; -. DR PDBsum; 2WCG; -. DR PDBsum; 2WKL; -. DR PDBsum; 2XWD; -. DR PDBsum; 2XWE; -. DR PDBsum; 3GXD; -. DR PDBsum; 3GXF; -. DR PDBsum; 3GXI; -. DR PDBsum; 3GXM; -. DR PDBsum; 3KE0; -. DR PDBsum; 3KEH; -. DR PDBsum; 3RIK; -. DR PDBsum; 3RIL; -. DR PDBsum; 5LVX; -. DR PDBsum; 6MOZ; -. DR PDBsum; 6Q1N; -. DR PDBsum; 6Q1P; -. DR PDBsum; 6Q6K; -. DR PDBsum; 6Q6L; -. DR PDBsum; 6Q6N; -. DR PDBsum; 6T13; -. DR PDBsum; 6TJJ; -. DR PDBsum; 6TJK; -. DR PDBsum; 6TJQ; -. DR PDBsum; 6TN1; -. DR PDBsum; 6YTP; -. DR PDBsum; 6YTR; -. DR PDBsum; 6YUT; -. DR PDBsum; 6YV3; -. DR PDBsum; 6Z39; -. DR PDBsum; 6Z3I; -. DR PDBsum; 7NWV; -. DR PDBsum; 8AWK; -. DR PDBsum; 8AWR; -. DR PDBsum; 8AX3; -. DR PDBsum; 8P3E; -. DR PDBsum; 8P41; -. DR PDBsum; 9ENA; -. DR PDBsum; 9F9Z; -. DR PDBsum; 9FA3; -. DR PDBsum; 9FA6; -. DR PDBsum; 9FAD; -. DR PDBsum; 9FAL; -. DR PDBsum; 9FAY; -. DR PDBsum; 9FAZ; -. DR PDBsum; 9FB2; -. DR PDBsum; 9FDI; -. DR PDBsum; 9FJF; -. DR AlphaFoldDB; P04062; -. DR EMDB; EMD-50502; -. DR EMDB; EMD-50936; -. DR EMDB; EMD-50937; -. DR EMDB; EMD-50938; -. DR SMR; P04062; -. DR BioGRID; 108899; 144. DR CORUM; P04062; -. DR DIP; DIP-38645N; -. DR FunCoup; P04062; 516. DR IntAct; P04062; 72. DR MINT; P04062; -. DR STRING; 9606.ENSP00000314508; -. DR BindingDB; P04062; -. DR ChEMBL; CHEMBL2179; -. DR DrugBank; DB08321; (1S,2S,3R,6R)-4-(hydroxymethyl)-6-(octylamino)cyclohex-4-ene-1,2,3-triol. DR DrugBank; DB08283; (2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOL. DR DrugBank; DB04545; Afegostat. DR DrugBank; DB03740; N-acetyl-alpha-D-glucosamine. DR DrugBank; DB03106; scyllo-inositol. DR DrugBank; DB06720; Velaglucerase alfa. DR DrugCentral; P04062; -. DR SwissLipids; SLP:000001387; -. DR Allergome; 8244; Hom s Glucocerebrosidase. DR CAZy; GH30; Glycoside Hydrolase Family 30. DR GlyConnect; 1271; 26 N-Linked glycans (4 sites). DR GlyCosmos; P04062; 6 sites, 29 glycans. DR GlyGen; P04062; 8 sites, 35 N-linked glycans (4 sites), 1 O-linked glycan (2 sites). DR iPTMnet; P04062; -. DR MetOSite; P04062; -. DR PhosphoSitePlus; P04062; -. DR SwissPalm; P04062; -. DR BioMuta; GBA; -. DR DMDM; 55584151; -. DR jPOST; P04062; -. DR MassIVE; P04062; -. DR PaxDb; 9606-ENSP00000314508; -. DR PeptideAtlas; P04062; -. DR ProteomicsDB; 51642; -. [P04062-1] DR ProteomicsDB; 51643; -. [P04062-2] DR ProteomicsDB; 51644; -. [P04062-3] DR Pumba; P04062; -. DR ABCD; P04062; 7 sequenced antibodies. DR Antibodypedia; 1678; 510 antibodies from 33 providers. DR DNASU; 2629; -. DR Ensembl; ENST00000327247.9; ENSP00000314508.5; ENSG00000177628.17. [P04062-1] DR Ensembl; ENST00000368373.8; ENSP00000357357.3; ENSG00000177628.17. [P04062-1] DR Ensembl; ENST00000427500.7; ENSP00000402577.2; ENSG00000177628.17. [P04062-5] DR Ensembl; ENST00000428024.3; ENSP00000397986.2; ENSG00000177628.17. [P04062-4] DR GeneID; 2629; -. DR KEGG; hsa:2629; -. DR MANE-Select; ENST00000368373.8; ENSP00000357357.3; NM_000157.4; NP_000148.2. DR UCSC; uc001fjh.4; human. [P04062-1] DR AGR; HGNC:4177; -. DR ClinPGx; PA28591; -. DR CTD; 2629; -. DR DisGeNET; 2629; -. DR GeneCards; GBA1; -. DR GeneReviews; GBA1; -. DR HGNC; HGNC:4177; GBA1. DR HPA; ENSG00000177628; Low tissue specificity. DR MalaCards; GBA1; -. DR MIM; 168600; phenotype. DR MIM; 230800; phenotype. DR MIM; 230900; phenotype. DR MIM; 231000; phenotype. DR MIM; 231005; phenotype. DR MIM; 606463; gene. DR MIM; 608013; phenotype. DR OpenTargets; ENSG00000177628; -. DR Orphanet; 85212; Fetal Gaucher disease. DR Orphanet; 77259; Gaucher disease type 1. DR Orphanet; 77260; Gaucher disease type 2. DR Orphanet; 77261; Gaucher disease type 3. DR Orphanet; 2072; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000177628; -. DR eggNOG; KOG2566; Eukaryota. DR GeneTree; ENSGT00390000009464; -. DR HOGENOM; CLU_014379_1_2_1; -. DR InParanoid; P04062; -. DR OMA; FGGIAWH; -. DR OrthoDB; 2160638at2759; -. DR PAN-GO; P04062; 2 GO annotations based on evolutionary models. DR PhylomeDB; P04062; -. DR BRENDA; 3.2.1.45; 2681. DR PathwayCommons; P04062; -. DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SignaLink; P04062; -. DR SIGNOR; P04062; -. DR UniPathway; UPA00296; -. DR Agora; ENSG00000177628; -. DR BioGRID-ORCS; 2629; 10 hits in 1162 CRISPR screens. DR ChiTaRS; GBA; human. DR EvolutionaryTrace; P04062; -. DR GeneWiki; Glucocerebrosidase; -. DR GenomeRNAi; 2629; -. DR Pharos; P04062; Tclin. DR PRO; PR:P04062; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P04062; protein. DR Bgee; ENSG00000177628; Expressed in stromal cell of endometrium and 101 other cell types or tissues. DR ExpressionAtlas; P04062; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; ISS:BHF-UCL. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IMP:ARUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB. DR GO; GO:0008422; F:beta-glucosidase activity; IDA:MGI. DR GO; GO:0004336; F:galactosylceramidase activity; IEA:UniProtKB-EC. DR GO; GO:0004348; F:glucosylceramidase activity; IDA:UniProtKB. DR GO; GO:0046527; F:glucosyltransferase activity; IDA:UniProtKB. DR GO; GO:0005124; F:scavenger receptor binding; IPI:ARUK-UCL. DR GO; GO:0005102; F:signaling receptor binding; ISS:BHF-UCL. DR GO; GO:0050295; F:steryl-beta-glucosidase activity; IDA:UniProtKB. DR GO; GO:0019882; P:antigen processing and presentation; IEA:Ensembl. DR GO; GO:1905037; P:autophagosome organization; IEA:Ensembl. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1901805; P:beta-glucoside catabolic process; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0048469; P:cell maturation; IEA:Ensembl. DR GO; GO:0009267; P:cellular response to starvation; IEA:Ensembl. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IMP:BHF-UCL. DR GO; GO:0046513; P:ceramide biosynthetic process; IMP:BHF-UCL. DR GO; GO:0021694; P:cerebellar Purkinje cell layer formation; IEA:Ensembl. DR GO; GO:0008203; P:cholesterol metabolic process; IDA:UniProtKB. DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl. DR GO; GO:0061436; P:establishment of skin barrier; IEA:Ensembl. DR GO; GO:0006680; P:glucosylceramide catabolic process; IDA:UniProtKB. DR GO; GO:0009247; P:glycolipid biosynthetic process; IDA:UniProtKB. DR GO; GO:0071425; P:hematopoietic stem cell proliferation; IEA:Ensembl. DR GO; GO:0048872; P:homeostasis of number of cells; IEA:Ensembl. DR GO; GO:0006955; P:immune response; IEA:Ensembl. DR GO; GO:0019915; P:lipid storage; IEA:Ensembl. DR GO; GO:0072676; P:lymphocyte migration; IEA:Ensembl. DR GO; GO:1905146; P:lysosomal protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0007040; P:lysosome organization; IMP:UniProtKB. DR GO; GO:0014004; P:microglia differentiation; IEA:Ensembl. DR GO; GO:0061518; P:microglial cell proliferation; IEA:Ensembl. DR GO; GO:0000423; P:mitophagy; IEA:Ensembl. DR GO; GO:0061744; P:motor behavior; IEA:Ensembl. DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:BHF-UCL. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IMP:BHF-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051248; P:negative regulation of protein metabolic process; IEA:Ensembl. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:1904457; P:positive regulation of neuronal action potential; IMP:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0021859; P:pyramidal neuron differentiation; IEA:Ensembl. DR GO; GO:1905165; P:regulation of lysosomal protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0032006; P:regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:0022904; P:respiratory electron transport chain; IEA:Ensembl. DR GO; GO:0071548; P:response to dexamethasone; IEA:Ensembl. DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl. DR GO; GO:0009268; P:response to pH; IEA:Ensembl. DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl. DR GO; GO:0097066; P:response to thyroid hormone; IEA:Ensembl. DR GO; GO:0046512; P:sphingosine biosynthetic process; IMP:BHF-UCL. DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl. DR GO; GO:0023021; P:termination of signal transduction; IMP:BHF-UCL. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR FunFam; 3.20.20.80:FF:000030; Lysosomal acid glucosylceramidase; 1. DR Gene3D; 3.20.20.80; Glycosidases; 1. DR InterPro; IPR017853; GH. DR InterPro; IPR033452; GH30_C. DR InterPro; IPR001139; Glyco_hydro_30. DR InterPro; IPR033453; Glyco_hydro_30_TIM-barrel. DR PANTHER; PTHR11069; GLUCOSYLCERAMIDASE; 1. DR PANTHER; PTHR11069:SF33; LYSOSOMAL ACID GLUCOSYLCERAMIDASE; 1. DR Pfam; PF02055; Glyco_hydro_30; 1. DR Pfam; PF17189; Glyco_hydro_30C; 1. DR PRINTS; PR00843; GLHYDRLASE30. DR SUPFAM; SSF51445; (Trans)glycosidases; 1. DR SUPFAM; SSF51011; Glycosyl hydrolase domain; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Alternative splicing; KW Cholesterol metabolism; Direct protein sequencing; Disease variant; KW Disulfide bond; Gaucher disease; Glycoprotein; Glycosidase; KW Glycosyltransferase; Hydrolase; Ichthyosis; Lipid metabolism; Lysosome; KW Membrane; Neurodegeneration; Parkinson disease; Parkinsonism; KW Pharmaceutical; Proteomics identification; Reference proteome; Signal; KW Sphingolipid metabolism; Steroid metabolism; Sterol metabolism; KW Transferase. FT SIGNAL 1..39 FT /evidence="ECO:0000269|Ref.12" FT CHAIN 40..536 FT /note="Lysosomal acid glucosylceramidase" FT /id="PRO_0000012177" FT ACT_SITE 274 FT /note="Proton donor" FT /evidence="ECO:0000269|PubMed:15817452" FT ACT_SITE 379 FT /note="Nucleophile" FT /evidence="ECO:0000269|PubMed:15817452" FT CARBOHYD 58 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0000269|PubMed:17139081" FT CARBOHYD 98 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:17139081, ECO:0000269|PubMed:19159218" FT CARBOHYD 185 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:17139081" FT CARBOHYD 309 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:19159218" FT CARBOHYD 501 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 43..55 FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0007744|PDB:1OGS" FT DISULFID 57..62 FT /evidence="ECO:0000269|PubMed:12792654, FT ECO:0007744|PDB:1OGS" FT VAR_SEQ 1..161 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025216" FT VAR_SEQ 1..87 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054655" FT VAR_SEQ 1..20 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000303|PubMed:3001061, FT ECO:0000303|PubMed:3864160" FT /id="VSP_018800" FT VAR_SEQ 103..151 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054656" FT VAR_SEQ 422..423 FT /note="LA -> PS (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025217" FT VAR_SEQ 425..536 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:8294033" FT /id="VSP_025218" FT VARIANT 46 FT /note="K -> E (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs142761046)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063066" FT VARIANT 54 FT /note="V -> L (in GD; dbSNP:rs121908302)" FT /evidence="ECO:0000269|PubMed:8829654" FT /id="VAR_003255" FT VARIANT 55 FT /note="C -> S (in GD; neuronopathic and perinatal lethal FT forms; loss of glucosylceramidase activity; FT dbSNP:rs773007510)" FT /evidence="ECO:0000269|PubMed:11992489, FT ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:16293621" FT /id="VAR_032394" FT VARIANT 62 FT /note="C -> W (in GD1)" FT /evidence="ECO:0000269|PubMed:24434810" FT /id="VAR_081188" FT VARIANT 63 FT /note="D -> N (in GD1; very low glucosylceramidase FT activity)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032395" FT VARIANT 76 FT /note="F -> V (in GD)" FT /evidence="ECO:0000269|PubMed:9217217" FT /id="VAR_003256" FT VARIANT 80 FT /note="E -> K (in GD2)" FT /evidence="ECO:0000269|PubMed:9851895" FT /id="VAR_009033" FT VARIANT 82 FT /note="T -> I (in GD1; dbSNP:rs1141811)" FT /evidence="ECO:0000269|PubMed:7655857" FT /id="VAR_003257" FT VARIANT 85 FT /note="G -> E (in GD; dbSNP:rs77829017)" FT /evidence="ECO:0000269|PubMed:8829654, FT ECO:0000269|PubMed:9217217" FT /id="VAR_003258" FT VARIANT 87 FT /note="R -> Q (in GD1; decreased glucosylceramidase FT activity; 20% of normal activity; dbSNP:rs78769774)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:32547927" FT /id="VAR_032197" FT VARIANT 87 FT /note="R -> W (in GD1; decreased glucosylceramidase FT activity; dbSNP:rs1141814)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:7655857, ECO:0000269|PubMed:9153297, FT ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9295080, FT ECO:0000269|PubMed:9683600, ECO:0000269|PubMed:9856561" FT /id="VAR_003259" FT VARIANT 92 FT /note="M -> T (in dbSNP:rs1141815)" FT /id="VAR_032396" FT VARIANT 118 FT /note="K -> N (in GD1; mild; decreased glucosylceramidase FT activity; 8% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs121908312)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621" FT /id="VAR_003260" FT VARIANT 120 FT /note="F -> L (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088437" FT VARIANT 129 FT /note="A -> T (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032397" FT VARIANT 146 FT /note="S -> L (in GD2 and GD3; dbSNP:rs758447515)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9554454" FT /id="VAR_009034" FT VARIANT 147 FT /note="Y -> C (in GD3)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088438" FT VARIANT 152 FT /note="G -> E (in GD1)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003261" FT VARIANT 155 FT /note="Y -> H (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088439" FT VARIANT 156 FT /note="N -> D (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032398" FT VARIANT 158 FT /note="I -> S (in GD1; very low glucosylceramidase FT activity; dbSNP:rs77834747)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032399" FT VARIANT 158 FT /note="I -> T (in GD1; dbSNP:rs77834747)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003262" FT VARIANT 159 FT /note="R -> Q (in GD1 and GD2; decreased glucosylceramidase FT activity; 13% of normal activity; dbSNP:rs79653797)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621" FT /id="VAR_003263" FT VARIANT 159 FT /note="R -> W (in GD1 and GD2; dbSNP:rs439898)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9683600, FT ECO:0000269|PubMed:9856561" FT /id="VAR_003264" FT VARIANT 161 FT /note="P -> L (in GD; decreased glucosylceramidase FT activity; 16% of normal activity; dbSNP:rs79637617)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032198" FT VARIANT 161 FT /note="P -> S (in GD1; dbSNP:rs121908299)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003265" FT VARIANT 162 FT /note="M -> V (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation; FT dbSNP:rs377325220)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032199" FT VARIANT 166 FT /note="D -> V (in GD; decreased glucosylceramidase FT activity; 9% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs79796061)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032200" FT VARIANT 170 FT /note="R -> C (in GD1 and GD2; also found in a patient with FT Parkinson disease; dbSNP:rs398123530)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:9851895" FT /id="VAR_009035" FT VARIANT 170 FT /note="R -> L (in GD1 and GD2; dbSNP:rs80356763)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875" FT /id="VAR_009036" FT VARIANT 173 FT /note="T -> I (in GD1; dbSNP:rs78657146)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032400" FT VARIANT 173 FT /note="T -> P (in GD1; dbSNP:rs1441909908)" FT /evidence="ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:9554746" FT /id="VAR_003266" FT VARIANT 174 FT /note="Y -> S (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088440" FT VARIANT 175 FT /note="A -> E (in GD; dbSNP:rs79660787)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032401" FT VARIANT 179 FT /note="D -> H (in GD1; decreased glucosylceramide catabolic FT process; dbSNP:rs147138516)" FT /evidence="ECO:0000269|PubMed:15916907, FT ECO:0000269|PubMed:1864608" FT /id="VAR_003267" FT VARIANT 196 FT /note="K -> Q (in GD1; decreased protein abundance; FT decreased glucosylceramide catabolic process; FT dbSNP:rs121908297)" FT /evidence="ECO:0000269|PubMed:15916907, FT ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:1899336" FT /id="VAR_003268" FT VARIANT 198 FT /note="P -> L (in GD; dbSNP:rs80222298)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009037" FT VARIANT 198 FT /note="P -> S (in GD1; decreased glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081189" FT VARIANT 198 FT /note="P -> T (in GD1)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032402" FT VARIANT 200 FT /note="I -> N (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs77933015)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032201" FT VARIANT 200 FT /note="I -> S (in GD1; dbSNP:rs77933015)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010059" FT VARIANT 201 FT /note="H -> P (in GD1; dbSNP:rs76500263)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032403" FT VARIANT 209 FT /note="R -> C (in GD1; dbSNP:rs398123532)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005" FT /id="VAR_032404" FT VARIANT 209 FT /note="R -> P (in GD1; dbSNP:rs749416070)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:9683600" FT /id="VAR_003269" FT VARIANT 213 FT /note="L -> F (in GD; decreased glucosylceramidase FT activity; 12% of normal activity; dbSNP:rs374591570)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032202" FT VARIANT 214 FT /note="L -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088441" FT VARIANT 215 FT /note="A -> D (in GD1)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003270" FT VARIANT 217 FT /note="P -> S (in GD2)" FT /evidence="ECO:0000269|PubMed:7627192" FT /id="VAR_003271" FT VARIANT 221 FT /note="P -> L (in GD1; very low glucosylceramidase FT activity; dbSNP:rs80205046)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032405" FT VARIANT 221 FT /note="P -> T (in GD1; dbSNP:rs866075757)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003272" FT VARIANT 223 FT /note="W -> R (in GD1 and GD2; dbSNP:rs61748906)" FT /evidence="ECO:0000269|PubMed:10679038, FT ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:8294033" FT /id="VAR_003273" FT VARIANT 224 FT /note="L -> F (in GD; decreased glucosylceramidase FT activity; 4% of normal activity; increases susceptibility FT to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032203" FT VARIANT 227 FT /note="N -> I (in GD2; decreased glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081190" FT VARIANT 227 FT /note="N -> K (in GD1 and GD2; dbSNP:rs381418)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003275" FT VARIANT 227 FT /note="N -> S (in GD1 and GD3; decreased glucosylceramide FT catabolic process; dbSNP:rs364897)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:9217217" FT /id="VAR_003274" FT VARIANT 228 FT /note="G -> V (in GD; dbSNP:rs78911246)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010060" FT VARIANT 229 FT /note="A -> E (in GD2; dbSNP:rs75636769)" FT /evidence="ECO:0000269|PubMed:10649495" FT /id="VAR_009038" FT VARIANT 229 FT /note="A -> T (in GD3)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032406" FT VARIANT 230 FT /note="V -> E (in GD1; very low glucosylceramidase FT activity; dbSNP:rs381427)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032407" FT VARIANT 230 FT /note="V -> G (in GD1; dbSNP:rs381427)" FT /evidence="ECO:0000269|PubMed:10206680, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003276" FT VARIANT 232 FT /note="G -> E (in GD; also found in a patient with FT Parkinson disease; decreased glucosylceramidase activity; FT 7% of normal activity; dbSNP:rs1376479747)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695" FT /id="VAR_032204" FT VARIANT 234 FT /note="G -> E (in GD1; severely decreased FT glucosylceramidase activity; dbSNP:rs74462743)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_003277" FT VARIANT 234 FT /note="G -> W (in GD)" FT /evidence="ECO:0000269|PubMed:10447266" FT /id="VAR_009039" FT VARIANT 235 FT /note="S -> P (in GD1 and GD2; dbSNP:rs1064644)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003278" FT VARIANT 237 FT /note="K -> E (in GD2; severe; loss of glucosylceramidase FT activity; increases susceptibility to proteolytic FT degradation; dbSNP:rs773409311)" FT /evidence="ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:16293621" FT /id="VAR_032205" FT VARIANT 241 FT /note="G -> R (in GD1, GD2 and GD3; severely decreased FT glucosylceramidase activity; dbSNP:rs409652)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:8790604, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9856561" FT /id="VAR_003279" FT VARIANT 244 FT /note="Y -> C (in GD1 and GD3; dbSNP:rs76026102)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:11933202" FT /id="VAR_010062" FT VARIANT 251 FT /note="Y -> H (in GD; uncertain significance; FT dbSNP:rs121908300)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003280" FT VARIANT 252 FT /note="F -> I (in GD1, GD2 and GD3; dbSNP:rs381737)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:1301953, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:9061570, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9217217" FT /id="VAR_003281" FT VARIANT 255 FT /note="F -> Y (in GD; loss of glucosylceramidase activity;; FT dbSNP:rs74500255)" FT /evidence="ECO:0000269|PubMed:1974409, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003282" FT VARIANT 266 FT /note="F -> L (in GD1)" FT /evidence="ECO:0000269|PubMed:24577513" FT /id="VAR_081191" FT VARIANT 270 FT /note="T -> I (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088442" FT VARIANT 270 FT /note="T -> R (in GD2; dbSNP:rs76725886)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032408" FT VARIANT 274 FT /note="E -> K (in GD2; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081192" FT VARIANT 276 FT /note="S -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003283" FT VARIANT 284 FT /note="P -> T (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081193" FT VARIANT 289 FT /note="G -> V (in GD1; dbSNP:rs878853321)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081194" FT VARIANT 290 FT /note="F -> L (in GDPL; dbSNP:rs121908313)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032409" FT VARIANT 294 FT /note="H -> Q (in GD1, GD2 and GD3; associated in cis with FT H-448 in all patients analyzed; uncertain significance; FT dbSNP:rs367968666)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:15690354, ECO:0000269|PubMed:32547927" FT /id="VAR_009040" FT VARIANT 296 FT /note="R -> Q (in GD1 and GD2; also found in a patient with FT Parkinson disease; dbSNP:rs78973108)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:8790604" FT /id="VAR_003284" FT VARIANT 298 FT /note="F -> L (in GD and GD2; decreased glucosylceramidase FT activity; 4% of normal activity)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:3001061" FT /id="VAR_009041" FT VARIANT 301 FT /note="R -> G (in GD1)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081195" FT VARIANT 303 FT /note="L -> I (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs1296507371)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032206" FT VARIANT 304 FT /note="G -> D (in GD1; dbSNP:rs80116658)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010063" FT VARIANT 304 FT /note="G -> R (in GD3; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081196" FT VARIANT 305 FT /note="P -> R (in GD1; dbSNP:rs79215220)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003285" FT VARIANT 310 FT /note="S -> G (in dbSNP:rs1057942)" FT /evidence="ECO:0000269|PubMed:8294033" FT /id="VAR_032410" FT VARIANT 310 FT /note="S -> N (in GD1; severely decreased FT glucosylceramidase activity; less than 5% of normal FT activity; dbSNP:rs74731340)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_010064" FT VARIANT 322 FT /note="D -> N (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088443" FT VARIANT 324 FT /note="R -> C (in GD1 and GD3; dbSNP:rs765633380)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:8790604, ECO:0000269|PubMed:9856561" FT /id="VAR_003286" FT VARIANT 324 FT /note="R -> H (in GD1 and GD2; dbSNP:rs79696831)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:12204005" FT /id="VAR_009042" FT VARIANT 328 FT /note="P -> L (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs121908298)" FT /evidence="ECO:0000269|PubMed:1301953, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003287" FT VARIANT 342 FT /note="K -> I (in GD1; dbSNP:rs77714449)" FT /evidence="ECO:0000269|PubMed:9683600" FT /id="VAR_003288" FT VARIANT 343 FT /note="Y -> C (in GD2; decreased glucosylceramidase FT activity; 16% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs77321207)" FT /evidence="ECO:0000269|PubMed:10649495, FT ECO:0000269|PubMed:16293621" FT /id="VAR_009043" FT VARIANT 347 FT /note="I -> S (in GD1)" FT /evidence="ECO:0000269|PubMed:24577513" FT /id="VAR_081197" FT VARIANT 348 FT /note="A -> V (in GD1; dbSNP:rs78396650)" FT /evidence="ECO:0000269|PubMed:1899336, FT ECO:0000269|PubMed:32547927" FT /id="VAR_003289" FT VARIANT 350 FT /note="H -> R (in GDPL, GD1 and GD2; dbSNP:rs78198234)" FT /evidence="ECO:0000269|PubMed:10352942, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927" FT /id="VAR_009044" FT VARIANT 351 FT /note="W -> C (in GD1; dbSNP:rs121908304)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:1899336" FT /id="VAR_003290" FT VARIANT 351 FT /note="W -> S (in GD1; loss of glucosylceramide catabolic FT process; dbSNP:rs1553217294)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081198" FT VARIANT 352 FT /note="Y -> H (in GD)" FT /evidence="ECO:0000269|PubMed:8829663" FT /id="VAR_003291" FT VARIANT 354 FT /note="D -> H (in GD1; uncertain significance; FT dbSNP:rs398123526)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003292" FT VARIANT 357 FT /note="A -> D (in GD1; uncertain significance; FT dbSNP:rs78188205)" FT /evidence="ECO:0000269|PubMed:8547070" FT /id="VAR_003293" FT VARIANT 362 FT /note="T -> I (in GD1; decreased glucosylceramidase FT activity; 4-6% of normal activity; dbSNP:rs76539814)" FT /evidence="ECO:0000269|PubMed:1301953, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:8294487" FT /id="VAR_003294" FT VARIANT 363 FT /note="L -> P (in GD1; uncertain significance; also found FT in a patient with Parkinson disease; uncertain FT significance; dbSNP:rs1178732315)" FT /evidence="ECO:0000269|PubMed:26528954, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003295" FT VARIANT 364 FT /note="G -> R (in GD2; dbSNP:rs121908305)" FT /evidence="ECO:0000269|PubMed:2269438, FT ECO:0000269|PubMed:8294033" FT /id="VAR_003296" FT VARIANT 365 FT /note="E -> K (in GD1; benign; decreased glucosylceramidase FT activity; 42% of normal activity; dbSNP:rs2230288)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:11903352, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:1864608, ECO:0000269|PubMed:24022302" FT /id="VAR_003297" FT VARIANT 368 FT /note="R -> H (in dbSNP:rs1064648)" FT /evidence="ECO:0000269|PubMed:8294033" FT /id="VAR_032411" FT VARIANT 380 FT /note="A -> T (in GD1; dbSNP:rs781306264)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:9554454" FT /id="VAR_009045" FT VARIANT 381 FT /note="C -> G (in GD2; loss of glucosylceramidase activity; FT dbSNP:rs121908306)" FT /evidence="ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:2269438" FT /id="VAR_003298" FT VARIANT 388 FT /note="E -> K (in GD; decreased glucosylceramidase FT activity; 12% of normal activity; dbSNP:rs1161552095)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032207" FT VARIANT 391 FT /note="V -> L (in GD1; decreased glucosylceramidase FT activity; dbSNP:rs398123527)" FT /evidence="ECO:0000269|PubMed:9153297" FT /id="VAR_010065" FT VARIANT 392 FT /note="R -> G (in GD and GD3; dbSNP:rs121908308)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9650766" FT /id="VAR_010066" FT VARIANT 392 FT /note="R -> W (in GD; decreased glucosylceramidase FT activity; 5% of normal activity; dbSNP:rs121908308)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032208" FT VARIANT 398 FT /note="R -> Q (in GD1; mild; dbSNP:rs74979486)" FT /evidence="ECO:0000269|PubMed:1487244, FT ECO:0000269|PubMed:8829663" FT /id="VAR_003299" FT VARIANT 400 FT /note="M -> I (in GD2; uncertain significance; FT dbSNP:rs149487315)" FT /evidence="ECO:0000269|PubMed:12204005" FT /id="VAR_032412" FT VARIANT 402 FT /note="Y -> C (in GD; decreased glucosylceramidase FT activity; 8% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs76228122)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032209" FT VARIANT 403 FT /note="S -> T (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs121908307)" FT /evidence="ECO:0000269|PubMed:1899336, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003300" FT VARIANT 405 FT /note="S -> G (in GD)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010067" FT VARIANT 405 FT /note="S -> N (in GD; dbSNP:rs1392291885)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009046" FT VARIANT 405 FT /note="S -> R (in GD1; loss of glucosylceramide catabolic FT process; dbSNP:rs75528494)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081199" FT VARIANT 408 FT /note="T -> M (in GD1; likely benign; dbSNP:rs75548401)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:12694238, ECO:0000269|PubMed:14702039" FT /id="VAR_003301" FT VARIANT 409 FT /note="N -> S (in GD1; risk factor for Parkinson disease; FT increased proteasomal degradation; decreased protein FT abundance; decreased glucosylceramide catabolic process; FT decreased glucosylceramidase activity; 23% of normal FT activity when expressed in a heterologous system; alters FT interaction with saposin-C; dbSNP:rs76763715)" FT /evidence="ECO:0000269|PubMed:10206680, FT ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:15826241, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:18332251, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:19846850, FT ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7915932, FT ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9240741, FT ECO:0000269|PubMed:9683600, ECO:0000269|PubMed:9856561, FT ECO:0000269|Ref.14" FT /id="VAR_003302" FT VARIANT 410 FT /note="L -> V (in GD; decreased glucosylceramidase FT activity; 15% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs121908314)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032210" FT VARIANT 414 FT /note="V -> L (in GD and GD1; mild; dbSNP:rs398123528)" FT /evidence="ECO:0000269|PubMed:36776904, FT ECO:0000269|PubMed:9182788" FT /id="VAR_010068" FT VARIANT 416 FT /note="G -> S (in GD1 and GD3; dbSNP:rs121908311)" FT /evidence="ECO:0000269|PubMed:10447266, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:9683600" FT /id="VAR_003303" FT VARIANT 417 FT /note="W -> G (in GD1; dbSNP:rs1450426641)" FT /evidence="ECO:0000269|PubMed:8790604" FT /id="VAR_003304" FT VARIANT 419 FT /note="D -> A (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs77284004)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_003305" FT VARIANT 419 FT /note="D -> H (in GD; decreased glucosylceramidase FT activity; 4% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032211" FT VARIANT 419 FT /note="D -> N (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302, FT ECO:0000269|PubMed:8790604" FT /id="VAR_003306" FT VARIANT 420 FT /note="W -> C (in GD1; loss of glucosylceramide catabolic FT process)" FT /evidence="ECO:0000269|PubMed:24022302" FT /id="VAR_081200" FT VARIANT 421 FT /note="N -> K (in GD; decreased glucosylceramidase FT activity; 22% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032212" FT VARIANT 426 FT /note="P -> L (in GD; dbSNP:rs1057519357 and FT dbSNP:rs994723035)" FT /evidence="ECO:0000269|PubMed:8937765" FT /id="VAR_010069" FT VARIANT 428 FT /note="G -> E (in GD2)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003307" FT VARIANT 429 FT /note="G -> R (in GD; decreased glucosylceramidase FT activity; 17% of normal activity)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032213" FT VARIANT 430 FT /note="P -> L (in GD1; dbSNP:rs76910485)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003308" FT VARIANT 431 FT /note="N -> I (in GD2; dbSNP:rs77738682)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003309" FT VARIANT 432 FT /note="W -> R (in GD)" FT /evidence="ECO:0000269|PubMed:9554454" FT /id="VAR_009047" FT VARIANT 433 FT /note="V -> L (in GD1 and GD3; severe; decreased FT glucosylceramidase activity; 12% of normal activity; FT dbSNP:rs80356769)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:2508065, FT ECO:0000269|PubMed:8294487, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003310" FT VARIANT 435 FT /note="N -> T (in GD1; mild; dbSNP:rs75385858)" FT /evidence="ECO:0000269|PubMed:8889591" FT /id="VAR_003311" FT VARIANT 436 FT /note="F -> S (in GD; decreased glucosylceramidase FT activity; 6% of normal activity; alters protein stability FT and increases susceptibility to proteolytic degradation; FT dbSNP:rs75243000)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032214" FT VARIANT 437 FT /note="V -> F (in GDPL; dbSNP:rs121908310)" FT /evidence="ECO:0000269|PubMed:10352942" FT /id="VAR_009048" FT VARIANT 437 FT /note="V -> L (in GD3; dbSNP:rs121908310)" FT /evidence="ECO:0000269|PubMed:8780099" FT /id="VAR_010070" FT VARIANT 438 FT /note="D -> N (in GD1 and GD2; decreased glucosylceramidase FT activity; 14% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs1553217009)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:8112750, ECO:0000269|PubMed:9856561" FT /id="VAR_003312" FT VARIANT 438 FT /note="D -> Y (in GD1)" FT /evidence="ECO:0000269|PubMed:10796875" FT /id="VAR_032413" FT VARIANT 440 FT /note="P -> L (in GD1; dbSNP:rs74598136)" FT /evidence="ECO:0000269|PubMed:10340647, FT ECO:0000269|PubMed:15605411" FT /id="VAR_010071" FT VARIANT 441 FT /note="I -> F (in GD3)" FT /evidence="ECO:0000269|PubMed:11933202" FT /id="VAR_032414" FT VARIANT 441 FT /note="I -> T (in GD; mild; dbSNP:rs75564605)" FT /evidence="ECO:0000269|PubMed:9182788" FT /id="VAR_010072" FT VARIANT 448 FT /note="D -> H (in GD1, GD2, GD3 and GD3C; associated in cis FT with Q-294 in some patients; at homozygosity it causes FT GD3C; also found in a patient with Parkinson disease; loss FT of glucosylceramidase activity; alters protein stability; FT dbSNP:rs1064651)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, FT ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:15690354, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:2269438, FT ECO:0000269|PubMed:2508065, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:36776904, ECO:0000269|PubMed:7475546, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:9040001, FT ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9856561" FT /id="VAR_003313" FT VARIANT 448 FT /note="D -> V (in GD3; loss of glucosylceramidase activity; FT results in glycosphingolipid accumulation in brain and FT liver of a knockin mouse model due to impaired FT glucosylceramidase activity; dbSNP:rs77369218)" FT /evidence="ECO:0000269|PubMed:2508065, FT ECO:0000269|PubMed:34106956, ECO:0000269|PubMed:8294487" FT /id="VAR_003314" FT VARIANT 450 FT /note="F -> I (in GD1; dbSNP:rs1553216985)" FT /evidence="ECO:0000269|PubMed:9856561" FT /id="VAR_010073" FT VARIANT 451 FT /note="Y -> H (in GD1)" FT /evidence="ECO:0000269|PubMed:9554746" FT /id="VAR_003315" FT VARIANT 452 FT /note="K -> Q (in GD)" FT /evidence="ECO:0000269|PubMed:9061570" FT /id="VAR_010074" FT VARIANT 454 FT /note="P -> R (in GD2; loss of glucosylceramidase activity; FT dbSNP:rs121908295)" FT /evidence="ECO:0000269|PubMed:2464926, FT ECO:0000269|PubMed:8294487" FT /id="VAR_003316" FT VARIANT 455 FT /note="M -> V (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032215" FT VARIANT 456 FT /note="F -> V (in GD1; severely decreased FT glucosylceramidase activity; 3% of normal activity when FT expressed in a heterologous system)" FT /evidence="ECO:0000269|PubMed:7915932, FT ECO:0000269|PubMed:9240741" FT /id="VAR_003317" FT VARIANT 457 FT /note="Y -> C (in GD and GD1; dbSNP:rs74752878)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:8076951" FT /id="VAR_003318" FT VARIANT 460 FT /note="G -> D (in GD1; associated in cis with R-490; loss FT of glucosylceramidase activity)" FT /evidence="ECO:0000269|PubMed:15605411" FT /id="VAR_032415" FT VARIANT 464 FT /note="K -> E (in GD3; severe; uncertain significance)" FT /evidence="ECO:0000269|PubMed:1487244" FT /id="VAR_003319" FT VARIANT 482 FT /note="D -> N (likely benign; found in a patient with FT Parkinson disease; dbSNP:rs75671029)" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063067" FT VARIANT 483 FT /note="L -> P (in GD1, GD2 and GD3; risk factor for FT Parkinson disease; gene conversion; alters protein FT stability; increased proteasomal degradation; decreased FT protein abundance; very low glucosylceramide catabolic FT process; severe decrease of glucosylceramidase activity; 3% FT of normal activity when expressed in a heterologous system; FT dbSNP:rs421016)" FT /evidence="ECO:0000269|PubMed:10360404, FT ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10679038, FT ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:15605411, FT ECO:0000269|PubMed:16293621, ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:21098288, ECO:0000269|PubMed:2464926, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:32547927, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:8937765, FT ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9217217, FT ECO:0000269|PubMed:9240741, ECO:0000269|PubMed:9683600, FT ECO:0000269|PubMed:9851895, ECO:0000269|PubMed:9856561" FT /id="VAR_003321" FT VARIANT 483 FT /note="L -> R (in GD1 and GD2; dbSNP:rs421016)" FT /evidence="ECO:0000269|PubMed:27825739, FT ECO:0000269|PubMed:7981693" FT /id="VAR_003320" FT VARIANT 485 FT /note="A -> P (in GD1)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:9683600" FT /id="VAR_003322" FT VARIANT 486 FT /note="V -> E (in GD1)" FT /evidence="ECO:0000269|PubMed:22658918" FT /id="VAR_081201" FT VARIANT 490 FT /note="H -> R (in GD1; associated in cis with D-460; FT uncertain significance; no effect on glucosylceramidase FT activity; dbSNP:rs76071730)" FT /evidence="ECO:0000269|PubMed:12204005, FT ECO:0000269|PubMed:15605411" FT /id="VAR_032416" FT VARIANT 495 FT /note="A -> P (in GD1; loss of glucosylceramidase activity; FT dbSNP:rs368060)" FT /evidence="ECO:0000269|PubMed:19286695, FT ECO:0000269|PubMed:27825739, ECO:0000269|PubMed:8294487" FT /id="VAR_003323" FT VARIANT 497 FT /note="V -> L" FT /evidence="ECO:0000269|PubMed:19286695" FT /id="VAR_063068" FT VARIANT 500 FT /note="L -> P (in GD; decreased glucosylceramidase FT activity; 10% of normal activity; increases susceptibility FT to proteolytic degradation; dbSNP:rs1362103320)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032216" FT VARIANT 501 FT /note="N -> K (in GD2)" FT /evidence="ECO:0000269|PubMed:9279145" FT /id="VAR_009049" FT VARIANT 501 FT /note="N -> Y (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088444" FT VARIANT 502 FT /note="R -> C (in GD1 and GD2; also found in patients with FT Parkinson disease; no effect on protein abundance; FT decreased glucosylceramidase activity; dbSNP:rs80356771)" FT /evidence="ECO:0000269|PubMed:10796875, FT ECO:0000269|PubMed:1301953, ECO:0000269|PubMed:16293621, FT ECO:0000269|PubMed:19286695, ECO:0000269|PubMed:1972019, FT ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:8294487, FT ECO:0000269|PubMed:8598642, ECO:0000269|PubMed:9683600" FT /id="VAR_003324" FT VARIANT 502 FT /note="R -> P (in GD; loss of glucosylceramidase activity; FT increases susceptibility to proteolytic degradation)" FT /evidence="ECO:0000269|PubMed:16293621" FT /id="VAR_032217" FT VARIANT 509 FT /note="L -> P" FT /id="VAR_003325" FT VARIANT 513 FT /note="D -> Y (in GD2)" FT /evidence="ECO:0000269|PubMed:9637431" FT /id="VAR_009050" FT VARIANT 517 FT /note="G -> S (in GD; dbSNP:rs121908301)" FT /evidence="ECO:0000269|PubMed:8432537" FT /id="VAR_003326" FT VARIANT 521 FT /note="T -> K (in GD1)" FT /evidence="ECO:0000269|PubMed:32547927" FT /id="VAR_088445" FT VARIANT 530 FT /note="T -> I (in GD3; dbSNP:rs78016673)" FT /evidence="ECO:0000269|PubMed:8780099" FT /id="VAR_010075" FT VARIANT 535 FT /note="R -> C (in GD1; mild; dbSNP:rs747506979)" FT /evidence="ECO:0000269|PubMed:1487244, FT ECO:0000269|PubMed:32547927, ECO:0000269|PubMed:9061570" FT /id="VAR_003327" FT VARIANT 535 FT /note="R -> H (in GD1; decreased glucosylceramidase FT activity; 7% of normal activity when expressed in a FT heterologous system; dbSNP:rs75822236)" FT /evidence="ECO:0000269|PubMed:7916532, FT ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:9240741" FT /id="VAR_003328" FT MUTAGEN 43 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 57 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 62 FT /note="C->S: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:16293621" FT MUTAGEN 379 FT /note="E->G: 1000-fold decreases of glucosylceramidase FT activity." FT /evidence="ECO:0000269|PubMed:7908905" FT MUTAGEN 482 FT /note="D->E: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 482 FT /note="D->G: Decreased glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 482 FT /note="D->S: Severe decrease of glucosylceramidase FT activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 501 FT /note="N->D: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT MUTAGEN 501 FT /note="N->Q: Loss of glucosylceramidase activity." FT /evidence="ECO:0000269|PubMed:8294487" FT CONFLICT 176 FT /note="D -> G (in Ref. 7; BAH13357)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="N -> R (in Ref. 5; BAA02546)" FT /evidence="ECO:0000305" FT CONFLICT 470 FT /note="S -> I (in Ref. 15; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 534 FT /note="R -> H (in Ref. 1; AAA35873)" FT /evidence="ECO:0000305" FT STRAND 44..46 FT /evidence="ECO:0007829|PDB:6Q1P" FT STRAND 49..52 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 54..57 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 75..82 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 88..94 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 96..98 FT /evidence="ECO:0007829|PDB:6Q6N" FT STRAND 102..116 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 119..123 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 126..133 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 137..148 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 150..153 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 157..163 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 166..170 FT /evidence="ECO:0007829|PDB:6Q6N" FT STRAND 177..179 FT /evidence="ECO:0007829|PDB:6Q6K" FT HELIX 190..193 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 196..206 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 212..218 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 222..224 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 225..227 FT /evidence="ECO:0007829|PDB:6Q1N" FT STRAND 228..233 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 236..238 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 243..261 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 267..271 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 275..279 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:3GXF" FT HELIX 292..301 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 303..308 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 311..314 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 315..323 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 324..326 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 329..335 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 346..350 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 354..356 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 359..362 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 363..369 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 373..379 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 385..388 FT /evidence="ECO:0007829|PDB:6MOZ" FT HELIX 396..411 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 414..422 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:3KEH" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6Q1N" FT STRAND 440..444 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 445..447 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 449..452 FT /evidence="ECO:0007829|PDB:8AX3" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 471..479 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 482..489 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 495..501 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 507..513 FT /evidence="ECO:0007829|PDB:8AX3" FT TURN 514..516 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 517..523 FT /evidence="ECO:0007829|PDB:8AX3" FT STRAND 527..533 FT /evidence="ECO:0007829|PDB:8AX3" SQ SEQUENCE 536 AA; 59716 MW; FA1E15684344A0E6 CRC64; MEFSSPSREE CPKPLSRVSI MAGSLTGLLL LQAVSWASGA RPCIPKSFGY SSVVCVCNAT YCDSFDPPTF PALGTFSRYE STRSGRRMEL SMGPIQANHT GTGLLLTLQP EQKFQKVKGF GGAMTDAAAL NILALSPPAQ NLLLKSYFSE EGIGYNIIRV PMASCDFSIR TYTYADTPDD FQLHNFSLPE EDTKLKIPLI HRALQLAQRP VSLLASPWTS PTWLKTNGAV NGKGSLKGQP GDIYHQTWAR YFVKFLDAYA EHKLQFWAVT AENEPSAGLL SGYPFQCLGF TPEHQRDFIA RDLGPTLANS THHNVRLLML DDQRLLLPHW AKVVLTDPEA AKYVHGIAVH WYLDFLAPAK ATLGETHRLF PNTMLFASEA CVGSKFWEQS VRLGSWDRGM QYSHSIITNL LYHVVGWTDW NLALNPEGGP NWVRNFVDSP IIVDITKDTF YKQPMFYHLG HFSKFIPEGS QRVGLVASQK NDLDAVALMH PDGSAVVVVL NRSSKDVPLT IKDPAVGFLE TISPGYSIHT YLWRRQ // ID GGYF2_HUMAN Reviewed; 1299 AA. AC Q6Y7W6; A6H8W4; B9EG55; E9PBB0; O75137; Q7Z2Z8; Q7Z3I2; Q96HU4; Q9NV82; DT 09-JAN-2007, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 176. DE RecName: Full=GRB10-interacting GYF protein 2 {ECO:0000303|PubMed:12771153}; DE AltName: Full=PERQ amino acid-rich with GYF domain-containing protein 2; DE AltName: Full=Trinucleotide repeat-containing gene 15 protein {ECO:0000303|PubMed:18358451}; GN Name=GIGYF2 {ECO:0000303|PubMed:12771153, ECO:0000312|HGNC:HGNC:11960}; GN Synonyms=KIAA0642 {ECO:0000303|PubMed:9734811}, PERQ2, GN TNRC15 {ECO:0000303|PubMed:18358451}; 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. RC TISSUE=Kidney; RX PubMed=12771153; DOI=10.1074/jbc.m211572200; RA Giovannone B., Lee E., Laviola L., Giorgino F., Cleveland K.A., Smith R.J.; RT "Two novel proteins that are linked to insulin-like growth factor (IGF-I) RT receptors by the Grb10 adapter and modulate IGF-I signaling."; RL J. Biol. Chem. 278:31564-31573(2003). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=9734811; DOI=10.1093/dnares/5.3.169; RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., RA Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. X. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:169-176(1998). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Uterus; RA Lauber J., Bahr A., Mewes H.W., Weil B., Amid C., Osanger A., Fobo G., RA Han M., Wiemann S.; RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1096 (ISOFORM 1). RC TISSUE=Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLN-1211 RP DEL. RC TISSUE=Fetal kidney, and Uterus; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLN-1211 DEL. 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP GLN-1211 DEL. RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236, 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 [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26, AND IDENTIFICATION BY RP 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 [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-30, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP 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 [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-30; SER-160; SER-189 RP AND THR-382, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [15] 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 [16] 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 [17] RP LACK OF INVOLVEMENT IN PARK11. RX PubMed=19279319; DOI=10.1212/01.wnl.0000346517.98982.1b; RG Parkinson Study Group-PROGENI Investigators; RA Nichols W.C., Kissell D.K., Pankratz N., Pauciulo M.W., Elsaesser V.E., RA Clark K.A., Halter C.A., Rudolph A., Wojcieszek J., Pfeiffer R.F., RA Foroud T.; RT "Variation in GIGYF2 is not associated with Parkinson disease."; RL Neurology 72:1886-1892(2009). RN [18] RP LACK OF INVOLVEMENT IN PARK11. RX PubMed=19482505; DOI=10.1016/j.parkreldis.2009.05.001; RG Italian Parkinson Genetics Network; RA Di Fonzo A., Fabrizio E., Thomas A., Fincati E., Marconi R., Tinazzi M., RA Breedveld G.J., Simons E.J., Chien H.F., Ferreira J.J., Horstink M.W., RA Abbruzzese G., Borroni B., Cossu G., Dalla Libera A., Fabbrini G., RA Guidi M., De Mari M., Lopiano L., Martignoni E., Marini P., Onofrj M., RA Padovani A., Stocchi F., Toni V., Sampaio C., Barbosa E.R., Meco G., RA Oostra B.A., Bonifati V.; RT "GIGYF2 mutations are not a frequent cause of familial Parkinson's RT disease."; RL Parkinsonism Relat. Disord. 15:703-705(2009). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-30; SER-139 AND RP THR-382, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [20] RP LACK OF INVOLVEMENT IN PARK11. RX PubMed=20004041; DOI=10.1016/j.neurobiolaging.2009.06.008; RG French Parkinson's Disease Genetics Study Group (FPDGSG); RA Lesage S., Condroyer C., Lohman E., Troiano A., Tison F., Viallet F., RA Damier P., Tranchant C., Vidhaillet M., Ouvrard-Hernandez A.M., Duerr A., RA Brice A.; RT "Follow-up study of the GIGYF2 gene in French families with Parkinson's RT disease."; RL Neurobiol. Aging 31:1069-1071(2010). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-236; THR-382 AND RP SER-593, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [22] RP 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 [23] RP LACK OF INVOLVEMENT IN PARK11. RX PubMed=19321232; DOI=10.1016/j.neurobiolaging.2009.02.016; RA Meeus B., Nuytemans K., Crosiers D., Engelborghs S., Pals P., Pickut B., RA Peeters K., Mattheijssens M., Corsmit E., Cras P., De Deyn P.P., Theuns J., RA Van Broeckhoven C.; RT "GIGYF2 has no major role in Parkinson genetic etiology in a Belgian RT population."; RL Neurobiol. Aging 32:308-312(2011). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-30; SER-139 AND RP SER-236, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [25] RP FUNCTION, IDENTIFICATION IN THE 4EHP-GYF2 COMPLEX, AND MUTAGENESIS OF RP 41-TYR--LEU-49. RX PubMed=22751931; DOI=10.1128/mcb.00455-12; RA Morita M., Ler L.W., Fabian M.R., Siddiqui N., Mullin M., Henderson V.C., RA Alain T., Fonseca B.D., Karashchuk G., Bennett C.F., Kabuta T., Higashi S., RA Larsson O., Topisirovic I., Smith R.J., Gingras A.C., Sonenberg N.; RT "A novel 4EHP-GIGYF2 translational repressor complex is essential for RT mammalian development."; RL Mol. Cell. Biol. 32:3585-3593(2012). RN [26] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [27] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19; SER-26; SER-30; SER-139; RP SER-160; SER-189; THR-382; SER-993 AND SER-1284, AND IDENTIFICATION BY MASS RP 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 [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-26; SER-236 AND SER-388, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [29] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [30] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-1123, 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 [31] RP FUNCTION, INTERACTION WITH DDX6; EIF4E2 AND TTP, AND MUTAGENESIS OF RP TRP-288; PHE-300 AND PHE-306. RX PubMed=31439631; DOI=10.1101/gad.329219.119; RA Peter D., Ruscica V., Bawankar P., Weber R., Helms S., Valkov E., RA Igreja C., Izaurralde E.; RT "Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated RT translational repression."; RL Genes Dev. 33:1355-1360(2019). RN [32] RP FUNCTION, AND IDENTIFICATION IN THE 4EHP-GYF2 COMPLEX. RX PubMed=32726578; DOI=10.1016/j.molcel.2020.07.007; RA Hickey K.L., Dickson K., Cogan J.Z., Replogle J.M., Schoof M., RA D'Orazio K.N., Sinha N.K., Hussmann J.A., Jost M., Frost A., Green R., RA Weissman J.S., Kostova K.K.; RT "GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs RT to Assist Ribosome-Associated Quality Control."; RL Mol. Cell 79:950.e6-962.e6(2020). RN [33] RP FUNCTION, FUNCTION (MICROBIAL INFECTION), AND INTERACTION WITH SARS-COV RP NON-STRUCTURAL PROTEIN 2 PROTEIN (MICROBIAL INFECTION). RX PubMed=35878012; DOI=10.1073/pnas.2204539119; RA Xu Z., Choi J.H., Dai D.L., Luo J., Ladak R.J., Li Q., Wang Y., Zhang C., RA Wiebe S., Liu A.C.H., Ran X., Yang J., Naeli P., Garzia A., Zhou L., RA Mahmood N., Deng Q., Elaish M., Lin R., Mahal L.K., Hobman T.C., RA Pelletier J., Alain T., Vidal S.M., Duchaine T., Mazhab-Jafari M.T., RA Mao X., Jafarnejad S.M., Sonenberg N.; RT "SARS-CoV-2 impairs interferon production via NSP2-induced repression of RT mRNA translation."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2204539119-e2204539119(2022). RN [34] RP VARIANTS PARK11 ALA-112; VAL-278; THR-335; THR-457; GLU-606 AND ILE-1242, RP AND VARIANTS SER-56; THR-460; ARG-1171; GLN-1211 DEL AND GLN-1212 INS. RX PubMed=18358451; DOI=10.1016/j.ajhg.2008.01.015; RA Lautier C., Goldwurm S., Duerr A., Giovannone B., Tsiaras W.G., Pezzoli G., RA Brice A., Smith R.J.; RT "Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial RT Parkinson disease."; RL Am. J. Hum. Genet. 82:822-833(2008). RN [35] RP VARIANT THR-460. RX PubMed=19429085; DOI=10.1016/j.neulet.2009.03.039; RA Guo Y., Jankovic J., Zhu S., Le W., Song Z., Xie W., Liao D., Yang H., RA Deng H.; RT "GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients."; RL Neurosci. Lett. 454:209-211(2009). RN [36] RP VARIANT SER-56. RX PubMed=19638301; DOI=10.1016/j.neulet.2009.07.067; RA Zhang Y., Zheng L., Zhang T., Wang Y., Xiao Q., Fei Q.Z., Cui P.J., Cao L., RA Chen S.D.; RT "GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson's disease RT patients."; RL Neurosci. Lett. 463:172-175(2009). RN [37] RP VARIANTS PARK11 LYS-256; VAL-345; TYR-377; SER-473; LYS-492; TYR-519; RP PHE-580; GLN-979 DEL AND HIS-1070. RX PubMed=20178831; DOI=10.1016/j.neulet.2010.02.037; RA Wang L., Guo J.F., Zhang W.W., Xu Q., Zuo X., Shi C.H., Luo L.Z., Liu J., RA Hu L., Hu Y.C., She L., Jiang H., Yan X.X., Xia K., Pan Q., Tang B.S.; RT "Novel GIGYF2 gene variants in patients with Parkinson's disease in Chinese RT population."; RL Neurosci. Lett. 473:131-135(2010). RN [38] RP VARIANTS SER-56; VAL-560; VAL-1131 AND ARG-1171, AND VARIANTS PARK11 RP CYS-273; GLU-349; THR-457 AND PRO-1209. RX PubMed=20060621; DOI=10.1016/j.neurobiolaging.2009.12.016; RA Guella I., Pistocchi A., Asselta R., Rimoldi V., Ghilardi A., Sironi F., RA Trotta L., Primignani P., Zini M., Zecchinelli A., Coviello D., Pezzoli G., RA Del Giacco L., Duga S., Goldwurm S.; RT "Mutational screening and zebrafish functional analysis of GIGYF2 as a RT Parkinson-disease gene."; RL Neurobiol. Aging 32:1994-2005(2011). RN [39] RP VARIANT PARK11 GLY-589. RX PubMed=26134514; DOI=10.1038/jhg.2015.69; RA Ruiz-Martinez J., Krebs C.E., Makarov V., Gorostidi A., Marti-Masso J.F., RA Paisan-Ruiz C.; RT "GIGYF2 mutation in late-onset Parkinson's disease with cognitive RT impairment."; RL J. Hum. Genet. 60:637-640(2015). CC -!- FUNCTION: Key component of the 4EHP-GYF2 complex, a multiprotein CC complex that acts as a repressor of translation initiation CC (PubMed:22751931, PubMed:31439631, PubMed:35878012). In the 4EHP-GYF2 CC complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking CC translation repression with mRNA decay (PubMed:31439631). Also recruits CC and bridges the association of the 4EHP complex with the decapping CC effector protein DDX6, which is required for the ZFP36/TTP-mediated CC down-regulation of AU-rich mRNA (PubMed:31439631). May act CC cooperatively with GRB10 to regulate tyrosine kinase receptor CC signaling, including IGF1 and insulin receptors (PubMed:12771153). In CC association with EIF4E2, assists ribosome-associated quality control CC (RQC) by sequestering the mRNA cap, blocking ribosome initiation and CC decreasing the translational load on problematic messages. Part of a CC pathway that works in parallel to RQC-mediated degradation of the CC stalled nascent polypeptide (PubMed:32726578). GIGYF2 and EIF4E2 work CC downstream and independently of ZNF598, which seems to work as a CC scaffold that can recruit them to faulty mRNA even if alternative CC recruitment mechanisms may exist (PubMed:32726578). CC {ECO:0000269|PubMed:12771153, ECO:0000269|PubMed:22751931, CC ECO:0000269|PubMed:31439631, ECO:0000269|PubMed:32726578, CC ECO:0000269|PubMed:35878012}. CC -!- FUNCTION: (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 CC infection, the interaction with non-structural protein 2 (nsp2) CC enhances GIGYF2 binding to EIF4E2 and increases repression of CC translation initiation of genes involved in antiviral innate immune CC response such as IFNB1. {ECO:0000269|PubMed:35878012}. CC -!- SUBUNIT: Component of the 4EHP-GYF2 complex, at least composed of CC EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931, PubMed:31439631, CC PubMed:32726578). Interacts (via the 4EHP-binding motif) with EIF4E2; CC the interaction is direct (PubMed:22751931, PubMed:31439631, CC PubMed:32726578). Interacts with ZFP36/TTP (via P-P-P-P-G repeats); the CC interaction is direct (PubMed:31439631). Interacts with GRB10 (By CC similarity). Interacts (via DDX6 motif) with DDX6 (via RecA-like domain CC 2) (PubMed:31439631). {ECO:0000250|UniProtKB:Q6Y7W8, CC ECO:0000269|PubMed:22751931, ECO:0000269|PubMed:31439631, CC ECO:0000269|PubMed:32726578}. CC -!- SUBUNIT: (Microbial infection) Interacts with SARS coronavirus-2/SARS- CC CoV-2 non-structural protein 2 (nsp2); the interaction enhances GIGYF2 CC binding to EIF4E2. {ECO:0000269|PubMed:35878012}. CC -!- INTERACTION: CC Q6Y7W6; O60573: EIF4E2; NbExp=4; IntAct=EBI-765394, EBI-398610; CC Q6Y7W6; O60573-1: EIF4E2; NbExp=6; IntAct=EBI-765394, EBI-32715389; CC Q6Y7W6; P63104: YWHAZ; NbExp=2; IntAct=EBI-765394, EBI-347088; CC Q6Y7W6-1; O60573-1: EIF4E2; NbExp=11; IntAct=EBI-25762361, EBI-32715389; CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q6Y7W6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q6Y7W6-3; Sequence=VSP_022244, VSP_043471; CC Name=3; CC IsoId=Q6Y7W6-4; Sequence=VSP_044996, VSP_044997; CC Name=4; CC IsoId=Q6Y7W6-5; Sequence=VSP_044996; CC -!- DISEASE: Parkinson disease 11 (PARK11) [MIM:607688]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:18358451, ECO:0000269|PubMed:20060621, CC ECO:0000269|PubMed:20178831, ECO:0000269|PubMed:26134514}. Note=Disease CC susceptibility may be associated with variants affecting the gene CC represented in this entry. Its association with Parkinson disease is CC however unclear. According to a number of studies, variations affecting CC this gene are not a frequent cause of Parkinson disease, suggesting CC that GIGYF2 does not play a major role in Parkinson disease etiology CC (PubMed:19279319, PubMed:19321232, PubMed:19429085, PubMed:19482505, CC PubMed:19638301, PubMed:20004041, PubMed:20060621). CC {ECO:0000269|PubMed:19279319, ECO:0000269|PubMed:19321232, CC ECO:0000269|PubMed:19429085, ECO:0000269|PubMed:19482505, CC ECO:0000269|PubMed:19638301, ECO:0000269|PubMed:20004041, CC ECO:0000269|PubMed:20060621}. CC -!- SIMILARITY: Belongs to the GIGYF family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA31617.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA91873.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform.; 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; AY176045; AAO46889.1; -; mRNA. DR EMBL; AB014542; BAA31617.2; ALT_INIT; mRNA. DR EMBL; BX538172; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK001739; BAA91873.1; ALT_SEQ; mRNA. DR EMBL; BX537885; CAD97881.1; -; mRNA. DR EMBL; BX538321; CAD98095.1; -; mRNA. DR EMBL; AC016692; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC064852; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471063; EAW71016.1; -; Genomic_DNA. DR EMBL; BC008072; AAH08072.2; -; mRNA. DR EMBL; BC136251; AAI36252.1; -; mRNA. DR EMBL; BC146775; AAI46776.1; -; mRNA. DR CCDS; CCDS33401.1; -. [Q6Y7W6-1] DR CCDS; CCDS46542.1; -. [Q6Y7W6-3] DR CCDS; CCDS46543.1; -. [Q6Y7W6-5] DR PIR; T00377; T00377. DR RefSeq; NP_001096616.1; NM_001103146.3. [Q6Y7W6-1] DR RefSeq; NP_001096617.1; NM_001103147.2. [Q6Y7W6-3] DR RefSeq; NP_001096618.1; NM_001103148.2. [Q6Y7W6-5] DR RefSeq; NP_056390.2; NM_015575.3. [Q6Y7W6-1] DR PDB; 5NVL; X-ray; 2.30 A; B/D=35-105. DR PDB; 5NVM; X-ray; 2.00 A; B/D=35-72. DR PDB; 7RUP; X-ray; 1.23 A; A=529-597. DR PDBsum; 5NVL; -. DR PDBsum; 5NVM; -. DR PDBsum; 7RUP; -. DR AlphaFoldDB; Q6Y7W6; -. DR SMR; Q6Y7W6; -. DR BioGRID; 117520; 294. DR ComplexPortal; CPX-2332; 4EHP-GIGYF2 co-translational mRNA decay complex, ZNF598 variant. DR ComplexPortal; CPX-2338; 4EHP-GIGYF2 co-translational mRNA decay complex, DDX6 variant. DR CORUM; Q6Y7W6; -. DR FunCoup; Q6Y7W6; 3093. DR IntAct; Q6Y7W6; 146. DR MINT; Q6Y7W6; -. DR STRING; 9606.ENSP00000387170; -. DR BindingDB; Q6Y7W6; -. DR ChEMBL; CHEMBL2331055; -. DR GlyCosmos; Q6Y7W6; 3 sites, 1 glycan. DR GlyGen; Q6Y7W6; 10 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (8 sites). DR iPTMnet; Q6Y7W6; -. DR MetOSite; Q6Y7W6; -. DR PhosphoSitePlus; Q6Y7W6; -. DR BioMuta; GIGYF2; -. DR DMDM; 74710467; -. DR CPTAC; CPTAC-969; -. DR jPOST; Q6Y7W6; -. DR MassIVE; Q6Y7W6; -. DR PaxDb; 9606-ENSP00000387170; -. DR PeptideAtlas; Q6Y7W6; -. DR ProteomicsDB; 19183; -. DR ProteomicsDB; 67836; -. [Q6Y7W6-1] DR ProteomicsDB; 67837; -. [Q6Y7W6-3] DR Pumba; Q6Y7W6; -. DR Antibodypedia; 62944; 87 antibodies from 25 providers. DR DNASU; 26058; -. DR Ensembl; ENST00000373563.9; ENSP00000362664.5; ENSG00000204120.17. [Q6Y7W6-1] DR Ensembl; ENST00000409196.7; ENSP00000387070.3; ENSG00000204120.17. [Q6Y7W6-5] DR Ensembl; ENST00000409451.7; ENSP00000387170.3; ENSG00000204120.17. [Q6Y7W6-3] DR Ensembl; ENST00000409547.5; ENSP00000386537.1; ENSG00000204120.17. [Q6Y7W6-1] DR GeneID; 26058; -. DR KEGG; hsa:26058; -. DR MANE-Select; ENST00000373563.9; ENSP00000362664.5; NM_001103146.3; NP_001096616.1. DR UCSC; uc002vth.6; human. [Q6Y7W6-1] DR AGR; HGNC:11960; -. DR ClinPGx; PA36647; -. DR CTD; 26058; -. DR DisGeNET; 26058; -. DR GeneCards; GIGYF2; -. DR HGNC; HGNC:11960; GIGYF2. DR HPA; ENSG00000204120; Low tissue specificity. DR MalaCards; GIGYF2; -. DR MIM; 607688; phenotype. DR MIM; 612003; gene. DR OpenTargets; ENSG00000204120; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000204120; -. DR eggNOG; KOG1862; Eukaryota. DR GeneTree; ENSGT00940000156108; -. DR HOGENOM; CLU_007300_0_0_1; -. DR InParanoid; Q6Y7W6; -. DR OMA; QNRICLQ; -. DR OrthoDB; 9539369at2759; -. DR PAN-GO; Q6Y7W6; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6Y7W6; -. DR PathwayCommons; Q6Y7W6; -. DR SignaLink; Q6Y7W6; -. DR SIGNOR; Q6Y7W6; -. DR Agora; ENSG00000204120; -. DR BioGRID-ORCS; 26058; 91 hits in 1193 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; GIGYF2; human. DR GeneWiki; TNRC15; -. DR GenomeRNAi; 26058; -. DR Pharos; Q6Y7W6; Tchem. DR PRO; PR:Q6Y7W6; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q6Y7W6; protein. DR Bgee; ENSG00000204120; Expressed in calcaneal tendon and 211 other cell types or tissues. DR ExpressionAtlas; Q6Y7W6; baseline and differential. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005768; C:endosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0043204; C:perikaryon; IDA:ParkinsonsUK-UCL. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:1990635; C:proximal dendrite; IDA:ParkinsonsUK-UCL. DR GO; GO:0031982; C:vesicle; IBA:GO_Central. DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt. DR GO; GO:0070064; F:proline-rich region binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:0007631; P:feeding behavior; IEA:Ensembl. DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0031571; P:mitotic G1 DNA damage checkpoint signaling; IEA:Ensembl. DR GO; GO:0061157; P:mRNA destabilization; IDA:ParkinsonsUK-UCL. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:0050881; P:musculoskeletal movement; IEA:Ensembl. DR GO; GO:0017148; P:negative regulation of translation; IMP:MGI. DR GO; GO:0045947; P:negative regulation of translational initiation; IDA:UniProt. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IDA:UniProt. DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0016441; P:post-transcriptional gene silencing; IDA:ParkinsonsUK-UCL. DR GO; GO:0072344; P:rescue of stalled ribosome; IDA:UniProt. DR GO; GO:0021522; P:spinal cord motor neuron differentiation; IEA:Ensembl. DR CDD; cd00072; GYF; 1. DR FunFam; 3.30.1490.40:FF:000001; GRB10-interacting GYF protein 2 isoform X1; 1. DR Gene3D; 3.30.1490.40; -; 1. DR InterPro; IPR051640; GRB10-interact_GYF. DR InterPro; IPR003169; GYF. DR InterPro; IPR035445; GYF-like_dom_sf. DR PANTHER; PTHR14445; GRB10 INTERACTING GYF PROTEIN; 1. DR PANTHER; PTHR14445:SF38; GRB10-INTERACTING GYF PROTEIN 2; 1. DR Pfam; PF02213; GYF; 1. DR SMART; SM00444; GYF; 1. DR SUPFAM; SSF55277; GYF domain; 1. DR PROSITE; PS50829; GYF; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Disease variant; KW Isopeptide bond; Methylation; Neurodegeneration; Parkinson disease; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22223895" FT CHAIN 2..1299 FT /note="GRB10-interacting GYF protein 2" FT /id="PRO_0000270837" FT DOMAIN 533..581 FT /note="GYF" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00101" FT REGION 112..131 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 147..195 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 214..247 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 266..433 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 547..563 FT /note="Required for GRB10-binding" FT /evidence="ECO:0000250" FT REGION 733..793 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 845..866 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 860..919 FT /note="Required for interaction with SARS-CoV-2 non- FT structural protein 2 (nsp2)" FT /evidence="ECO:0000269|PubMed:35878012" FT REGION 872..891 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 917..936 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 957..997 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1048 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1084..1112 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1195..1230 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1247..1271 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 40..50 FT /note="4EHP-binding motif" FT /evidence="ECO:0000269|PubMed:22751931" FT MOTIF 280..310 FT /note="DDX6 binding motif" FT /evidence="ECO:0000269|PubMed:31439631" FT COMPBIAS 151..182 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 225..247 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 289..298 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 312..329 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 338..363 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 369..392 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 393..414 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 924..936 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 957..972 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1013..1025 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1026..1048 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1090..1104 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1202..1217 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22223895" FT MOD_RES 19 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 26 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:16964243, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 30 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 107 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q6Y7W8" FT MOD_RES 118 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q6Y7W8" FT MOD_RES 120 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q6Y7W8" FT MOD_RES 139 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 149 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q6Y7W8" FT MOD_RES 160 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 189 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 236 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:24275569" FT MOD_RES 382 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 388 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 593 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 993 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1284 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CROSSLNK 1123 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 177 FT /note="V -> VGKKNGYYCMYSPVLLLGQPLCQ (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9734811" FT /id="VSP_022244" FT VAR_SEQ 238..243 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_044996" FT VAR_SEQ 365 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9734811" FT /id="VSP_043471" FT VAR_SEQ 1205..1211 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_044997" FT VARIANT 56 FT /note="N -> S (probable risk factor for PARK11; FT dbSNP:rs72554080)" FT /evidence="ECO:0000269|PubMed:18358451, FT ECO:0000269|PubMed:19638301, ECO:0000269|PubMed:20060621" FT /id="VAR_044439" FT VARIANT 112 FT /note="T -> A (in PARK11; uncertain significance; FT dbSNP:rs1171688751)" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044440" FT VARIANT 256 FT /note="E -> K (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077935" FT VARIANT 273 FT /note="S -> C (in PARK11; uncertain significance; FT dbSNP:rs141225775)" FT /evidence="ECO:0000269|PubMed:20060621" FT /id="VAR_077936" FT VARIANT 278 FT /note="I -> V (probable risk factor for PARK11; FT dbSNP:rs118203904)" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044441" FT VARIANT 335 FT /note="S -> T (in PARK11; uncertain significance; FT dbSNP:rs776898936)" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044442" FT VARIANT 345 FT /note="A -> V (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077937" FT VARIANT 349 FT /note="D -> E (in PARK11; uncertain significance; FT dbSNP:rs148277228)" FT /evidence="ECO:0000269|PubMed:20060621" FT /id="VAR_077938" FT VARIANT 377 FT /note="S -> Y (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077939" FT VARIANT 423 FT /note="P -> L (in dbSNP:rs34845648)" FT /id="VAR_051268" FT VARIANT 457 FT /note="N -> T (probable risk factor for PARK11; FT dbSNP:rs116074753)" FT /evidence="ECO:0000269|PubMed:18358451, FT ECO:0000269|PubMed:20060621" FT /id="VAR_044443" FT VARIANT 460 FT /note="P -> T (in dbSNP:rs2289912)" FT /evidence="ECO:0000269|PubMed:18358451, FT ECO:0000269|PubMed:19429085" FT /id="VAR_044444" FT VARIANT 473 FT /note="P -> S (in PARK11; uncertain significance; FT dbSNP:rs1384919564)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077940" FT VARIANT 492 FT /note="E -> K (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077941" FT VARIANT 519 FT /note="H -> Y (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077942" FT VARIANT 560 FT /note="A -> V (in dbSNP:rs761136505)" FT /evidence="ECO:0000269|PubMed:20060621" FT /id="VAR_077943" FT VARIANT 580 FT /note="L -> F (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077944" FT VARIANT 589 FT /note="R -> G (probable risk factor for PARK11)" FT /evidence="ECO:0000269|PubMed:26134514" FT /id="VAR_077945" FT VARIANT 606 FT /note="D -> E (probable risk factor for PARK11; FT dbSNP:rs118203903)" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044445" FT VARIANT 979 FT /note="Missing (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077946" FT VARIANT 1070 FT /note="D -> H (in PARK11; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20178831" FT /id="VAR_077947" FT VARIANT 1131 FT /note="A -> V (in dbSNP:rs773011114)" FT /evidence="ECO:0000269|PubMed:20060621" FT /id="VAR_077948" FT VARIANT 1171 FT /note="H -> R (in dbSNP:rs72554081)" FT /evidence="ECO:0000269|PubMed:18358451, FT ECO:0000269|PubMed:20060621" FT /id="VAR_044446" FT VARIANT 1209 FT /note="L -> P (in PARK11; uncertain significance; FT dbSNP:rs114013774)" FT /evidence="ECO:0000269|PubMed:20060621" FT /id="VAR_077949" FT VARIANT 1211 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:18358451, FT ECO:0000269|Ref.8" FT /id="VAR_044447" FT VARIANT 1212 FT /note="Q -> QQ" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044448" FT VARIANT 1242 FT /note="V -> I (in PARK11; dbSNP:rs769022021)" FT /evidence="ECO:0000269|PubMed:18358451" FT /id="VAR_044449" FT MUTAGEN 41..49 FT /note="YRYGREEML->ARAGREEAA: Abolishes interaction with FT EIF4E2." FT /evidence="ECO:0000269|PubMed:22751931" FT MUTAGEN 288 FT /note="W->A: Abolishes interaction with DDX6." FT /evidence="ECO:0000269|PubMed:31439631" FT MUTAGEN 300 FT /note="F->A: Abolishes interaction with DDX6; when FT associated with A-306." FT /evidence="ECO:0000269|PubMed:31439631" FT MUTAGEN 306 FT /note="F->A: Abolishes interaction with DDX6; when FT associated with A-300." FT /evidence="ECO:0000269|PubMed:31439631" FT CONFLICT 565 FT /note="M -> T (in Ref. 4; BX538172)" FT /evidence="ECO:0000305" FT CONFLICT 792 FT /note="E -> G (in Ref. 6; CAD98095)" FT /evidence="ECO:0000305" FT CONFLICT 1153 FT /note="D -> G (in Ref. 6; CAD98095)" FT /evidence="ECO:0000305" FT HELIX 45..50 FT /evidence="ECO:0007829|PDB:5NVM" FT HELIX 60..62 FT /evidence="ECO:0007829|PDB:5NVM" FT HELIX 65..70 FT /evidence="ECO:0007829|PDB:5NVM" FT HELIX 79..81 FT /evidence="ECO:0007829|PDB:5NVL" FT HELIX 86..94 FT /evidence="ECO:0007829|PDB:5NVL" FT HELIX 99..102 FT /evidence="ECO:0007829|PDB:5NVL" FT STRAND 536..539 FT /evidence="ECO:0007829|PDB:7RUP" FT STRAND 545..549 FT /evidence="ECO:0007829|PDB:7RUP" FT HELIX 551..560 FT /evidence="ECO:0007829|PDB:7RUP" FT STRAND 568..571 FT /evidence="ECO:0007829|PDB:7RUP" FT STRAND 574..576 FT /evidence="ECO:0007829|PDB:7RUP" FT HELIX 580..587 FT /evidence="ECO:0007829|PDB:7RUP" SQ SEQUENCE 1299 AA; 150070 MW; 2282458102F64B71 CRC64; MAAETQTLNF GPEWLRALSS GGSITSPPLS PALPKYKLAD YRYGREEMLA LFLKDNKIPS DLLDKEFLPI LQEEPLPPLA LVPFTEEEQR NFSMSVNSAA VLRLTGRGGG GTVVGAPRGR SSSRGRGRGR GECGFYQRSF DEVEGVFGRG GGREMHRSQS WEERGDRRFE KPGRKDVGRP NFEEGGPTSV GRKHEFIRSE SENWRIFREE QNGEDEDGGW RLAGSRRDGE RWRPHSPDGP RSAGWREHME RRRRFEFDFR DRDDERGYRR VRSGSGSIDD DRDSLPEWCL EDAEEEMGTF DSSGAFLSLK KVQKEPIPEE QEMDFRPVDE GEECSDSEGS HNEEAKEPDK TNKKEGEKTD RVGVEASEET PQTSSSSARP GTPSDHQSQE ASQFERKDEP KTEQTEKAEE ETRMENSLPA KVPSRGDEMV ADVQQPLSQI PSDTASPLLI LPPPVPNPSP TLRPVETPVV GAPGMGSVST EPDDEEGLKH LEQQAEKMVA YLQDSALDDE RLASKLQEHR AKGVSIPLMH EAMQKWYYKD PQGEIQGPFN NQEMAEWFQA GYFTMSLLVK RACDESFQPL GDIMKMWGRV PFSPGPAPPP HMGELDQERL TRQQELTALY QMQHLQYQQF LIQQQYAQVL AQQQKAALSS QQQQQLALLL QQFQTLKMRI SDQNIIPSVT RSVSVPDTGS IWELQPTASQ PTVWEGGSVW DLPLDTTTPG PALEQLQQLE KAKAAKLEQE RREAEMRAKR EEEERKRQEE LRRQQEEILR RQQEEERKRR EEEELARRKQ EEALRRQREQ EIALRRQREE EERQQQEEAL RRLEERRREE EERRKQEELL RKQEEEAAKW AREEEEAQRR LEENRLRMEE EAARLRHEEE ERKRKELEVQ RQKELMRQRQ QQQEALRRLQ QQQQQQQLAQ MKLPSSSTWG QQSNTTACQS QATLSLAEIQ KLEEERERQL REEQRRQQRE LMKALQQQQQ QQQQKLSGWG NVSKPSGTTK SLLEIQQEEA RQMQKQQQQQ QQHQQPNRAR NNTHSNLHTS IGNSVWGSIN TGPPNQWASD LVSSIWSNAD TKNSNMGFWD DAVKEVGPRN STNKNKNNAS LSKSVGVSNR QNKKVEEEEK LLKLFQGVNK AQDGFTQWCE QMLHALNTAN NLDVPTFVSF LKEVESPYEV HDYIRAYLGD TSEAKEFAKQ FLERRAKQKA NQQRQQQQLP QQQQQQPPQQ PPQQPQQQDS VWGMNHSTLH SVFQTNQSNN QQSNFEAVQS GKKKKKQKMV RADPSLLGFS VNASSERLNM GEIETLDDY // ID HTRA2_HUMAN Reviewed; 458 AA. AC O43464; Q9HBZ4; Q9P0Y3; Q9P0Y4; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 2. DT 28-JAN-2026, entry version 241. DE RecName: Full=Serine protease HTRA2, mitochondrial; DE EC=3.4.21.108; DE AltName: Full=High temperature requirement protein A2; DE Short=HtrA2; DE AltName: Full=Omi stress-regulated endoprotease; DE AltName: Full=Serine protease 25; DE AltName: Full=Serine proteinase OMI; DE Flags: Precursor; GN Name=HTRA2; Synonyms=OMI, PRSS25; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF SER-306. RX PubMed=10644717; DOI=10.1074/jbc.275.4.2581; RA Faccio L., Fusco C., Chen A., Martinotti S., Bonventre J.V., Zervos A.S.; RT "Characterization of a novel human serine protease that has extensive RT homology to bacterial heat shock endoprotease HtrA and is regulated by RT kidney ischemia."; RL J. Biol. Chem. 275:2581-2588(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4), AND CHARACTERIZATION. RC TISSUE=Brain; RX PubMed=10971580; DOI=10.1046/j.1432-1327.2000.01589.x; RA Gray C.W., Ward R.V., Karran E.H., Turconi S., Rowles A., Viglienghi D., RA Southan C., Barton A., Fantom K.G., West A., Savopoulos J.W., Hassan N.J., RA Clinkenbeard H., Hanning C., Amegadzie B., Davis J.B., Dingwall C., RA Livi G.P., Creasy C.L.; RT "Characterization of human HtrA2, a novel serine protease involved in the RT mammalian cellular stress response."; RL Eur. J. Biochem. 267:5699-5710(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Kidney; RX PubMed=10995577; DOI=10.1006/geno.2000.6263; RA Faccio L., Fusco C., Viel A., Zervos A.S.; RT "Tissue-specific splicing of Omi stress-regulated endoprotease leads to an RT inactive protease with a modified PDZ motif."; RL Genomics 68:343-347(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 134-458, INTERACTION WITH XIAP, AND MUTAGENESIS OF RP ALA-134. RX PubMed=11583623; DOI=10.1016/s1097-2765(01)00341-0; RA Suzuki Y., Imai Y., Nakayama H., Takahashi K., Takio K., Takahashi R.; RT "A serine protease, HtrA2, is released from the mitochondria and interacts RT with XIAP, inducing cell death."; RL Mol. Cell 8:613-621(2001). RN [7] RP CHARACTERIZATION, AND PHOSPHORYLATION. RX PubMed=10873535; DOI=10.1006/prep.2000.1240; RA Savopoulos J.W., Carter P.S., Turconi S., Pettman G.R., Karran E.H., RA Gray C.W., Ward R.V., Jenkins O., Creasy C.L.; RT "Expression, purification, and functional analysis of the human serine RT protease HtrA2."; RL Protein Expr. Purif. 19:227-234(2000). RN [8] RP FUNCTION, AND INTERACTION WITH BIRC6/BRUCE. RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018; RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.; RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin RT ligase."; RL Mol. Cell 14:801-811(2004). RN [9] RP FUNCTION, AND INTERACTION WITH THAP5. RX PubMed=19502560; DOI=10.1152/ajpheart.00234.2009; RA Balakrishnan M.P., Cilenti L., Mashak Z., Popat P., Alnemri E.S., RA Zervos A.S.; RT "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved RT by the proapoptotic Omi/HtrA2 protease during cell death."; RL Am. J. Physiol. 297:H643-H653(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP INTERACTION WITH AREL1. RX PubMed=23479728; DOI=10.1074/jbc.m112.436113; RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y., RA Chae H.D., Shin D.Y.; RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, RT and ARTS."; RL J. Biol. Chem. 288:12014-12021(2013). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [14] {ECO:0007744|PDB:1LCY} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 134-458, SUBUNIT, AND ACTIVE SITE. RX PubMed=11967569; DOI=10.1038/nsb795; RA Li W., Srinivasula S.M., Chai J., Li P., Wu J.W., Zhang Z., Alnemri E.S., RA Shi Y.; RT "Structural insights into the pro-apoptotic function of mitochondrial RT serine protease HtrA2/Omi."; RL Nat. Struct. Biol. 9:436-441(2002). RN [15] {ECO:0007744|PDB:8E2K} RP STRUCTURE BY ELECTRON MICROSCOPY (3.21 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758104; DOI=10.1126/science.ade5750; RA Hunkeler M., Jin C.Y., Fischer E.S.; RT "Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated RT release of caspases."; RL Science 379:1105-1111(2023). RN [16] {ECO:0007744|PDB:8AUK} RP STRUCTURE BY ELECTRON MICROSCOPY (6.20 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758105; DOI=10.1126/science.ade8873; RA Ehrmann J.F., Grabarczyk D.B., Heinke M., Deszcz L., Kurzbauer R., RA Hudecz O., Shulkina A., Gogova R., Meinhart A., Versteeg G.A., Clausen T.; RT "Structural basis for regulation of apoptosis and autophagy by the RT BIRC6/SMAC complex."; RL Science 379:1117-1123(2023). RN [17] RP INVOLVEMENT IN PARK13, VARIANTS SER-141 AND SER-399, AND CHARACTERIZATION RP OF VARIANTS SER-141 AND SER-399. RX PubMed=15961413; DOI=10.1093/hmg/ddi215; RA Strauss K.M., Martins L.M., Plun-Favreau H., Marx F.P., Kautzmann S., RA Berg D., Gasser T., Wszolek Z., Mueller T., Bornemann A., Wolburg H., RA Downward J., Riess O., Schulz J.B., Krueger R.; RT "Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's RT disease."; RL Hum. Mol. Genet. 14:2099-2111(2005). RN [18] RP INVOLVEMENT IN PARK13, VARIANTS PRO-72 AND SER-141, AND VARIANT PARK13 RP TRP-404. RX PubMed=18401856; DOI=10.1002/humu.20713; RA Bogaerts V., Nuytemans K., Reumers J., Pals P., Engelborghs S., Pickut B., RA Corsmit E., Peeters K., Schymkowitz J., De Deyn P.P., Cras P., Rousseau F., RA Theuns J., Van Broeckhoven C.; RT "Genetic variability in the mitochondrial serine protease HTRA2 contributes RT to risk for Parkinson disease."; RL Hum. Mutat. 29:832-840(2008). RN [19] RP VARIANTS CYS-12; LEU-128; SER-141; SER-227 AND SER-399. RX PubMed=18364387; DOI=10.1093/hmg/ddn096; RA Simon-Sanchez J., Singleton A.B.; RT "Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic RT mutations in neurologically normal controls."; RL Hum. Mol. Genet. 17:1988-1993(2008). RN [20] RP VARIANT SER-399. RX PubMed=25422467; DOI=10.1073/pnas.1419581111; RA Unal Gulsuner H., Gulsuner S., Mercan F.N., Onat O.E., Walsh T., Shahin H., RA Lee M.K., Dogu O., Kansu T., Topaloglu H., Elibol B., Akbostanci C., RA King M.C., Ozcelik T., Tekinay A.B.; RT "Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential RT tremor and Parkinson disease."; RL Proc. Natl. Acad. Sci. U.S.A. 111:18285-18290(2014). RN [21] RP INVOLVEMENT IN MGCA8, VARIANT MGCA8 GLN-404, AND CHARACTERIZATION OF RP VARIANT MGCA8 GLN-404. RX PubMed=27208207; DOI=10.1136/jmedgenet-2016-103922; RA Mandel H., Saita S., Edvardson S., Jalas C., Shaag A., Goldsher D., RA Vlodavsky E., Langer T., Elpeleg O.; RT "Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and RT 3-methylglutaconic aciduria."; RL J. Med. Genet. 53:690-696(2016). RN [22] RP VARIANT SER-399. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [23] RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER, AND CHARACTERIZATION OF RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER. RX PubMed=27696117; DOI=10.1007/s10545-016-9977-2; RA Olahova M., Thompson K., Hardy S.A., Barbosa I.A., Besse A., RA Anagnostou M.E., White K., Davey T., Simpson M.A., Champion M., Enns G., RA Schelley S., Lightowlers R.N., Chrzanowska-Lightowlers Z.M., McFarland R., RA Deshpande C., Bonnen P.E., Taylor R.W.; RT "Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome RT associated with 3-methylglutaconic aciduria."; RL J. Inherit. Metab. Dis. 40:121-130(2017). CC -!- FUNCTION: [Isoform 1]: Serine protease that shows proteolytic activity CC against a non-specific substrate beta-casein (PubMed:10873535). CC Promotes apoptosis by either relieving the inhibition of BIRC proteins CC on caspases, leading to an increase in caspase activity; or by a BIRC CC inhibition-independent, caspase-independent and serine protease CC activity-dependent mechanism (PubMed:15200957). Cleaves BIRC6 and CC relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone CC to inhibition by BIRC6 (PubMed:36758104, PubMed:36758105). Cleaves CC THAP5 and promotes its degradation during apoptosis (PubMed:19502560). CC {ECO:0000269|PubMed:10873535, ECO:0000269|PubMed:15200957, CC ECO:0000269|PubMed:19502560, ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- FUNCTION: [Isoform 2]: Seems to be proteolytically inactive. CC {ECO:0000269|PubMed:10995577}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Cleavage of non-polar aliphatic amino-acids at the P1 CC position, with a preference for Val, Ile and Met. At the P2 and P3 CC positions, Arg is selected most strongly with a secondary preference CC for other hydrophilic residues.; EC=3.4.21.108; CC -!- ACTIVITY REGULATION: Inhibited by BIRC6. {ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- SUBUNIT: Homotrimer (PubMed:36758104, PubMed:36758105). Interacts with CC MXI2. Interacts with THAP5 under apoptotic conditions. The mature CC protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and CC XIAP/BIRC4. Interacts with AREL1 (via HECT domain); in the cytoplasm CC following induction of apoptosis (PubMed:23479728). CC {ECO:0000269|PubMed:11583623, ECO:0000269|PubMed:11967569, CC ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560, CC ECO:0000269|PubMed:23479728}. CC -!- INTERACTION: CC O43464; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-517086, EBI-25840993; CC O43464; Q8IUR7: ARMC8; NbExp=6; IntAct=EBI-517086, EBI-1049469; CC O43464; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-517086, EBI-25844820; CC O43464; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-517086, EBI-14199987; CC O43464; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-517086, EBI-25843552; CC O43464; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-517086, EBI-9089489; CC O43464; Q13490: BIRC2; NbExp=4; IntAct=EBI-517086, EBI-514538; CC O43464; Q96CA5: BIRC7; NbExp=5; IntAct=EBI-517086, EBI-517623; CC O43464; Q7Z7K6: CENPV; NbExp=3; IntAct=EBI-517086, EBI-1210604; CC O43464; P02489: CRYAA; NbExp=3; IntAct=EBI-517086, EBI-6875961; CC O43464; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-517086, EBI-25842815; CC O43464; O00303: EIF3F; NbExp=3; IntAct=EBI-517086, EBI-711990; CC O43464; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-517086, EBI-9246952; CC O43464; Q13216-2: ERCC8; NbExp=3; IntAct=EBI-517086, EBI-16466949; CC O43464; Q99871: HAUS7; NbExp=3; IntAct=EBI-517086, EBI-395719; CC O43464; Q02363: ID2; NbExp=3; IntAct=EBI-517086, EBI-713450; CC O43464; Q8IY31-2: IFT20; NbExp=3; IntAct=EBI-517086, EBI-11742277; CC O43464; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-517086, EBI-743960; CC O43464; Q6P597: KLC3; NbExp=3; IntAct=EBI-517086, EBI-1643885; CC O43464; P57682: KLF3; NbExp=3; IntAct=EBI-517086, EBI-8472267; CC O43464; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-517086, EBI-714379; CC O43464; P08727: KRT19; NbExp=3; IntAct=EBI-517086, EBI-742756; CC O43464; Q14525: KRT33B; NbExp=3; IntAct=EBI-517086, EBI-1049638; CC O43464; Q1L5Z9: LONRF2; NbExp=3; IntAct=EBI-517086, EBI-2510853; CC O43464; Q99683: MAP3K5; NbExp=3; IntAct=EBI-517086, EBI-476263; CC O43464; Q8NA82: MARCHF10; NbExp=3; IntAct=EBI-517086, EBI-2341554; CC O43464; Q8N594: MPND; NbExp=3; IntAct=EBI-517086, EBI-2512452; CC O43464; Q8WY64: MYLIP; NbExp=3; IntAct=EBI-517086, EBI-6952711; CC O43464; Q9P0J0: NDUFA13; NbExp=8; IntAct=EBI-517086, EBI-372742; CC O43464; Q13562: NEUROD1; NbExp=3; IntAct=EBI-517086, EBI-3908303; CC O43464; O15381-5: NVL; NbExp=3; IntAct=EBI-517086, EBI-18577082; CC O43464; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-517086, EBI-1058491; CC O43464; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-517086, EBI-25830200; CC O43464; Q9NUU6: OTULINL; NbExp=3; IntAct=EBI-517086, EBI-6916492; CC O43464; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-517086, EBI-11022007; CC O43464; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-517086, EBI-6309018; CC O43464; O14813: PHOX2A; NbExp=3; IntAct=EBI-517086, EBI-25844430; CC O43464; O75925: PIAS1; NbExp=3; IntAct=EBI-517086, EBI-629434; CC O43464; Q8WWB5: PIH1D2; NbExp=3; IntAct=EBI-517086, EBI-10232538; CC O43464; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-517086, EBI-10293968; CC O43464; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-517086, EBI-25835994; CC O43464; P17980: PSMC3; NbExp=3; IntAct=EBI-517086, EBI-359720; CC O43464; P57052: RBM11; NbExp=3; IntAct=EBI-517086, EBI-741332; CC O43464; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-517086, EBI-749039; CC O43464; Q96D59: RNF183; NbExp=3; IntAct=EBI-517086, EBI-743938; CC O43464; Q15287: RNPS1; NbExp=2; IntAct=EBI-517086, EBI-395959; CC O43464; Q96GQ5: RUSF1; NbExp=3; IntAct=EBI-517086, EBI-8636004; CC O43464; Q8N488: RYBP; NbExp=3; IntAct=EBI-517086, EBI-752324; CC O43464; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-517086, EBI-11528848; CC O43464; Q9NR46: SH3GLB2; NbExp=3; IntAct=EBI-517086, EBI-749607; CC O43464; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-517086, EBI-358489; CC O43464; Q16637-3: SMN2; NbExp=3; IntAct=EBI-517086, EBI-395447; CC O43464; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-517086, EBI-3942425; CC O43464; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-517086, EBI-745958; CC O43464; Q86WV5: TEN1; NbExp=3; IntAct=EBI-517086, EBI-2562799; CC O43464; O95150: TNFSF15; NbExp=3; IntAct=EBI-517086, EBI-16355546; CC O43464; Q6DKK2: TTC19; NbExp=4; IntAct=EBI-517086, EBI-948354; CC O43464; Q495M9: USH1G; NbExp=3; IntAct=EBI-517086, EBI-8601749; CC O43464; O75604-3: USP2; NbExp=3; IntAct=EBI-517086, EBI-10696113; CC O43464; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-517086, EBI-2850578; CC O43464; Q15007-2: WTAP; NbExp=3; IntAct=EBI-517086, EBI-25840023; CC O43464; O00308: WWP2; NbExp=3; IntAct=EBI-517086, EBI-743923; CC O43464; P98170: XIAP; NbExp=23; IntAct=EBI-517086, EBI-517127; CC O43464; P24278: ZBTB25; NbExp=3; IntAct=EBI-517086, EBI-739899; CC O43464; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-517086, EBI-749023; CC O43464; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-517086, EBI-12010736; CC O43464; O60304: ZNF500; NbExp=3; IntAct=EBI-517086, EBI-18234077; CC O43464; O15535: ZSCAN9; NbExp=3; IntAct=EBI-517086, EBI-751531; CC O43464; Q86V28; NbExp=3; IntAct=EBI-517086, EBI-10259496; CC O43464; P02666: CSN2; Xeno; NbExp=7; IntAct=EBI-517086, EBI-5260183; CC O43464; Q60855: Ripk1; Xeno; NbExp=2; IntAct=EBI-517086, EBI-529119; CC PRO_0000026946; P02666: CSN2; Xeno; NbExp=2; IntAct=EBI-5271862, EBI-5260183; CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space. Mitochondrion CC membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}. CC Note=Predominantly present in the intermembrane space. Released into CC the cytosol following apoptotic stimuli, such as UV treatment, and CC stimulation of mitochondria with caspase-8 truncated BID/tBID. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum CC {ECO:0000269|PubMed:10644717}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=13B; CC IsoId=O43464-1; Sequence=Displayed; CC Name=2; Synonyms=D-Omi; CC IsoId=O43464-2; Sequence=VSP_005359, VSP_005361; CC Name=3; Synonyms=p7; CC IsoId=O43464-3; Sequence=VSP_005360, VSP_005361; CC Name=4; Synonyms=p4; CC IsoId=O43464-4; Sequence=VSP_005362; CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed. CC {ECO:0000269|PubMed:10644717}. CC -!- DOMAIN: The mature N-terminus is involved in the interaction with XIAP. CC -!- DOMAIN: The PDZ domain mediates interaction with MXI2. CC -!- PTM: Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. CC {ECO:0000269|PubMed:36758104, ECO:0000269|PubMed:36758105}. CC -!- PTM: Autoproteolytically activated. {ECO:0000269|PubMed:10873535}. CC -!- DISEASE: 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248]: An CC autosomal recessive inborn error of metabolism resulting in early CC death. Clinical features include extreme hypertonia observed at birth, CC alternating with hypotonia, subsequent appearance of extrapyramidal CC symptoms, lack of psychomotor development, microcephaly, and CC intractable seizures. Patients show lactic acidemia, 3-methylglutaconic CC aciduria, intermittent neutropenia, and progressive brain atrophy. CC {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 13 (PARK13) [MIM:610297]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41879/HTRA2"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF020760; AAB94569.2; -; mRNA. DR EMBL; AF141305; AAF66596.1; -; mRNA. DR EMBL; AF141306; AAF66597.1; -; mRNA. DR EMBL; AF141307; AAF66598.1; -; mRNA. DR EMBL; AF184911; AAG13126.1; -; mRNA. DR EMBL; AC006544; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000096; AAH00096.1; -; mRNA. DR CCDS; CCDS1951.1; -. [O43464-1] DR CCDS; CCDS1952.1; -. [O43464-2] DR CCDS; CCDS92785.1; -. [O43464-3] DR RefSeq; NP_001308656.1; NM_001321727.1. [O43464-3] DR RefSeq; NP_037379.1; NM_013247.5. [O43464-1] DR RefSeq; NP_659540.1; NM_145074.2. [O43464-2] DR PDB; 1LCY; X-ray; 2.00 A; A=134-458. DR PDB; 2PZD; X-ray; 2.75 A; A/B=359-458. DR PDB; 5FHT; X-ray; 1.95 A; A=134-458. DR PDB; 5M3N; X-ray; 1.65 A; A=134-458. DR PDB; 5M3O; X-ray; 1.70 A; A=134-458. DR PDB; 5TNY; X-ray; 1.70 A; A=134-458. DR PDB; 5TNZ; X-ray; 1.75 A; A=134-458. DR PDB; 5TO0; X-ray; 1.90 A; A=134-458. DR PDB; 5TO1; X-ray; 1.69 A; A=134-458. DR PDB; 5WYN; X-ray; 2.05 A; A=134-458. DR PDB; 7VGE; X-ray; 4.00 A; A/B/C=140-342, D/F=140-341, E=140-340. DR PDB; 8AUK; EM; 6.20 A; C/D/E=134-458. DR PDB; 8E2K; EM; 3.21 A; X/Y/Z=134-458. DR PDBsum; 1LCY; -. DR PDBsum; 2PZD; -. DR PDBsum; 5FHT; -. DR PDBsum; 5M3N; -. DR PDBsum; 5M3O; -. DR PDBsum; 5TNY; -. DR PDBsum; 5TNZ; -. DR PDBsum; 5TO0; -. DR PDBsum; 5TO1; -. DR PDBsum; 5WYN; -. DR PDBsum; 7VGE; -. DR PDBsum; 8AUK; -. DR PDBsum; 8E2K; -. DR AlphaFoldDB; O43464; -. DR EMDB; EMD-15672; -. DR EMDB; EMD-27841; -. DR SASBDB; O43464; -. DR SMR; O43464; -. DR BioGRID; 118165; 304. DR CORUM; O43464; -. DR ELM; O43464; -. DR FunCoup; O43464; 1709. DR IntAct; O43464; 313. DR MINT; O43464; -. DR STRING; 9606.ENSP00000258080; -. DR BindingDB; O43464; -. DR ChEMBL; CHEMBL4523137; -. DR MEROPS; S01.278; -. DR MoonDB; O43464; Predicted. DR TCDB; 8.A.217.1.1; the apoptosis cell death regulator (acdr) family. DR iPTMnet; O43464; -. DR PhosphoSitePlus; O43464; -. DR BioMuta; HTRA2; -. DR OGP; O43464; -. DR jPOST; O43464; -. DR MassIVE; O43464; -. DR PaxDb; 9606-ENSP00000258080; -. DR PeptideAtlas; O43464; -. DR ProteomicsDB; 48958; -. [O43464-1] DR ProteomicsDB; 48959; -. [O43464-2] DR ProteomicsDB; 48960; -. [O43464-3] DR ProteomicsDB; 48961; -. [O43464-4] DR Pumba; O43464; -. DR TopDownProteomics; O43464-2; -. [O43464-2] DR ABCD; O43464; 1 sequenced antibody. DR Antibodypedia; 3554; 772 antibodies from 43 providers. DR DNASU; 27429; -. DR Ensembl; ENST00000258080.8; ENSP00000258080.3; ENSG00000115317.14. [O43464-1] DR Ensembl; ENST00000352222.7; ENSP00000312893.3; ENSG00000115317.14. [O43464-2] DR Ensembl; ENST00000437202.2; ENSP00000399166.2; ENSG00000115317.14. [O43464-3] DR GeneID; 27429; -. DR KEGG; hsa:27429; -. DR MANE-Select; ENST00000258080.8; ENSP00000258080.3; NM_013247.5; NP_037379.1. DR UCSC; uc002smi.2; human. [O43464-1] DR AGR; HGNC:14348; -. DR ClinPGx; PA33836; -. DR CTD; 27429; -. DR DisGeNET; 27429; -. DR GeneCards; HTRA2; -. DR HGNC; HGNC:14348; HTRA2. DR HPA; ENSG00000115317; Low tissue specificity. DR MalaCards; HTRA2; -. DR MIM; 168600; phenotype. DR MIM; 606441; gene. DR MIM; 610297; phenotype. DR MIM; 617248; phenotype. DR OpenTargets; ENSG00000115317; -. DR Orphanet; 505208; 3-methylglutaconic aciduria type 8. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000115317; -. DR eggNOG; KOG1320; Eukaryota. DR GeneTree; ENSGT00940000155108; -. DR HOGENOM; CLU_020120_6_0_1; -. DR InParanoid; O43464; -. DR OMA; MDNYRDE; -. DR OrthoDB; 4217619at2759; -. DR PAN-GO; O43464; 5 GO annotations based on evolutionary models. DR PhylomeDB; O43464; -. DR BRENDA; 3.4.21.108; 2681. DR PathwayCommons; O43464; -. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9841251; Mitochondrial unfolded protein response (UPRmt). DR SignaLink; O43464; -. DR SIGNOR; O43464; -. DR Agora; ENSG00000115317; -. DR BioGRID-ORCS; 27429; 97 hits in 1167 CRISPR screens. DR ChiTaRS; HTRA2; human. DR EvolutionaryTrace; O43464; -. DR GeneWiki; HtrA_serine_peptidase_2; -. DR GenomeRNAi; 27429; -. DR Pharos; O43464; Tbio. DR PRO; PR:O43464; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O43464; protein. DR Bgee; ENSG00000115317; Expressed in cortical plate and 199 other cell types or tissues. DR ExpressionAtlas; O43464; baseline and differential. DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; NAS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:MGI. DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:1905370; C:serine-type endopeptidase complex; IMP:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:CAFA. DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB. DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB. DR GO; GO:1990948; F:ubiquitin ligase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IDA:UniProtKB. DR GO; GO:0035458; P:cellular response to interferon-beta; IDA:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0071300; P:cellular response to retinoic acid; IDA:ParkinsonsUK-UCL. DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl. DR GO; GO:0097194; P:execution phase of apoptosis; TAS:UniProtKB. DR GO; GO:0030900; P:forebrain development; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:ParkinsonsUK-UCL. DR GO; GO:0035694; P:mitochondrial protein catabolic process; TAS:Reactome. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0045786; P:negative regulation of cell cycle; TAS:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:1905090; P:negative regulation of type 2 mitophagy; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0019742; P:pentacyclic triterpenoid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IDA:ParkinsonsUK-UCL. DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL. DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central. DR GO; GO:0016540; P:protein autoprocessing; TAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl. DR CDD; cd06785; cpPDZ_HtrA-like; 1. DR DisProt; DP00315; -. DR FunFam; 2.40.10.120:FF:000004; Serine protease HTRA2, mitochondrial; 1. DR FunFam; 2.30.42.10:FF:000145; serine protease HTRA2, mitochondrial; 1. DR Gene3D; 2.30.42.10; -; 1. DR Gene3D; 2.40.10.120; -; 1. DR InterPro; IPR001478; PDZ. DR InterPro; IPR041489; PDZ_6. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR001940; Peptidase_S1C. DR PANTHER; PTHR22939; SERINE PROTEASE FAMILY S1C HTRA-RELATED; 1. DR PANTHER; PTHR22939:SF127; SERINE PROTEASE HTRA2, MITOCHONDRIAL; 1. DR Pfam; PF17820; PDZ_6; 1. DR Pfam; PF13365; Trypsin_2; 1. DR PRINTS; PR00834; PROTEASES2C. DR SMART; SM00228; PDZ; 1. DR SUPFAM; SSF50156; PDZ domain-like; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS50106; PDZ; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Epilepsy; Hydrolase; Membrane; Mitochondrion; Neurodegeneration; KW Parkinson disease; Parkinsonism; Protease; Proteomics identification; KW Reference proteome; Serine protease; Transit peptide; Transmembrane; KW Transmembrane helix; Ubl conjugation; Zymogen. FT TRANSIT 1..31 FT /note="Mitochondrion" FT PROPEP 32..133 FT /evidence="ECO:0000269|PubMed:11583623" FT /id="PRO_0000026945" FT CHAIN 134..458 FT /note="Serine protease HTRA2, mitochondrial" FT /id="PRO_0000026946" FT TRANSMEM 105..125 FT /note="Helical" FT /evidence="ECO:0000255" FT DOMAIN 364..445 FT /note="PDZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT REGION 166..342 FT /note="Serine protease" FT MOTIF 134..137 FT /note="IAP-binding motif" FT ACT_SITE 198 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 228 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 306 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT VAR_SEQ 238..302 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10995577" FT /id="VSP_005359" FT VAR_SEQ 313 FT /note="L -> LARELGAVSLQ (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005360" FT VAR_SEQ 314..458 FT /note="DGEVIGVNTMKVTAGISFAIPSDRLREFLHRGEKKNSSSGISGSQRRYIGVM FT MLTLSPSILAELQLREPSFPDVQHGVLIHKVILGSPAHRAGLRPGDVILAIGEQMVQNA FT EDVYEAVRTQSQLAVQIRRGRETLTLYVTPEVTE -> VSETSFLPRIPAPGQCGKGRF FT PLIQGCLVKFLSSSLLAISQYPTRSPQHLLVLLFGCPHPLLFV (in isoform 4)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005362" FT VAR_SEQ 372..403 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580, FT ECO:0000303|PubMed:10995577" FT /id="VSP_005361" FT VARIANT 12 FT /note="W -> C (in dbSNP:rs775840965)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076967" FT VARIANT 72 FT /note="L -> P (in dbSNP:rs150047108)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046134" FT VARIANT 128 FT /note="P -> L (in dbSNP:rs757704467)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076968" FT VARIANT 141 FT /note="A -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470544)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:18401856" FT /id="VAR_027349" FT VARIANT 227 FT /note="A -> S (in dbSNP:rs375322953)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076969" FT VARIANT 243..244 FT /note="LP -> PS (in MGCA8; loss of protein expression; FT dbSNP:rs1057519082)" FT /evidence="ECO:0000269|PubMed:27696117" FT /id="VAR_077960" FT VARIANT 399 FT /note="G -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470545)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:25422467, FT ECO:0000269|PubMed:27535533" FT /id="VAR_027350" FT VARIANT 404 FT /note="R -> Q (in MGCA8; may lead to skipping of exon 7 and FT the resultant protein may be truncated; loss of protein FT expression in patient cells homozygous for the mutation; FT dbSNP:rs767006508)" FT /evidence="ECO:0000269|PubMed:27208207" FT /id="VAR_077961" FT VARIANT 404 FT /note="R -> W (in PARK13; dbSNP:rs1380794702)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046135" FT MUTAGEN 134 FT /note="A->M: Loss of interaction with XIAP. Loss of FT inhibition of XIAP activity." FT /evidence="ECO:0000269|PubMed:11583623" FT MUTAGEN 306 FT /note="S->A: Loss of protease activity." FT /evidence="ECO:0000269|PubMed:10644717" FT HELIX 143..147 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 149..157 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 158..160 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 161..170 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 171..174 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 175..188 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 192..195 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 198..200 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 204..209 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 211..213 FT /evidence="ECO:0007829|PDB:5TO0" FT STRAND 215..224 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 225..228 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 229..233 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 256..259 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 265..268 FT /evidence="ECO:0007829|PDB:5FHT" FT STRAND 271..275 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 295..299 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 303..307 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 308..311 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 317..326 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 329..334 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 335..342 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 359..361 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 364..368 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 371..380 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:5WYN" FT STRAND 391..396 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 401..405 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 412..416 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 424..433 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 435..443 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 446..452 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 455..457 FT /evidence="ECO:0007829|PDB:5M3N" SQ SEQUENCE 458 AA; 48841 MW; CEA955A7D0DD8C0D CRC64; MAAPRAGRGA GWSLRAWRAL GGIRWGRRPR LTPDLRALLT SGTSDPRARV TYGTPSLWAR LSVGVTEPRA CLTSGTPGPR AQLTAVTPDT RTREASENSG TRSRAWLAVA LGAGGAVLLL LWGGGRGPPA VLAAVPSPPP ASPRSQYNFI ADVVEKTAPA VVYIEILDRH PFLGREVPIS NGSGFVVAAD GLIVTNAHVV ADRRRVRVRL LSGDTYEAVV TAVDPVADIA TLRIQTKEPL PTLPLGRSAD VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQT NVEYIQTDAA IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS SSGISGSQRR YIGVMMLTLS PSILAELQLR EPSFPDVQHG VLIHKVILGS PAHRAGLRPG DVILAIGEQM VQNAEDVYEA VRTQSQLAVQ IRRGRETLTL YVTPEVTE // ID IF4G1_HUMAN Reviewed; 1599 AA. AC Q04637; D3DNT2; D3DNT4; D3DNT5; E9PFM1; G5E9S1; O43177; O95066; Q5HYG0; AC Q6ZN21; Q8N102; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 20-APR-2010, sequence version 4. DT 28-JAN-2026, entry version 251. DE RecName: Full=Eukaryotic translation initiation factor 4 gamma 1; DE Short=eIF-4-gamma 1; DE Short=eIF-4G 1; DE Short=eIF-4G1; DE AltName: Full=p220; GN Name=EIF4G1; Synonyms=EIF4F, EIF4G, EIF4GI; 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 7), AND VARIANT VAL-432. RC TISSUE=Brain; RX PubMed=1429670; DOI=10.1016/s0021-9258(18)50080-6; RA Yan R., Rychlik W., Etchison D., Rhoads R.E.; RT "Amino acid sequence of the human protein synthesis initiation factor eIF-4 RT gamma."; RL J. Biol. Chem. 267:23226-23231(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND INTERACTION WITH PABPC1. RX PubMed=9857202; DOI=10.1093/emboj/17.24.7480; RA Imataka H., Gradi A., Sonenberg N.; RT "A newly identified N-terminal amino acid sequence of human eIF4G binds RT poly(A)-binding protein and functions in poly(A)-dependent translation."; RL EMBO J. 17:7480-7489(1998). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM C). RX PubMed=9418880; DOI=10.1128/mcb.18.1.334; RA Gradi A., Imataka H., Svitkin Y.V., Rom E., Raught B., Morino S., RA Sonenberg N.; RT "A novel functional human eukaryotic translation initiation factor 4G."; RL Mol. Cell. Biol. 18:334-342(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), VARIANTS ALA-161 AND VAL-432, AND RP ALTERNATIVE INITIATION. RX PubMed=12052860; DOI=10.1128/mcb.22.13.4499-4511.2002; RA Byrd M.P., Zamora M., Lloyd R.E.; RT "Generation of multiple isoforms of eukaryotic translation initiation RT factor 4GI by use of alternate translation initiation codons."; RL Mol. Cell. Biol. 22:4499-4511(2002). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A), AND VARIANT ALA-161. RC TISSUE=Endometrial tumor; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-206, NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF RP 180-234, VARIANT ALA-161, AND INTERACTION WITH ROTAVIRAL NSP3. RX PubMed=9755181; DOI=10.1093/emboj/17.19.5811; RA Piron M., Vende P., Cohen J., Poncet D.; RT "Rotavirus RNA binding protein NSP3, interacts with eIF-4GI and evicts the RT poly(A) binding protein from eIF4F."; RL EMBO J. 17:5811-5821(1998). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-1599 (ISOFORM 8), INTERACTION WITH EIF4A, RP VARIANTS ALA-161 AND VAL-432, AND MUTAGENESIS OF LEU-768; LEU-771; PHE-776; RP 842-LEU-LEU-843; 851-PHE-GLU-852; LEU-896; ILE-902; LEU-905; ARG-974; RP PHE-977; LEU-985 AND TRP-990. RX PubMed=9372926; DOI=10.1128/mcb.17.12.6940; RA Imataka H., Sonenberg N.; RT "Human eukaryotic translation initiation factor 4G (eIF4G) possesses two RT separate and independent binding sites for eIF4A."; RL Mol. Cell. Biol. 17:6940-6947(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 605-721, INTERACTION WITH EIF4E, AND RP MUTAGENESIS OF TYR-612 AND 617-LEU-LEU-618. RX PubMed=7651417; DOI=10.1128/mcb.15.9.4990; RA Mader S., Lee H., Pause A., Sonenberg N.; RT "The translation initiation factor eIF-4E binds to a common motif shared by RT the translation factor eIF-4 gamma and the translational repressors 4E- RT binding proteins."; RL Mol. Cell. Biol. 15:4990-4997(1995). RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 682-912 (ISOFORM 8). RA De Gregorio E.; RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases. RN [13] RP CLEAVAGE BY RHINOVIRUS AND COXSACKIEVIRUS PROTEASE. RX PubMed=8396129; DOI=10.1016/s0021-9258(19)36499-3; RA Lamphear B.J., Yan R., Yang F., Waters D., Liebig H.-D., Klump H., RA Kuechler E., Skern T., Rhoads R.E.; RT "Mapping the cleavage site in protein synthesis initiation factor eIF-4 RT gamma of the 2A proteases from human Coxsackievirus and rhinovirus."; RL J. Biol. Chem. 268:19200-19203(1993). RN [14] RP INTERACTION WITH EIF4E. RC TISSUE=Placenta; RX PubMed=7935836; DOI=10.1038/371762a0; RA Pause A., Belsham G.J., Gingras A.-C., Donze O., Lin T.-A., RA Lawrence J.C. Jr., Sonenberg N.; RT "Insulin-dependent stimulation of protein synthesis by phosphorylation of a RT regulator of 5'-cap function."; RL Nature 371:762-767(1994). RN [15] RP INTERACTION WITH EIF4E AND EIF4EBP1. RX PubMed=8521827; DOI=10.1002/j.1460-2075.1995.tb00257.x; RA Haghighat A., Mader S., Pause A., Sonenberg N.; RT "Repression of cap-dependent translation by 4E-binding protein 1: RT competition with p220 for binding to eukaryotic initiation factor-4E."; RL EMBO J. 14:5701-5709(1995). RN [16] RP MUTAGENESIS OF GLY-682. RX PubMed=8961935; DOI=10.1021/bi961864t; RA Lamphear B.J., Rhoads R.E.; RT "A single amino acid change in protein synthesis initiation factor 4G RT renders cap-dependent translation resistant to picornaviral 2A proteases."; RL Biochemistry 35:15726-15733(1996). RN [17] RP CLEAVAGE BY POLIOVIRUS. RX PubMed=9755863; DOI=10.1016/s0014-5793(98)01027-8; RA Ventoso I., MacMillan S.E., Hershey J.W., Carrasco L.; RT "Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F RT complex."; RL FEBS Lett. 435:79-83(1998). RN [18] RP REVIEW. RX PubMed=10872469; DOI=10.1146/annurev.biochem.68.1.913; RA Gingras A.-C., Raught B., Sonenberg N.; RT "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and RT regulators of translation."; RL Annu. Rev. Biochem. 68:913-963(1999). RN [19] RP INTERACTION WITH MKNK1. RX PubMed=9878069; DOI=10.1093/emboj/18.1.270; RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T., RA Sonenberg N.; RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to RT phosphorylate eIF4E."; RL EMBO J. 18:270-279(1999). RN [20] RP INTERACTION WITH PABPC1, AND MUTAGENESIS OF 174-LYS--LYS-178 AND RP 184-ASP--GLN-197. RX PubMed=10996799; DOI=10.1016/s0960-9822(00)00701-6; RA Wakiyama M., Imataka H., Sonenberg N.; RT "Interaction of eIF4G with poly(A)-binding protein stimulates translation RT and is critical for Xenopus oocyte maturation."; RL Curr. Biol. 10:1147-1150(2000). RN [21] RP INTERACTION WITH PABPC1. RX PubMed=10970864; DOI=10.1093/emboj/19.17.4723; RA Gray N.K., Coller J.M., Dickson K.S., Wickens M.; RT "Multiple portions of poly(A)-binding protein stimulate translation in RT vivo."; RL EMBO J. 19:4723-4733(2000). RN [22] RP CLEAVAGE BY FMDV AND HRV-2. RX PubMed=11034318; DOI=10.1016/s0014-5793(00)01928-1; RA Glaser W., Skern T.; RT "Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A RT in vitro."; RL FEBS Lett. 480:151-155(2000). RN [23] RP INTERACTION WITH MKNK2. RX PubMed=11154262; DOI=10.1128/mcb.21.3.743-754.2001; RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.; RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a RT eukaryotic initiation factor 4E kinase with high levels of basal activity RT in mammalian cells."; RL Mol. Cell. Biol. 21:743-754(2001). RN [24] RP INTERACTION WITH HADV5 100K PROTEIN (MICROBIAL INFECTION). RX PubMed=15314025; DOI=10.1101/gad.1212504; RA Xi Q., Cuesta R., Schneider R.J.; RT "Tethering of eIF4G to adenoviral mRNAs by viral 100k protein drives RT ribosome shunting."; RL Genes Dev. 18:1997-2009(2004). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, 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 [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND IDENTIFICATION BY RP 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 [27] RP INTERACTION WITH CIRBP. RX PubMed=16513844; DOI=10.1093/nar/gkj519; RA Yang R., Weber D.J., Carrier F.; RT "Post-transcriptional regulation of thioredoxin by the stress inducible RT heterogeneous ribonucleoprotein A18."; RL Nucleic Acids Res. 34:1224-1236(2006). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1092, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17924679; DOI=10.1021/pr070152u; RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.; RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa cells RT and high confident phosphopeptide identification by cross-validation of RT MS/MS and MS/MS/MS spectra."; RL J. Proteome Res. 6:4150-4162(2007). RN [29] RP INTERACTION WITH RBM4. RX PubMed=17284590; DOI=10.1073/pnas.0611015104; RA Lin J.C., Hsu M., Tarn W.Y.; RT "Cell stress modulates the function of splicing regulatory protein RBM4 in RT translation control."; RL Proc. Natl. Acad. Sci. U.S.A. 104:2235-2240(2007). RN [30] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [31] RP INTERACTION WITH ROTAVIRUS A NSP3 (MICROBIAL INFECTION). RX PubMed=18799579; DOI=10.1128/jvi.00872-08; RA Harb M., Becker M.M., Vitour D., Baron C.H., Vende P., Brown S.C., RA Bolte S., Arold S.T., Poncet D.; RT "Nuclear localization of cytoplasmic poly(A)-binding protein upon rotavirus RT infection involves the interaction of NSP3 with eIF4G and RoXaN."; RL J. Virol. 82:11283-11293(2008). RN [32] RP INTERACTION WITH DAZAP2, AND SUBCELLULAR LOCATION. RX PubMed=17984221; DOI=10.1128/mcb.01226-07; RA Kim J.E., Ryu I., Kim W.J., Song O.K., Ryu J., Kwon M.Y., Kim J.H., RA Jang S.K.; RT "Proline-rich transcript in brain protein induces stress granule RT formation."; RL Mol. Cell. Biol. 28:803-813(2008). RN [33] RP INTERACTION WITH MIF4GD. RX PubMed=18025107; DOI=10.1128/mcb.01500-07; RA Cakmakci N.G., Lerner R.S., Wagner E.J., Zheng L., Marzluff W.F.; RT "SLIP1, a factor required for activation of histone mRNA translation by the RT stem-loop binding protein."; RL Mol. Cell. Biol. 28:1182-1194(2008). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-223; THR-647; RP SER-1092 AND SER-1209, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [35] 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 [36] 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 [37] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1095, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092; SER-1185; RP SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, 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 [39] 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 [40] RP PHOSPHORYLATION AT SER-1185. RX PubMed=21576361; DOI=10.1128/mcb.05589-11; RA Dobrikov M., Dobrikova E., Shveygert M., Gromeier M.; RT "Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) RT by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1."; RL Mol. Cell. Biol. 31:2947-2959(2011). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092; SER-1145; RP SER-1147; SER-1185; SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [42] RP INTERACTION WITH DDX3X, AND SUBCELLULAR LOCATION. RX PubMed=22872150; DOI=10.1038/emboj.2012.220; RA Soto-Rifo R., Rubilar P.S., Limousin T., de Breyne S., Decimo D., RA Ohlmann T.; RT "DEAD-box protein DDX3 associates with eIF4F to promote translation of RT selected mRNAs."; RL EMBO J. 31:3745-3756(2012). RN [43] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-2 (ISOFORM C), CLEAVAGE OF RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS] (ISOFORM C), AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE 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 [44] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-647; SER-1028; RP SER-1077; SER-1092; SER-1145; SER-1147; SER-1185; SER-1187; SER-1194; RP SER-1209; SER-1231; SER-1238 AND SER-1596, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-509 (ISOFORM 7), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT RP SER-705 (ISOFORM 8), 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 [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-314, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [46] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-73; ARG-110; ARG-685; ARG-694; RP ARG-1032 AND ARG-1042, METHYLATION [LARGE SCALE ANALYSIS] AT ARG-489 AND RP ARG-498 (ISOFORM 7), METHYLATION [LARGE SCALE ANALYSIS] AT ARG-685 AND RP ARG-694 (ISOFORM 8), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [47] RP INTERACTION WITH HNRNPD, AND RNA-BINDING. RX PubMed=24423872; DOI=10.1093/nar/gkt1379; RA Lee K.H., Kim S.H., Kim H.J., Kim W., Lee H.R., Jung Y., Choi J.H., RA Hong K.Y., Jang S.K., Kim K.T.; RT "AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic RT translation."; RL Nucleic Acids Res. 42:3590-3606(2014). RN [48] RP FUNCTION. RX PubMed=29062139; DOI=10.1038/s41598-017-14262-7; RA Adjibade P., Grenier St-Sauveur V., Bergeman J., Huot M.E., Khandjian E.W., RA Mazroui R.; RT "DDX3 regulates endoplasmic reticulum stress-induced ATF4 expression."; RL Sci. Rep. 7:13832-13832(2017). RN [49] RP FUNCTION, AND INTERACTION WITH EIF1 AND EIF4E. RX PubMed=29987188; DOI=10.1128/mcb.00139-18; RA Haimov O., Sehrawat U., Tamarkin-Ben Harush A., Bahat A., Uzonyi A., RA Will A., Hiraishi H., Asano K., Dikstein R.; RT "Dynamic interaction of eukaryotic initiation factor 4G1 (eIF4G1) with RT eIF4E and eIF1 underlies scanning-dependent and -independent translation."; RL Mol. Cell. Biol. 38:0-0(2018). RN [50] RP INTERACTION WITH HUMAN NOROVIRUS VIRAL GENOME-LINKED PROTEIN (MICROBIAL RP INFECTION). RX PubMed=31403400; DOI=10.7554/elife.46681; RA Hosmillo M., Lu J., McAllaster M.R., Eaglesham J.B., Wang X., Emmott E., RA Domingues P., Chaudhry Y., Fitzmaurice T.J., Tung M.K., Panas M.D., RA McInerney G., Locker N., Wilen C.B., Goodfellow I.G.; RT "Noroviruses subvert the core stress granule component G3BP1 to promote RT viral VPg-dependent translation."; RL Elife 8:0-0(2019). RN [51] RP VARIANT [LARGE SCALE ANALYSIS] VAL-432, AND IDENTIFICATION BY MASS RP 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 [52] RP VARIANT HIS-201. RX PubMed=26740508; DOI=10.1136/jmedgenet-2015-103568; RA Lopes F., Barbosa M., Ameur A., Soares G., de Sa J., Dias A.I., RA Oliveira G., Cabral P., Temudo T., Calado E., Cruz I.F., Vieira J.P., RA Oliveira R., Esteves S., Sauer S., Jonasson I., Syvaenen A.C., RA Gyllensten U., Pinto D., Maciel P.; RT "Identification of novel genetic causes of Rett syndrome-like phenotypes."; RL J. Med. Genet. 53:190-199(2016). RN [53] RP X-RAY CRYSTALLOGRAPHY (2.38 ANGSTROMS) OF 172-199 IN COMPLEX WITH ROTAVIRAL RP NSP3, INTERACTION WITH PABPC1, AND MUTAGENESIS OF ILE-180; ILE-182; ILE-192 RP AND ILE-196. RX PubMed=12086624; DOI=10.1016/s1097-2765(02)00555-5; RA Groft C.M., Burley S.K.; RT "Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA RT circularization."; RL Mol. Cell 9:1273-1283(2002). RN [54] RP X-RAY CRYSTALLOGRAPHY (2.24 ANGSTROMS) OF 1234-1571. RX PubMed=16698552; DOI=10.1016/j.str.2006.03.012; RA Bellsolell L., Cho-Park P.F., Poulin F., Sonenberg N., Burley S.K.; RT "Two structurally atypical HEAT domains in the C-terminal portion of human RT eIF4G support binding to eIF4A and Mnk1."; RL Structure 14:913-923(2006). RN [55] RP VARIANT [LARGE SCALE ANALYSIS] LEU-696. 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 [56] RP VARIANTS PARK18 VAL-502 AND HIS-1205, AND VARIANTS SER-71; ALA-161; RP CYS-311; VAL-432; 466-GLY--ALA-468 DEL; CYS-686; VAL-806; SER-829; RP ARG-1164; TRP-1197; ALA-1229; PRO-1233 AND SER-1257. RX PubMed=21907011; DOI=10.1016/j.ajhg.2011.08.009; RA Chartier-Harlin M.C., Dachsel J.C., Vilarino-Guell C., Lincoln S.J., RA Lepretre F., Hulihan M.M., Kachergus J., Milnerwood A.J., Tapia L., RA Song M.S., Le Rhun E., Mutez E., Larvor L., Duflot A., RA Vanbesien-Mailliot C., Kreisler A., Ross O.A., Nishioka K., RA Soto-Ortolaza A.I., Cobb S.A., Melrose H.L., Behrouz B., Keeling B.H., RA Bacon J.A., Hentati E., Williams L., Yanagiya A., Sonenberg N., RA Lockhart P.J., Zubair A.C., Uitti R.J., Aasly J.O., Krygowska-Wajs A., RA Opala G., Wszolek Z.K., Frigerio R., Maraganore D.M., Gosal D., Lynch T., RA Hutchinson M., Bentivoglio A.R., Valente E.M., Nichols W.C., Pankratz N., RA Foroud T., Gibson R.A., Hentati F., Dickson D.W., Destee A., Farrer M.J.; RT "Translation initiator EIF4G1 mutations in familial Parkinson disease."; RL Am. J. Hum. Genet. 89:398-406(2011). CC -!- FUNCTION: Component of the protein complex eIF4F, which is involved in CC the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal CC secondary structure and recruitment of mRNA to the ribosome CC (PubMed:29987188). Exists in two complexes, either with EIF1 or with CC EIF4E (mutually exclusive) (PubMed:29987188). Together with EIF1, is CC required for leaky scanning, in particular for avoiding cap-proximal CC start codon (PubMed:29987188). Together with EIF4E, antagonizes the CC scanning promoted by EIF1-EIF4G1 and locates the start codon (through a CC TISU element) without scanning (PubMed:29987188). As a member of the CC eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 CC mRNA translation (PubMed:29062139). {ECO:0000269|PubMed:29062139, CC ECO:0000269|PubMed:29987188}. CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of which CC varies with external and internal environmental conditions. It is CC composed of at least EIF4A, EIF4E (cap-binding) and EIF4G1/EIF4G3 CC (PubMed:7651417, PubMed:7935836, PubMed:9372926). Interacts with eIF3 CC complex, mutually exclusive with EIF4A1 or EIF4A2, EIF4E and through CC its N-terminus with PABPC1 (PubMed:10970864, PubMed:10996799, CC PubMed:12086624, PubMed:16698552, PubMed:7651417, PubMed:7935836, CC PubMed:9372926, PubMed:9857202). Interacts with EIF4E or with EIF1 CC (mutually exclusive) through a common binding site (PubMed:29987188). CC Interacts through its C-terminus with the serine/threonine kinases CC MKNK1, and with MKNK2 (PubMed:11154262, PubMed:9878069). Appears to act CC as a scaffold protein, holding these enzymes in place to phosphorylate CC EIF4E (PubMed:11154262, PubMed:9878069). Non-phosphorylated EIF4EBP1 CC competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin stimulated CC MAP-kinase (MAPK1 and MAPK3) phosphorylation of EIF4EBP1 causes CC dissociation of the complex allowing EIF4G1/EIF4G3 to bind and CC consequent initiation of translation (PubMed:8521827). EIF4G1/EIF4G3 CC interacts with PABPC1 to bring about circularization of the mRNA CC (PubMed:10970864, PubMed:10996799, PubMed:12086624, PubMed:9857202). CC Interacts with EIF4E3 (By similarity). Interacts with CIRBP and MIF4GD CC (PubMed:10970864, PubMed:10996799, PubMed:16513844, PubMed:18025107). CC Interacts with RBM4 (PubMed:17284590). Interacts with HNRNPD/AUF1; the CC interaction requires RNA (PubMed:24423872). Interacts with DDX3X; the CC interaction requires RNA (PubMed:22872150). Interacts with DAZAP2 CC (PubMed:17984221). {ECO:0000250|UniProtKB:Q6NZJ6, CC ECO:0000269|PubMed:10970864, ECO:0000269|PubMed:10996799, CC ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:12086624, CC ECO:0000269|PubMed:16513844, ECO:0000269|PubMed:17284590, CC ECO:0000269|PubMed:17984221, ECO:0000269|PubMed:18025107, CC ECO:0000269|PubMed:22872150, ECO:0000269|PubMed:24423872, CC ECO:0000269|PubMed:29987188, ECO:0000269|PubMed:7651417, CC ECO:0000269|PubMed:7935836, ECO:0000269|PubMed:8521827, CC ECO:0000269|PubMed:9372926, ECO:0000269|PubMed:9857202, CC ECO:0000269|PubMed:9878069}. CC -!- SUBUNIT: (Microbial infection) Interacts with rotavirus A NSP3; in this CC interaction, NSP3 takes the place of PABPC1 thereby inducing shutoff of CC host protein synthesis. {ECO:0000269|PubMed:18799579, CC ECO:0000269|PubMed:9755181}. CC -!- SUBUNIT: (Microbial infection) Interacts with human adenovirus 5 CC protein 100K; this interaction promotes translational shunt in presence CC of polysomes containing viral tripartite leader mRNAs. CC {ECO:0000269|PubMed:15314025}. CC -!- SUBUNIT: (Microbial infection) Interacts with viral genome-linked CC protein (via c-terminus); this interaction plays a role in the CC translation of viral proteins. {ECO:0000269|PubMed:31403400}. CC -!- INTERACTION: CC Q04637; O00571: DDX3X; NbExp=3; IntAct=EBI-73711, EBI-353779; CC Q04637; P55884: EIF3B; NbExp=2; IntAct=EBI-73711, EBI-366696; CC Q04637; O75822: EIF3J; NbExp=2; IntAct=EBI-73711, EBI-366647; CC Q04637; P60842: EIF4A1; NbExp=18; IntAct=EBI-73711, EBI-73449; CC Q04637; Q14240: EIF4A2; NbExp=4; IntAct=EBI-73711, EBI-73473; CC Q04637; P06730: EIF4E; NbExp=15; IntAct=EBI-73711, EBI-73440; CC Q04637; Q14103-4: HNRNPD; NbExp=3; IntAct=EBI-73711, EBI-432545; CC Q04637; Q9BUB5: MKNK1; NbExp=3; IntAct=EBI-73711, EBI-73837; CC Q04637; P11940: PABPC1; NbExp=6; IntAct=EBI-73711, EBI-81531; CC Q04637; Q9BWF3-1: RBM4; NbExp=4; IntAct=EBI-73711, EBI-15621561; CC Q04637; Q9UGR2: ZC3H7B; NbExp=3; IntAct=EBI-73711, EBI-948845; CC Q04637; Q9J0X9: UL54; Xeno; NbExp=3; IntAct=EBI-73711, EBI-7967856; CC Q04637-1; P60842: EIF4A1; NbExp=2; IntAct=EBI-5456295, EBI-73449; CC Q04637-9; Q9NQ94: A1CF; NbExp=3; IntAct=EBI-12012124, EBI-2809489; CC Q04637-9; Q8N5M1: ATPAF2; NbExp=3; IntAct=EBI-12012124, EBI-1166928; CC Q04637-9; Q2TAC2-2: CCDC57; NbExp=3; IntAct=EBI-12012124, EBI-10961624; CC Q04637-9; P55273: CDKN2D; NbExp=3; IntAct=EBI-12012124, EBI-745859; CC Q04637-9; Q99828: CIB1; NbExp=7; IntAct=EBI-12012124, EBI-372594; CC Q04637-9; P56545-3: CTBP2; NbExp=3; IntAct=EBI-12012124, EBI-10171902; CC Q04637-9; Q86UW9: DTX2; NbExp=3; IntAct=EBI-12012124, EBI-740376; CC Q04637-9; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-12012124, EBI-744099; CC Q04637-9; P51116: FXR2; NbExp=3; IntAct=EBI-12012124, EBI-740459; CC Q04637-9; Q15323: KRT31; NbExp=3; IntAct=EBI-12012124, EBI-948001; CC Q04637-9; O76011: KRT34; NbExp=3; IntAct=EBI-12012124, EBI-1047093; CC Q04637-9; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-12012124, EBI-741158; CC Q04637-9; Q9UBV8: PEF1; NbExp=3; IntAct=EBI-12012124, EBI-724639; CC Q04637-9; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-12012124, EBI-358489; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17984221}. Nucleus CC {ECO:0000269|PubMed:17984221}. Cytoplasm, Stress granule CC {ECO:0000269|PubMed:22872150}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=8; CC Name=A; CC IsoId=Q04637-1; Sequence=Displayed; CC Name=B; CC IsoId=Q04637-3; Sequence=VSP_018720; CC Name=C; CC IsoId=Q04637-4; Sequence=VSP_018721; CC Name=D; CC IsoId=Q04637-5; Sequence=VSP_018722; CC Name=E; CC IsoId=Q04637-6; Sequence=VSP_018723; CC Name=7; CC IsoId=Q04637-7; Sequence=VSP_018723, VSP_047397; CC Name=8; CC IsoId=Q04637-8; Sequence=VSP_047397; CC Name=9; CC IsoId=Q04637-9; Sequence=VSP_047396; CC -!- PTM: Phosphorylated at multiple sites in vivo. Phosphorylation at Ser- CC 1185 by PRKCA induces binding to MKNK1. {ECO:0000269|PubMed:21576361}. CC -!- PTM: Following infection by certain enteroviruses, rhinoviruses and CC aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or the CC leader protease in the case of aphthoviruses. This shuts down the CC capped cellular mRNA transcription. {ECO:0000269|PubMed:11034318, CC ECO:0000269|PubMed:8396129, ECO:0000269|PubMed:9755863}. CC -!- DISEASE: Parkinson disease 18 (PARK18) [MIM:614251]: An autosomal CC dominant, late-onset form of Parkinson disease. Parkinson disease is a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:21907011}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform B]: Produced by alternative initiation at Met- CC 41 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform C]: Produced by alternative initiation at Met- CC 88 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform D]: Produced by alternative initiation at Met- CC 165 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform E]: Produced by alternative initiation at Met- CC 197 of isoform A. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 7]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 8]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 9]: Produced by alternative splicing. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4G family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC78444.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC82471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA02185.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAD18554.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing.; 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; D12686; BAA02185.1; ALT_FRAME; mRNA. DR EMBL; AY082886; AAL92872.1; -; mRNA. DR EMBL; AF281070; AAM69365.1; -; mRNA. DR EMBL; AK131407; BAD18554.1; ALT_SEQ; mRNA. DR EMBL; BX647812; CAI46013.1; -; mRNA. DR EMBL; AC078797; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471052; EAW78257.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78259.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78262.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78263.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78264.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78265.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78266.1; -; Genomic_DNA. DR EMBL; CH471052; EAW78267.1; -; Genomic_DNA. DR EMBL; AF002816; AAC78443.1; -; mRNA. DR EMBL; AF004836; AAC78444.1; ALT_INIT; Genomic_DNA. DR EMBL; AF104913; AAC82471.1; ALT_INIT; mRNA. DR EMBL; AJ001046; CAA04500.1; -; mRNA. DR CCDS; CCDS3259.1; -. [Q04637-1] DR CCDS; CCDS3260.1; -. [Q04637-4] DR CCDS; CCDS3261.1; -. [Q04637-5] DR CCDS; CCDS46970.2; -. [Q04637-7] DR CCDS; CCDS54687.1; -. [Q04637-9] DR CCDS; CCDS54688.1; -. [Q04637-8] DR CCDS; CCDS77866.1; -. [Q04637-3] DR PIR; A44453; A44453. DR RefSeq; NP_001181875.2; NM_001194946.2. [Q04637-9] DR RefSeq; NP_001181876.2; NM_001194947.2. [Q04637-9] DR RefSeq; NP_001278086.2; NM_001291157.2. [Q04637-3] DR RefSeq; NP_004944.3; NM_004953.4. [Q04637-7] DR RefSeq; NP_886553.3; NM_182917.4. DR RefSeq; NP_937884.2; NM_198241.3. [Q04637-1] DR RefSeq; NP_937885.1; NM_198242.3. [Q04637-5] DR RefSeq; NP_937887.2; NM_198244.3. [Q04637-4] DR PDB; 1LJ2; X-ray; 2.38 A; C/D=172-199. DR PDB; 1UG3; X-ray; 2.24 A; A/B=1233-1571. DR PDB; 2W97; X-ray; 2.29 A; E/F=609-622. DR PDB; 4AZA; X-ray; 2.16 A; B/D=609-620. DR PDB; 4F02; X-ray; 2.00 A; C/F=178-203. DR PDB; 5EHC; X-ray; 2.40 A; B=609-622. DR PDB; 5EI3; X-ray; 1.71 A; B=609-622. DR PDB; 5EIR; X-ray; 2.69 A; B=609-622. DR PDB; 5T46; X-ray; 1.53 A; B/D=592-653. DR PDB; 5ZK5; X-ray; 2.25 A; B=609-623. DR PDB; 6ZMW; EM; 3.70 A; g=290-1599. DR PDB; 8HUJ; EM; 3.76 A; B=746-992. DR PDB; 8J7R; EM; 3.70 A; B=746-992. DR PDB; 8OZ0; EM; 3.50 A; 2=197-1599. DR PDBsum; 1LJ2; -. DR PDBsum; 1UG3; -. DR PDBsum; 2W97; -. DR PDBsum; 4AZA; -. DR PDBsum; 4F02; -. DR PDBsum; 5EHC; -. DR PDBsum; 5EI3; -. DR PDBsum; 5EIR; -. DR PDBsum; 5T46; -. DR PDBsum; 5ZK5; -. DR PDBsum; 6ZMW; -. DR PDBsum; 8HUJ; -. DR PDBsum; 8J7R; -. DR PDBsum; 8OZ0; -. DR AlphaFoldDB; Q04637; -. DR BMRB; Q04637; -. DR EMDB; EMD-11302; -. DR EMDB; EMD-17297; -. DR EMDB; EMD-35041; -. DR EMDB; EMD-36046; -. DR SMR; Q04637; -. DR BioGRID; 108296; 468. DR ComplexPortal; CPX-2666; Eukaryotic translation initiation factor 4F, EIF4A1 and EIF4G1 variant. DR ComplexPortal; CPX-5634; Eukaryotic translation initiation factor 4F, EIF4A2 and EIF4G1 variant. DR CORUM; Q04637; -. DR DIP; DIP-1161N; -. DR ELM; Q04637; -. DR FunCoup; Q04637; 2647. DR IntAct; Q04637; 183. DR MINT; Q04637; -. DR STRING; 9606.ENSP00000416255; -. DR BindingDB; Q04637; -. DR ChEMBL; CHEMBL4523621; -. DR MoonProt; Q04637; -. DR GlyConnect; 2847; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; Q04637; 6 sites, 1 glycan. DR GlyGen; Q04637; 24 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (19 sites). DR iPTMnet; Q04637; -. DR MetOSite; Q04637; -. DR PhosphoSitePlus; Q04637; -. DR SwissPalm; Q04637; -. DR BioMuta; EIF4G1; -. DR DMDM; 294862538; -. DR jPOST; Q04637; -. DR MassIVE; Q04637; -. DR PaxDb; 9606-ENSP00000416255; -. DR PeptideAtlas; Q04637; -. DR ProteomicsDB; 20132; -. DR ProteomicsDB; 34026; -. DR ProteomicsDB; 58250; -. [Q04637-1] DR ProteomicsDB; 58251; -. [Q04637-3] DR ProteomicsDB; 58252; -. [Q04637-4] DR ProteomicsDB; 58253; -. [Q04637-5] DR ProteomicsDB; 58254; -. [Q04637-6] DR Pumba; Q04637; -. DR Antibodypedia; 3406; 617 antibodies from 40 providers. DR DNASU; 1981; -. DR Ensembl; ENST00000342981.8; ENSP00000343450.4; ENSG00000114867.23. [Q04637-8] DR Ensembl; ENST00000346169.7; ENSP00000316879.5; ENSG00000114867.23. [Q04637-1] DR Ensembl; ENST00000350481.9; ENSP00000317600.8; ENSG00000114867.23. [Q04637-5] DR Ensembl; ENST00000352767.7; ENSP00000338020.4; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000382330.7; ENSP00000371767.3; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000392537.6; ENSP00000376320.2; ENSG00000114867.23. [Q04637-4] DR Ensembl; ENST00000414031.5; ENSP00000391935.1; ENSG00000114867.23. [Q04637-3] DR Ensembl; ENST00000424196.5; ENSP00000416255.1; ENSG00000114867.23. [Q04637-9] DR Ensembl; ENST00000434061.6; ENSP00000411826.2; ENSG00000114867.23. [Q04637-7] DR GeneID; 1981; -. DR KEGG; hsa:1981; -. DR MANE-Select; ENST00000346169.7; ENSP00000316879.5; NM_198241.3; NP_937884.2. DR UCSC; uc003fnp.4; human. [Q04637-1] DR AGR; HGNC:3296; -. DR ClinPGx; PA27722; -. DR CTD; 1981; -. DR DisGeNET; 1981; -. DR GeneCards; EIF4G1; -. DR HGNC; HGNC:3296; EIF4G1. DR HPA; ENSG00000114867; Tissue enhanced (skeletal). DR MalaCards; EIF4G1; -. DR MIM; 600495; gene. DR MIM; 614251; phenotype. DR OpenTargets; ENSG00000114867; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000114867; -. DR eggNOG; KOG0401; Eukaryota. DR GeneTree; ENSGT00940000154648; -. DR HOGENOM; CLU_001519_2_0_1; -. DR InParanoid; Q04637; -. DR OMA; PRGGPNM; -. DR OrthoDB; 514777at2759; -. DR PAN-GO; Q04637; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q04637; -. DR PathwayCommons; Q04637; -. DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism. DR Reactome; R-HSA-156827; L13a-mediated translational silencing of Ceruloplasmin expression. DR Reactome; R-HSA-166208; mTORC1-mediated signalling. DR Reactome; R-HSA-429947; Deadenylation of mRNA. DR Reactome; R-HSA-450408; AUF1 (hnRNP D0) binds and destabilizes mRNA. DR Reactome; R-HSA-72649; Translation initiation complex formation. DR Reactome; R-HSA-72662; Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S. DR Reactome; R-HSA-72702; Ribosomal scanning and start codon recognition. DR Reactome; R-HSA-72706; GTP hydrolysis and joining of the 60S ribosomal subunit. DR Reactome; R-HSA-9010553; Regulation of expression of SLITs and ROBOs. DR Reactome; R-HSA-975956; Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC). DR Reactome; R-HSA-975957; Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC). DR Reactome; R-HSA-9820841; M-decay: degradation of maternal mRNAs by maternally stored factors. DR Reactome; R-HSA-9820865; Z-decay: degradation of maternal mRNAs by zygotically expressed factors. DR SignaLink; Q04637; -. DR SIGNOR; Q04637; -. DR Agora; ENSG00000114867; -. DR BioGRID-ORCS; 1981; 612 hits in 1167 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; EIF4G1; human. DR EvolutionaryTrace; Q04637; -. DR GeneWiki; Eukaryotic_translation_initiation_factor_4_gamma; -. DR GenomeRNAi; 1981; -. DR Pharos; Q04637; Tbio. DR PRO; PR:Q04637; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q04637; protein. DR Bgee; ENSG00000114867; Expressed in gastrocnemius and 206 other cell types or tissues. DR ExpressionAtlas; Q04637; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:AgBase. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; IDA:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005840; C:ribosome; IMP:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; IDA:AgBase. DR GO; GO:0060090; F:molecular adaptor activity; TAS:ParkinsonsUK-UCL. DR GO; GO:0003729; F:mRNA binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0008135; F:translation factor activity, RNA binding; IMP:ParkinsonsUK-UCL. DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB. DR GO; GO:0031369; F:translation initiation factor binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0002191; P:cap-dependent translational initiation; TAS:ParkinsonsUK-UCL. DR GO; GO:0031669; P:cellular response to nutrient levels; IMP:ParkinsonsUK-UCL. DR GO; GO:0097009; P:energy homeostasis; IMP:ParkinsonsUK-UCL. DR GO; GO:0035278; P:miRNA-mediated gene silencing by inhibition of translation; IDA:ParkinsonsUK-UCL. DR GO; GO:0010507; P:negative regulation of autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl. DR GO; GO:0030307; P:positive regulation of cell growth; IMP:ParkinsonsUK-UCL. DR GO; GO:1905537; P:positive regulation of eukaryotic translation initiation factor 4F complex assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; IMP:ParkinsonsUK-UCL. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0051247; P:positive regulation of protein metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036493; P:positive regulation of translation in response to endoplasmic reticulum stress; IMP:UniProtKB. DR GO; GO:0080135; P:regulation of cellular response to stress; TAS:ParkinsonsUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:0006446; P:regulation of translational initiation; IMP:UniProtKB. DR GO; GO:0006412; P:translation; IMP:ParkinsonsUK-UCL. DR GO; GO:0006413; P:translational initiation; IDA:UniProtKB. DR CDD; cd11559; W2_eIF4G1_like; 1. DR DisProt; DP02398; -. DR DisProt; DP03499; -. [Q04637-8] DR FunFam; 1.25.40.180:FF:000001; Eukaryotic translation initiation factor 4 gamma, 3, putative; 1. DR FunFam; 1.25.40.180:FF:000002; Eukaryotic translation initiation factor 4 gamma, 3, putative; 1. DR FunFam; 1.25.40.180:FF:000003; Putative eukaryotic translation initiation factor 4 gamma 1; 1. DR Gene3D; 1.25.40.180; -; 3. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR003891; Initiation_fac_eIF4g_MI. DR InterPro; IPR003890; MIF4G-like_typ-3. DR InterPro; IPR003307; W2_domain. DR PANTHER; PTHR23253; EUKARYOTIC TRANSLATION INITIATION FACTOR 4 GAMMA; 1. DR PANTHER; PTHR23253:SF10; EUKARYOTIC TRANSLATION INITIATION FACTOR 4 GAMMA 1; 1. DR Pfam; PF02847; MA3; 1. DR Pfam; PF02854; MIF4G; 1. DR Pfam; PF02020; W2; 1. DR SMART; SM00515; eIF5C; 1. DR SMART; SM00544; MA3; 1. DR SMART; SM00543; MIF4G; 1. DR SUPFAM; SSF48371; ARM repeat; 3. DR PROSITE; PS51366; MI; 1. DR PROSITE; PS51363; W2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Alternative splicing; KW Cytoplasm; Disease variant; Host-virus interaction; Initiation factor; KW Methylation; Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Protein biosynthesis; Proteomics identification; KW Reference proteome; RNA-binding; Translation regulation; KW Translational shunt. FT CHAIN 1..1599 FT /note="Eukaryotic translation initiation factor 4 gamma 1" FT /id="PRO_0000007786" FT DOMAIN 565..792 FT /note="MIF4G" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698" FT DOMAIN 1241..1363 FT /note="MI" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698" FT DOMAIN 1433..1599 FT /note="W2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00695" FT REGION 1..77 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 166..222 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 172..200 FT /note="PABPC1-binding" FT REGION 239..319 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 332..600 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 607..618 FT /note="EIF4E-binding" FT REGION 667..713 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 682..1085 FT /note="eIF3/EIF4A-binding" FT REGION 731..757 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1024..1227 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1450..1599 FT /note="EIF4A-binding" FT REGION 1585..1599 FT /note="Necessary but not sufficient for MKNK1-binding" FT COMPBIAS 8..24 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 34..48 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 53..72 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 249..260 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 261..271 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 289..304 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 429..452 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 453..474 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 519..535 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 548..563 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 574..583 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 674..683 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 741..757 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1116..1134 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1146..1178 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1186..1225 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 674..675 FT /note="Cleavage; by foot-and-mouth disease virus leader FT protease" FT SITE 681..682 FT /note="Cleavage; by enterovirus/rhinovirus protease 2A" FT MOD_RES 15 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6NZJ6" FT MOD_RES 73 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 110 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 207 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 223 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 314 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 602 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q6NZJ6" FT MOD_RES 647 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 685 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 694 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1028 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1032 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1042 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 1077 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1092 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17924679, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1095 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 1145 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1147 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1185 FT /note="Phosphoserine; by PKC/PRKCA" FT /evidence="ECO:0000269|PubMed:21576361, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1187 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1194 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1209 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1211 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692" FT MOD_RES 1231 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:16964243, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 1238 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1596 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..196 FT /note="Missing (in isoform E and isoform 7)" FT /evidence="ECO:0000303|PubMed:1429670" FT /id="VSP_018723" FT VAR_SEQ 1..164 FT /note="Missing (in isoform D)" FT /evidence="ECO:0000305" FT /id="VSP_018722" FT VAR_SEQ 1..87 FT /note="Missing (in isoform C)" FT /evidence="ECO:0000303|PubMed:9418880" FT /id="VSP_018721" FT VAR_SEQ 1..40 FT /note="Missing (in isoform B)" FT /evidence="ECO:0000303|PubMed:9857202" FT /id="VSP_018720" FT VAR_SEQ 48 FT /note="R -> RQGGFRSL (in isoform 9)" FT /evidence="ECO:0000305" FT /id="VSP_047396" FT VAR_SEQ 696 FT /note="P -> PQ (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|PubMed:12052860, FT ECO:0000303|PubMed:1429670, ECO:0000303|PubMed:9372926, FT ECO:0000303|Ref.12" FT /id="VSP_047397" FT VARIANT 71 FT /note="P -> S (in dbSNP:rs113810947)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066571" FT VARIANT 161 FT /note="T -> A (in dbSNP:rs13319149)" FT /evidence="ECO:0000269|PubMed:12052860, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:21907011, FT ECO:0000269|PubMed:9372926, ECO:0000269|PubMed:9755181" FT /id="VAR_061147" FT VARIANT 201 FT /note="R -> H (found in a patient with Rett syndrome-like FT phenotype; uncertain significance; dbSNP:rs34838305)" FT /evidence="ECO:0000269|PubMed:26740508" FT /id="VAR_079031" FT VARIANT 311 FT /note="Y -> C (in dbSNP:rs16858632)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_055704" FT VARIANT 432 FT /note="M -> V (in dbSNP:rs2178403)" FT /evidence="ECO:0000269|PubMed:12052860, FT ECO:0000269|PubMed:1429670, ECO:0000269|PubMed:21907011, FT ECO:0000269|PubMed:9372926, ECO:0007744|PubMed:19413330" FT /id="VAR_063040" FT VARIANT 466..468 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066572" FT VARIANT 502 FT /note="A -> V (in PARK18; dbSNP:rs111290936)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066573" FT VARIANT 686 FT /note="G -> C (found in patients with Parkinson disease; FT uncertain significance; dbSNP:rs112019125)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066574" FT VARIANT 696 FT /note="P -> L (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs754755344)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036117" FT VARIANT 806 FT /note="I -> V (in dbSNP:rs62287499)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066575" FT VARIANT 829 FT /note="T -> S (in dbSNP:rs111500185)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066576" FT VARIANT 1164 FT /note="S -> R (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs113169049)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066577" FT VARIANT 1197 FT /note="R -> W (found in a patient with Parkinson disease; FT uncertain significance; dbSNP:rs113388242)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066578" FT VARIANT 1205 FT /note="R -> H (in PARK18; dbSNP:rs112176450)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066579" FT VARIANT 1229 FT /note="P -> A (in dbSNP:rs35629949)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_061148" FT VARIANT 1233 FT /note="L -> P (in dbSNP:rs2230570)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_055705" FT VARIANT 1257 FT /note="N -> S (in dbSNP:rs73053766)" FT /evidence="ECO:0000269|PubMed:21907011" FT /id="VAR_066580" FT MUTAGEN 174..178 FT /note="KRERK->AAAAA: Loss of PABPC1 binding; when FT associated with 184-AAAA-187." FT /evidence="ECO:0000269|PubMed:10996799" FT MUTAGEN 180 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 182 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 184..187 FT /note="DPNQ->AAAA: Loss of PABPC1 binding; when associated FT with 174-AAAAA-178." FT MUTAGEN 192 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 196 FT /note="I->A: Loss of PABPC1 binding." FT /evidence="ECO:0000269|PubMed:12086624" FT MUTAGEN 612 FT /note="Y->A,F: Abolishes binding to EIF4E." FT /evidence="ECO:0000269|PubMed:7651417" FT MUTAGEN 617..618 FT /note="LL->AA: Abolishes binding to EIF4E." FT /evidence="ECO:0000269|PubMed:7651417" FT MUTAGEN 682 FT /note="G->A,V,W,R,E: Reduced cleavage by protease 2A from FT human rhinovirus 2." FT /evidence="ECO:0000269|PubMed:8961935" FT MUTAGEN 768 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-770 and A-775." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 771 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-767 and A-775." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 776 FT /note="F->A: Abolishes binding to EIF4A; when associated FT with A-767 and A-770." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 842..843 FT /note="LL->AA: Abolishes binding to EIF4A; when associated FT with A-850 and K-851." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 851..852 FT /note="FE->AK: Abolishes binding to EIF4A; when associated FT with A-841 and A-842." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 896 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-92 and A-95." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 902 FT /note="I->A: Abolishes binding to EIF4A; when associated FT with A-895 and A-95." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 905 FT /note="L->A: Abolishes binding to EIF4A; when associated FT with A-895 and A-92." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 974 FT /note="R->A: Abolishes binding to EIF4A; when associated FT with A-976." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 977 FT /note="F->A: Abolishes binding to EIF4A; when associated FT with A-973." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 985 FT /note="L->A: Slightly reduced binding to EIF4A; when FT associated with A-989." FT /evidence="ECO:0000269|PubMed:9372926" FT MUTAGEN 990 FT /note="W->A: Slightly reduced binding to EIF4A; when FT associated with A-984." FT /evidence="ECO:0000269|PubMed:9372926" FT CONFLICT 30 FT /note="P -> R (in Ref. 9; AAC78443)" FT /evidence="ECO:0000305" FT CONFLICT 138 FT /note="F -> L (in Ref. 5; AAL92872/AAM69365)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="Q -> R (in Ref. 5; AAL92872/AAM69365)" FT /evidence="ECO:0000305" FT CONFLICT 214 FT /note="G -> S (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 462 FT /note="E -> D (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 468 FT /note="A -> V (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 474 FT /note="A -> G (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 479 FT /note="G -> R (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 604 FT /note="L -> P (in Ref. 1; BAA02185, 5; AAL92872/AAM69365 FT and 10; AAC82471)" FT /evidence="ECO:0000305" FT CONFLICT 625..626 FT /note="AS -> CQ (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 693 FT /note="P -> A (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 696 FT /note="P -> A (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 764 FT /note="V -> W (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 878 FT /note="G -> E (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 894 FT /note="R -> C (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1104 FT /note="K -> Q (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1121 FT /note="N -> I (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1185 FT /note="S -> T (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT CONFLICT 1384 FT /note="C -> Y (in Ref. 6; CAI46013)" FT /evidence="ECO:0000305" FT CONFLICT 1472 FT /note="Missing (in Ref. 1; BAA02185)" FT /evidence="ECO:0000305" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:1LJ2" FT HELIX 185..187 FT /evidence="ECO:0007829|PDB:4F02" FT HELIX 193..197 FT /evidence="ECO:0007829|PDB:4F02" FT HELIX 614..618 FT /evidence="ECO:0007829|PDB:5T46" FT TURN 619..622 FT /evidence="ECO:0007829|PDB:5T46" FT HELIX 624..627 FT /evidence="ECO:0007829|PDB:5T46" FT TURN 637..639 FT /evidence="ECO:0007829|PDB:5T46" FT HELIX 1234..1256 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1259..1267 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1272..1274 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1275..1286 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1287..1289 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1291..1306 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1312..1329 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1330..1332 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1336..1344 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1345..1348 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1355..1362 FT /evidence="ECO:0007829|PDB:1UG3" FT TURN 1363..1365 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1366..1369 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1372..1387 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1389..1398 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1403..1405 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1413..1419 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1423..1425 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1439..1452 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1457..1467 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1470..1473 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1476..1489 FT /evidence="ECO:0007829|PDB:1UG3" FT STRAND 1494..1496 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1501..1514 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1518..1534 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1541..1551 FT /evidence="ECO:0007829|PDB:1UG3" FT HELIX 1557..1563 FT /evidence="ECO:0007829|PDB:1UG3" FT INIT_MET Q04637-4:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q04637-4:2 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q04637-7:489 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-7:498 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-7:509 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES Q04637-8:685 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-8:694 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES Q04637-8:705 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" SQ SEQUENCE 1599 AA; 175491 MW; 324088B60863DA34 CRC64; MNKAPQSTGP PPAPSPGLPQ PAFPPGQTAP VVFSTPQATQ MNTPSQPRQH FYPSRAQPPS SAASRVQSAA PARPGPAAHV YPAGSQVMMI PSQISYPASQ GAYYIPGQGR STYVVPTQQY PVQPGAPGFY PGASPTEFGT YAGAYYPAQG VQQFPTGVAP TPVLMNQPPQ IAPKRERKTI RIRDPNQGGK DITEEIMSGA RTASTPTPPQ TGGGLEPQAN GETPQVAVIV RPDDRSQGAI IADRPGLPGP EHSPSESQPS SPSPTPSPSP VLEPGSEPNL AVLSIPGDTM TTIQMSVEES TPISRETGEP YRLSPEPTPL AEPILEVEVT LSKPVPESEF SSSPLQAPTP LASHTVEIHE PNGMVPSEDL EPEVESSPEL APPPACPSES PVPIAPTAQP EELLNGAPSP PAVDLSPVSE PEEQAKEVTA SMAPPTIPSA TPATAPSATS PAQEEEMEEE EEEEEGEAGE AGEAESEKGG EELLPPESTP IPANLSQNLE AAAATQVAVS VPKRRRKIKE LNKKEAVGDL LDAFKEANPA VPEVENQPPA GSNPGPESEG SGVPPRPEEA DETWDSKEDK IHNAENIQPG EQKYEYKSDQ WKPLNLEEKK RYDREFLLGF QFIFASMQKP EGLPHISDVV LDKANKTPLR PLDPTRLQGI NCGPDFTPSF ANLGRTTLST RGPPRGGPGG ELPRGPAGLG PRRSQQGPRK EPRKIIATVL MTEDIKLNKA EKAWKPSSKR TAADKDRGEE DADGSKTQDL FRRVRSILNK LTPQMFQQLM KQVTQLAIDT EERLKGVIDL IFEKAISEPN FSVAYANMCR CLMALKVPTT EKPTVTVNFR KLLLNRCQKE FEKDKDDDEV FEKKQKEMDE AATAEERGRL KEELEEARDI ARRRSLGNIK FIGELFKLKM LTEAIMHDCV VKLLKNHDEE SLECLCRLLT TIGKDLDFEK AKPRMDQYFN QMEKIIKEKK TSSRIRFMLQ DVLDLRGSNW VPRRGDQGPK TIDQIHKEAE MEEHREHIKV QQLMAKGSDK RRGGPPGPPI SRGLPLVDDG GWNTVPISKG SRPIDTSRLT KITKPGSIDS NNQLFAPGGR LSWGKGSSGG SGAKPSDAAS EAARPATSTL NRFSALQQAV PTESTDNRRV VQRSSLSRER GEKAGDRGDR LERSERGGDR GDRLDRARTP ATKRSFSKEV EERSRERPSQ PEGLRKAASL TEDRDRGRDA VKREAALPPV SPLKAALSEE ELEKKSKAII EEYLHLNDMK EAVQCVQELA SPSLLFIFVR HGVESTLERS AIAREHMGQL LHQLLCAGHL STAQYYQGLY EILELAEDME IDIPHVWLYL AELVTPILQE GGVPMGELFR EITKPLRPLG KAASLLLEIL GLLCKSMGPK KVGTLWREAG LSWKEFLPEG QDIGAFVAEQ KVEYTLGEES EAPGQRALPS EELNRQLEKL LKEGSSNQRV FDWIEANLSE QQIVSNTLVR ALMTAVCYSA IIFETPLRVD VAVLKARAKL LQKYLCDEQK ELQALYALQA LVVTLEQPPN LLRMFFDALY DEDVVKEDAF YSWESSKDPA EQQGKGVALK SVTAFFKWLR EAEEESDHN // ID KLK6_HUMAN Reviewed; 244 AA. AC Q92876; A6NJA1; A8MW09; Q6H301; DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1997, sequence version 1. DT 28-JAN-2026, entry version 204. DE RecName: Full=Kallikrein-6; DE EC=3.4.21.-; DE AltName: Full=Neurosin; DE AltName: Full=Protease M; DE AltName: Full=SP59; DE AltName: Full=Serine protease 18; DE AltName: Full=Serine protease 9; DE AltName: Full=Zyme; DE Flags: Precursor; GN Name=KLK6; Synonyms=PRSS18, PRSS9; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8898378; DOI=10.1007/bf03401646; RA Anisowicz A., Sotiropoulou G., Stenman G., Mok S.C., Sager R.; RT "A novel protease homolog differentially expressed in breast and ovarian RT cancer."; RL Mol. Med. 2:624-636(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Colon; RX PubMed=9003450; DOI=10.1016/s0167-4781(96)00187-x; RA Yamashiro K., Tsuruoka N., Kodama S., Tsujimoto M., Yamamura Y., Tanaka T., RA Nakazato H., Yamaguchi N.; RT "Molecular cloning of a novel trypsin-like serine protease (neurosin) RT preferentially expressed in brain."; RL Biochim. Biophys. Acta 1350:11-14(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=9312124; DOI=10.1074/jbc.272.40.25135; RA Little S.P., Dixon E.P., Norris F., Buckley W., Becker G.W., Johnson M., RA Dobbins J.R., Wyrick T., Miller J.R., Mackellar W., Hepburn D., RA Corvalan J., McClure D., Liu X., Stephenson D., Clemens J., Johnstone E.M.; RT "Zyme, a novel and potentially amyloidogenic enzyme cDNA isolated from RT Alzheimer's disease brain."; RL J. Biol. Chem. 272:25135-25142(1997). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10610719; DOI=10.1006/geno.1999.6012; RA Yousef G.M., Luo L.Y., Scherer S.W., Sotiropoulou G., Diamandis E.P.; RT "Molecular characterization of Zyme/protease M/neurosin(PRSS9), a RT hormonally regulated kallikrein-like serine protease."; RL Genomics 62:251-259(1999). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11054574; DOI=10.1016/s0378-1119(00)00382-6; RA Gan L., Lee I., Smith R., Argonza-Barrett R., Lei H., McCuaig J., Moss P., RA Paeper B., Wang K.; RT "Sequencing and expression analysis of the serine protease gene cluster RT located in chromosome 19q13 region."; RL Gene 257:119-130(2000). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3). RC TISSUE=Testis; RX PubMed=15207701; DOI=10.1016/j.bbrc.2004.04.205; RA Pampalakis G., Kurlender L., Diamandis E.P., Sotiropoulou G.; RT "Cloning and characterization of novel isoforms of the human kallikrein 6 RT gene."; RL Biochem. Biophys. Res. Commun. 320:54-61(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=16800739; DOI=10.1515/bc.2006.097; RA Pampalakis G., Sotiropoulou G.; RT "Multiple mechanisms underlie the aberrant expression of the human RT kallikrein 6 gene in breast cancer."; RL Biol. Chem. 387:773-782(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=11018688; DOI=10.1016/s0009-9120(00)00145-4; RA Diamandis E.P., Yousef G.M., Soosaipillai A.R., Grass L., Porter A., RA Little S., Sotiropoulou G.; RT "Immunofluorometric assay of human kallikrein 6 (zyme/protease M/neurosin) RT and preliminary clinical applications."; RL Clin. Biochem. 33:369-375(2000). RN [14] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=10997858; DOI=10.1046/j.1440-1819.2000.00731.x; RA Ogawa K., Yamada T., Tsujioka Y., Taguchi J., Takahashi M., Tsuboi Y., RA Fujino Y., Nakajima M., Yamamoto T., Akatsu H., Mitsui S., Yamaguchi N.; RT "Localization of a novel type trypsin-like serine protease, neurosin, in RT brain tissues of Alzheimer's disease and Parkinson's disease."; RL Psychiatry Clin. Neurosci. 54:419-426(2000). RN [15] RP TISSUE SPECIFICITY. RX PubMed=11668196; DOI=10.1177/002215540104901111; RA Petraki C.D., Karavana V.N., Skoufogiannis P.T., Little S.P., RA Howarth D.J.C., Yousef G.M., Diamandis E.P.; RT "The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression RT in human tissues as assessed by immunohistochemistry."; RL J. Histochem. Cytochem. 49:1431-1441(2001). RN [16] RP FUNCTION, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, AND RP AUTOCATALYTIC CLEAVAGE. RX PubMed=12878203; DOI=10.1016/s0006-291x(03)01271-3; RA Magklara A., Mellati A.A., Wasney G.A., Little S.P., Sotiropoulou G., RA Becker G.W., Diamandis E.P.; RT "Characterization of the enzymatic activity of human kallikrein 6: RT autoactivation, substrate specificity, and regulation by inhibitors."; RL Biochem. Biophys. Res. Commun. 307:948-955(2003). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=12928483; DOI=10.1093/hmg/ddg283; RA Iwata A., Maruyama M., Akagi T., Hashikawa T., Kanazawa I., Tsuji S., RA Nukina N.; RT "Alpha-synuclein degradation by serine protease neurosin: implication for RT pathogenesis of synucleinopathies."; RL Hum. Mol. Genet. 12:2625-2635(2003). RN [18] RP FUNCTION. RX PubMed=15557757; DOI=10.1159/000081102; RA Ghosh M.C., Grass L., Soosaipillai A., Sotiropoulou G., Diamandis E.P.; RT "Human kallikrein 6 degrades extracellular matrix proteins and may enhance RT the metastatic potential of tumour cells."; RL Tumor Biol. 25:193-199(2004). RN [19] RP FUNCTION, AND INDUCTION. RX PubMed=16987227; DOI=10.1111/j.1460-9568.2006.05021.x; RA Scarisbrick I.A., Sabharwal P., Cruz H., Larsen N., Vandell A.G., RA Blaber S.I., Ameenuddin S., Papke L.M., Fehlings M.G., Reeves R.K., RA Blaber M., Windebank A.J., Rodriguez M.; RT "Dynamic role of kallikrein 6 in traumatic spinal cord injury."; RL Eur. J. Neurosci. 24:1457-1469(2006). RN [20] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=16321973; DOI=10.1074/jbc.m510096200; RA Angelo P.F., Lima A.R., Alves F.M., Blaber S.I., Scarisbrick I.A., RA Blaber M., Juliano L., Juliano M.A.; RT "Substrate specificity of human kallikrein 6: salt and glycosaminoglycan RT activation effects."; RL J. Biol. Chem. 281:3116-3126(2006). RN [21] RP AUTOCATALYTIC CLEAVAGE. RX PubMed=17417874; DOI=10.1021/bi6025006; RA Blaber S.I., Yoon H., Scarisbrick I.A., Juliano M.A., Blaber M.; RT "The autolytic regulation of human kallikrein-related peptidase 6."; RL Biochemistry 46:5209-5217(2007). RN [22] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 21-243, AUTOCATALYTIC CLEAVAGE, RP ACTIVE SITES, AND DISULFIDE BONDS. RX PubMed=12016211; DOI=10.1074/jbc.m201534200; RA Gomis-Rueth F.X., Bayes A., Sotiropoulou G., Pampalakis G., Tsetsenis T., RA Villegas V., Aviles F.X., Coll M.; RT "The structure of human prokallikrein 6 reveals a novel activation RT mechanism for the kallikrein family."; RL J. Biol. Chem. 277:27273-27281(2002). RN [23] RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 22-244, PROTEIN SEQUENCE OF RP 22-25, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AUTOCATALYTIC CLEAVAGE, RP DISULFIDE BONDS, AND MASS SPECTROMETRY. RX PubMed=11983703; DOI=10.1074/jbc.m202392200; RA Bernett M.J., Blaber S.I., Scarisbrick I.A., Dhanarajan P., Thompson S.M., RA Blaber M.; RT "Crystal structure and biochemical characterization of human kallikrein 6 RT reveals that a trypsin-like kallikrein is expressed in the central nervous RT system."; RL J. Biol. Chem. 277:24562-24570(2002). CC -!- FUNCTION: Serine protease which exhibits a preference for Arg over Lys CC in the substrate P1 position and for Ser or Pro in the P2 position. CC Shows activity against amyloid precursor protein, myelin basic protein, CC gelatin, casein and extracellular matrix proteins such as fibronectin, CC laminin, vitronectin and collagen. Degrades alpha-synuclein and CC prevents its polymerization, indicating that it may be involved in the CC pathogenesis of Parkinson disease and other synucleinopathies. May be CC involved in regulation of axon outgrowth following spinal cord injury. CC Tumor cells treated with a neutralizing KLK6 antibody migrate less than CC control cells, suggesting a role in invasion and metastasis. CC {ECO:0000269|PubMed:11983703, ECO:0000269|PubMed:12878203, CC ECO:0000269|PubMed:12928483, ECO:0000269|PubMed:15557757, CC ECO:0000269|PubMed:16321973, ECO:0000269|PubMed:16987227}. CC -!- ACTIVITY REGULATION: Inhibited by a range of serine protease inhibitors CC including soybean trypsin inhibitor, benzamidine and serpins. Activated CC by a range of glycosaminoglycans including chondroitin sulfate, CC dermatan sulfate, heparan sulfate and heparin. CC {ECO:0000269|PubMed:12878203, ECO:0000269|PubMed:16321973}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1562 uM for Tosyl-Gly-Pro-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=777 uM for Tosyl-Gly-Pro-Lys-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.410 mM for Phe-Ser-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.455 mM for Gly-Gly-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.335 mM for Asp-Pro-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.758 mM for Gln-Gly-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.625 mM for Pro-Phe-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=0.271 mM for Val-Pro-Arg-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC KM=1.72 mM for Val-Leu-Lys-AMC {ECO:0000269|PubMed:11983703, CC ECO:0000269|PubMed:12878203}; CC -!- INTERACTION: CC Q92876; Q8NC06-3: ACBD4; NbExp=3; IntAct=EBI-2432309, EBI-12811089; CC Q92876; P11117: ACP2; NbExp=3; IntAct=EBI-2432309, EBI-2907070; CC Q92876; Q53FZ2-2: ACSM3; NbExp=3; IntAct=EBI-2432309, EBI-25887341; CC Q92876; Q96BT7-2: ALKBH8; NbExp=3; IntAct=EBI-2432309, EBI-13329511; CC Q92876; P05067: APP; NbExp=3; IntAct=EBI-2432309, EBI-77613; CC Q92876; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-2432309, EBI-2875816; CC Q92876; Q5H9R4-2: ARMCX4; NbExp=3; IntAct=EBI-2432309, EBI-21899904; CC Q92876; Q8WXK3-2: ASB13; NbExp=3; IntAct=EBI-2432309, EBI-12015080; CC Q92876; Q12797-6: ASPH; NbExp=3; IntAct=EBI-2432309, EBI-12092171; CC Q92876; Q9Y6H3: ATP23; NbExp=3; IntAct=EBI-2432309, EBI-12811889; CC Q92876; P27449: ATP6V0C; NbExp=3; IntAct=EBI-2432309, EBI-721179; CC Q92876; O95817: BAG3; NbExp=3; IntAct=EBI-2432309, EBI-747185; CC Q92876; Q8TBE0: BAHD1; NbExp=3; IntAct=EBI-2432309, EBI-742750; CC Q92876; Q9UQB8-3: BAIAP2; NbExp=3; IntAct=EBI-2432309, EBI-9091996; CC Q92876; Q9UQB8-6: BAIAP2; NbExp=3; IntAct=EBI-2432309, EBI-9092016; CC Q92876; P51572: BCAP31; NbExp=3; IntAct=EBI-2432309, EBI-77683; CC Q92876; O15155-2: BET1; NbExp=3; IntAct=EBI-2432309, EBI-25846497; CC Q92876; Q9BXY8: BEX2; NbExp=3; IntAct=EBI-2432309, EBI-745073; CC Q92876; Q7L1Q6-2: BZW1; NbExp=3; IntAct=EBI-2432309, EBI-21557060; CC Q92876; Q9H0W9-3: C11orf54; NbExp=3; IntAct=EBI-2432309, EBI-12108466; CC Q92876; Q9H257-2: CARD9; NbExp=3; IntAct=EBI-2432309, EBI-11530605; CC Q92876; Q86XM0: CATSPERD; NbExp=3; IntAct=EBI-2432309, EBI-10260328; CC Q92876; O75309: CDH16; NbExp=3; IntAct=EBI-2432309, EBI-2837263; CC Q92876; P49336-2: CDK8; NbExp=3; IntAct=EBI-2432309, EBI-11039720; CC Q92876; Q9Y281: CFL2; NbExp=3; IntAct=EBI-2432309, EBI-351218; CC Q92876; Q8NE62: CHDH; NbExp=3; IntAct=EBI-2432309, EBI-7127986; CC Q92876; O75508: CLDN11; NbExp=3; IntAct=EBI-2432309, EBI-12820543; CC Q92876; Q9BT09: CNPY3; NbExp=3; IntAct=EBI-2432309, EBI-2835965; CC Q92876; P20849: COL9A1; NbExp=3; IntAct=EBI-2432309, EBI-2528238; CC Q92876; Q86WV2: COX4I1; NbExp=3; IntAct=EBI-2432309, EBI-10260134; CC Q92876; P68400: CSNK2A1; NbExp=3; IntAct=EBI-2432309, EBI-347804; CC Q92876; P09668: CTSH; NbExp=3; IntAct=EBI-2432309, EBI-6189940; CC Q92876; P09172: DBH; NbExp=3; IntAct=EBI-2432309, EBI-8589586; CC Q92876; P61962: DCAF7; NbExp=3; IntAct=EBI-2432309, EBI-359808; CC Q92876; Q9BTE7: DCUN1D5; NbExp=3; IntAct=EBI-2432309, EBI-3924013; CC Q92876; Q6ZPD9-2: DPY19L3; NbExp=3; IntAct=EBI-2432309, EBI-25888224; CC Q92876; P63167: DYNLL1; NbExp=3; IntAct=EBI-2432309, EBI-349105; CC Q92876; Q13144: EIF2B5; NbExp=3; IntAct=EBI-2432309, EBI-4401110; CC Q92876; P23588: EIF4B; NbExp=3; IntAct=EBI-2432309, EBI-970310; CC Q92876; P16452: EPB42; NbExp=3; IntAct=EBI-2432309, EBI-1182496; CC Q92876; Q5RHP9-3: ERICH3; NbExp=3; IntAct=EBI-2432309, EBI-20839496; CC Q92876; Q6NXG1: ESRP1; NbExp=3; IntAct=EBI-2432309, EBI-10213520; CC Q92876; Q6NXG1-3: ESRP1; NbExp=3; IntAct=EBI-2432309, EBI-21567429; CC Q92876; Q7L5A8: FA2H; NbExp=3; IntAct=EBI-2432309, EBI-11337888; CC Q92876; Q6NZ36-4: FAAP20; NbExp=3; IntAct=EBI-2432309, EBI-12013806; CC Q92876; Q14296: FASTK; NbExp=3; IntAct=EBI-2432309, EBI-1754067; CC Q92876; P62861: FAU; NbExp=3; IntAct=EBI-2432309, EBI-358093; CC Q92876; P31994: FCGR2B; NbExp=3; IntAct=EBI-2432309, EBI-724784; CC Q92876; Q7L622: G2E3; NbExp=3; IntAct=EBI-2432309, EBI-751757; CC Q92876; P24522: GADD45A; NbExp=3; IntAct=EBI-2432309, EBI-448167; CC Q92876; P15976-2: GATA1; NbExp=3; IntAct=EBI-2432309, EBI-9090198; CC Q92876; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-2432309, EBI-8799578; CC Q92876; B2RAF7: hCG_1818547; NbExp=3; IntAct=EBI-2432309, EBI-25844370; CC Q92876; P52790: HK3; NbExp=3; IntAct=EBI-2432309, EBI-2965780; CC Q92876; Q9P0W2: HMG20B; NbExp=3; IntAct=EBI-2432309, EBI-713401; CC Q92876; Q4VB01: HOXB1; NbExp=3; IntAct=EBI-2432309, EBI-17494170; CC Q92876; Q7LGA3-3: HS2ST1; NbExp=3; IntAct=EBI-2432309, EBI-25887463; CC Q92876; Q96D96-2: HVCN1; NbExp=3; IntAct=EBI-2432309, EBI-25888137; CC Q92876; Q8IYA8: IHO1; NbExp=3; IntAct=EBI-2432309, EBI-8638439; CC Q92876; Q14005-2: IL16; NbExp=3; IntAct=EBI-2432309, EBI-17178971; CC Q92876; Q0VD86: INCA1; NbExp=3; IntAct=EBI-2432309, EBI-6509505; CC Q92876; Q9BT40: INPP5K; NbExp=3; IntAct=EBI-2432309, EBI-749162; CC Q92876; Q9Y283-3: INVS; NbExp=3; IntAct=EBI-2432309, EBI-11944909; CC Q92876; P57682: KLF3; NbExp=3; IntAct=EBI-2432309, EBI-8472267; CC Q92876; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-2432309, EBI-714379; CC Q92876; O60259: KLK8; NbExp=3; IntAct=EBI-2432309, EBI-3915857; CC Q92876; P08727: KRT19; NbExp=3; IntAct=EBI-2432309, EBI-742756; CC Q92876; Q14533: KRT81; NbExp=3; IntAct=EBI-2432309, EBI-739648; CC Q92876; Q3LI72: KRTAP19-5; NbExp=3; IntAct=EBI-2432309, EBI-1048945; CC Q92876; Q3SYF9: KRTAP19-7; NbExp=3; IntAct=EBI-2432309, EBI-10241353; CC Q92876; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-2432309, EBI-10261141; CC Q92876; Q92615: LARP4B; NbExp=3; IntAct=EBI-2432309, EBI-1052558; CC Q92876; Q14847-2: LASP1; NbExp=3; IntAct=EBI-2432309, EBI-9088686; CC Q92876; Q6DKI2: LGALS9C; NbExp=3; IntAct=EBI-2432309, EBI-9088829; CC Q92876; Q8TE12-2: LMX1A; NbExp=3; IntAct=EBI-2432309, EBI-25846312; CC Q92876; O95332: LOC57228; NbExp=3; IntAct=EBI-2432309, EBI-25846778; CC Q92876; Q96JB6: LOXL4; NbExp=3; IntAct=EBI-2432309, EBI-749562; CC Q92876; Q99683: MAP3K5; NbExp=3; IntAct=EBI-2432309, EBI-476263; CC Q92876; Q15759: MAPK11; NbExp=3; IntAct=EBI-2432309, EBI-298304; CC Q92876; P42679: MATK; NbExp=3; IntAct=EBI-2432309, EBI-751664; CC Q92876; Q8N6R0: METTL13; NbExp=3; IntAct=EBI-2432309, EBI-1053295; CC Q92876; Q14728: MFSD10; NbExp=3; IntAct=EBI-2432309, EBI-11337904; CC Q92876; A0A0A0MR05: MLST8; NbExp=3; IntAct=EBI-2432309, EBI-25835557; CC Q92876; Q9BRA0: NAA38; NbExp=3; IntAct=EBI-2432309, EBI-9106509; CC Q92876; Q92886: NEUROG1; NbExp=3; IntAct=EBI-2432309, EBI-10279647; CC Q92876; P48645: NMU; NbExp=3; IntAct=EBI-2432309, EBI-10210351; CC Q92876; Q9Y239: NOD1; NbExp=3; IntAct=EBI-2432309, EBI-1051262; CC Q92876; P06748: NPM1; NbExp=3; IntAct=EBI-2432309, EBI-78579; CC Q92876; Q6P4D5-2: PABIR3; NbExp=3; IntAct=EBI-2432309, EBI-9091052; CC Q92876; Q8WW12: PCNP; NbExp=3; IntAct=EBI-2432309, EBI-10972020; CC Q92876; Q16549: PCSK7; NbExp=3; IntAct=EBI-2432309, EBI-8059854; CC Q92876; Q13371: PDCL; NbExp=3; IntAct=EBI-2432309, EBI-5772890; CC Q92876; Q9NZ53-2: PODXL2; NbExp=3; IntAct=EBI-2432309, EBI-25887738; CC Q92876; Q9GZS1: POLR1E; NbExp=3; IntAct=EBI-2432309, EBI-359458; CC Q92876; P19388: POLR2E; NbExp=3; IntAct=EBI-2432309, EBI-395189; CC Q92876; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-2432309, EBI-25835994; CC Q92876; Q96QH2: PRAM1; NbExp=3; IntAct=EBI-2432309, EBI-2860740; CC Q92876; Q86UA1: PRPF39; NbExp=3; IntAct=EBI-2432309, EBI-2803203; CC Q92876; P61289: PSME3; NbExp=3; IntAct=EBI-2432309, EBI-355546; CC Q92876; P21246: PTN; NbExp=3; IntAct=EBI-2432309, EBI-473725; CC Q92876; P53801: PTTG1IP; NbExp=3; IntAct=EBI-2432309, EBI-3906138; CC Q92876; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-2432309, EBI-12123390; CC Q92876; Q9BWF3: RBM4; NbExp=3; IntAct=EBI-2432309, EBI-2856454; CC Q92876; P52756: RBM5; NbExp=3; IntAct=EBI-2432309, EBI-714003; CC Q92876; P47804-3: RGR; NbExp=3; IntAct=EBI-2432309, EBI-25834767; CC Q92876; Q9H0X6: RNF208; NbExp=3; IntAct=EBI-2432309, EBI-751555; CC Q92876; Q969K3: RNF34; NbExp=3; IntAct=EBI-2432309, EBI-2340642; CC Q92876; Q9BY12-3: SCAPER; NbExp=3; IntAct=EBI-2432309, EBI-25837959; CC Q92876; Q86SQ7-2: SDCCAG8; NbExp=3; IntAct=EBI-2432309, EBI-10696955; CC Q92876; Q9NTN9-3: SEMA4G; NbExp=3; IntAct=EBI-2432309, EBI-9089805; CC Q92876; Q8IUQ4-2: SIAH1; NbExp=3; IntAct=EBI-2432309, EBI-11522811; CC Q92876; Q9H2B4-2: SLC26A1; NbExp=3; IntAct=EBI-2432309, EBI-12908340; CC Q92876; Q99717: SMAD5; NbExp=3; IntAct=EBI-2432309, EBI-6391136; CC Q92876; P37840: SNCA; NbExp=3; IntAct=EBI-2432309, EBI-985879; CC Q92876; Q5T0L3: SPATA46; NbExp=3; IntAct=EBI-2432309, EBI-750105; CC Q92876; Q496A3: SPATS1; NbExp=3; IntAct=EBI-2432309, EBI-3923692; CC Q92876; Q9BUD6: SPON2; NbExp=3; IntAct=EBI-2432309, EBI-10298801; CC Q92876; Q9C004: SPRY4; NbExp=3; IntAct=EBI-2432309, EBI-354861; CC Q92876; Q99469: STAC; NbExp=3; IntAct=EBI-2432309, EBI-2652799; CC Q92876; O75558: STX11; NbExp=3; IntAct=EBI-2432309, EBI-714135; CC Q92876; Q9UMX1: SUFU; NbExp=3; IntAct=EBI-2432309, EBI-740595; CC Q92876; O43463: SUV39H1; NbExp=3; IntAct=EBI-2432309, EBI-349968; CC Q92876; O60506-4: SYNCRIP; NbExp=3; IntAct=EBI-2432309, EBI-11123832; CC Q92876; Q8TDR4: TCP10L; NbExp=3; IntAct=EBI-2432309, EBI-3923210; CC Q92876; Q96A09: TENT5B; NbExp=3; IntAct=EBI-2432309, EBI-752030; CC Q92876; Q01664: TFAP4; NbExp=3; IntAct=EBI-2432309, EBI-2514218; CC Q92876; Q6YHU6: THADA; NbExp=3; IntAct=EBI-2432309, EBI-2824523; CC Q92876; Q9H808: TLE6; NbExp=3; IntAct=EBI-2432309, EBI-3921684; CC Q92876; Q8IU80-2: TMPRSS6; NbExp=3; IntAct=EBI-2432309, EBI-25839648; CC Q92876; Q8IUR5-4: TMTC1; NbExp=3; IntAct=EBI-2432309, EBI-9089156; CC Q92876; Q8WVP5: TNFAIP8L1; NbExp=3; IntAct=EBI-2432309, EBI-752102; CC Q92876; Q96KP6: TNIP3; NbExp=3; IntAct=EBI-2432309, EBI-2509913; CC Q92876; O14787-2: TNPO2; NbExp=3; IntAct=EBI-2432309, EBI-12076664; CC Q92876; O94900: TOX; NbExp=3; IntAct=EBI-2432309, EBI-9088321; CC Q92876; P06753-2: TPM3; NbExp=3; IntAct=EBI-2432309, EBI-10977875; CC Q92876; Q9NX07: TRNAU1AP; NbExp=3; IntAct=EBI-2432309, EBI-12581310; CC Q92876; O60636: TSPAN2; NbExp=3; IntAct=EBI-2432309, EBI-3914288; CC Q92876; Q86UF1: TSPAN33; NbExp=3; IntAct=EBI-2432309, EBI-12045841; CC Q92876; Q5VYS8-5: TUT7; NbExp=3; IntAct=EBI-2432309, EBI-9088812; CC Q92876; Q9GZX9: TWSG1; NbExp=3; IntAct=EBI-2432309, EBI-10304067; CC Q92876; Q13404: UBE2V1; NbExp=3; IntAct=EBI-2432309, EBI-1050671; CC Q92876; Q9H9P5-5: UNKL; NbExp=3; IntAct=EBI-2432309, EBI-12817837; CC Q92876; Q9NVA1: UQCC1; NbExp=3; IntAct=EBI-2432309, EBI-11911675; CC Q92876; P61964: WDR5; NbExp=3; IntAct=EBI-2432309, EBI-540834; CC Q92876; Q9NZC7-5: WWOX; NbExp=3; IntAct=EBI-2432309, EBI-12040603; CC Q92876; O00308: WWP2; NbExp=3; IntAct=EBI-2432309, EBI-743923; CC Q92876; Q9HAV4: XPO5; NbExp=3; IntAct=EBI-2432309, EBI-517949; CC Q92876; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-2432309, EBI-12010736; CC Q92876; Q7Z783; NbExp=3; IntAct=EBI-2432309, EBI-9088990; CC Q92876; Q96EJ4; NbExp=3; IntAct=EBI-2432309, EBI-750454; CC -!- SUBCELLULAR LOCATION: Secreted. Nucleus, nucleolus. Cytoplasm. CC Mitochondrion. Microsome. Note=In brain, detected in the nucleus of CC glial cells and in the nucleus and cytoplasm of neurons. Detected in CC the mitochondrial and microsomal fractions of HEK-293 cells and CC released into the cytoplasm following cell stress. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q92876-1; Sequence=Displayed; CC Name=2; CC IsoId=Q92876-2; Sequence=VSP_034403; CC Name=3; CC IsoId=Q92876-3; Sequence=VSP_034404, VSP_034405; CC -!- TISSUE SPECIFICITY: In fluids, highest levels found in milk of CC lactating women followed by cerebrospinal fluid, nipple aspirate fluid CC and breast cyst fluid. Also found in serum, seminal plasma and some CC amniotic fluids and breast tumor cytosolic extracts. Not detected in CC urine. At the tissue level, highest concentrations found in glandular CC tissues such as salivary glands followed by lung, colon, fallopian CC tube, placenta, breast, pituitary and kidney. Not detected in skin, CC spleen, bone, thyroid, heart, ureter, liver, muscle, endometrium, CC testis, pancreas, seminal vesicle, ovary, adrenals and prostate. In CC brain, detected in gray matter neurons (at protein level). Colocalizes CC with pathological inclusions such as Lewy bodies and glial cytoplasmic CC inclusions. Overexpressed in primary breast tumors but not expressed in CC metastatic tumors. {ECO:0000269|PubMed:10997858, CC ECO:0000269|PubMed:11018688, ECO:0000269|PubMed:11668196, CC ECO:0000269|PubMed:12928483, ECO:0000269|PubMed:16800739}. CC -!- INDUCTION: By spinal cord injury. This effect is particularly prominent CC in macrophages, microglia and reactive astrocytes. CC {ECO:0000269|PubMed:16987227}. CC -!- PTM: Inactivated by autolytic cleavage after Arg-80. CC -!- MASS SPECTROMETRY: Mass=25866; Method=MALDI; CC Evidence={ECO:0000269|PubMed:11983703}; CC -!- SIMILARITY: Belongs to the peptidase S1 family. Kallikrein subfamily. CC {ECO:0000255|PROSITE-ProRule:PRU00274}. 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; U62801; AAB07113.1; -; mRNA. DR EMBL; D78203; BAA11306.1; -; mRNA. DR EMBL; AF013988; AAB66483.1; -; mRNA. DR EMBL; AF149289; AAD51475.1; -; Genomic_DNA. DR EMBL; AF243527; AAG33359.1; -; Genomic_DNA. DR EMBL; AY318867; AAP82446.1; -; mRNA. DR EMBL; AY318868; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AY318869; AAP82448.1; -; mRNA. DR EMBL; AY318870; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; DQ223012; ABB04464.1; -; mRNA. DR EMBL; AK314897; BAG37411.1; -; mRNA. DR EMBL; BT006852; AAP35498.1; -; mRNA. DR EMBL; AC011483; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471135; EAW71953.1; -; Genomic_DNA. DR EMBL; CH471135; EAW71954.1; -; Genomic_DNA. DR EMBL; BC015525; AAH15525.1; -; mRNA. DR CCDS; CCDS12811.1; -. [Q92876-1] DR CCDS; CCDS42599.1; -. [Q92876-2] DR RefSeq; NP_001012982.1; NM_001012964.3. [Q92876-1] DR RefSeq; NP_001012983.1; NM_001012965.3. [Q92876-2] DR RefSeq; NP_001306877.1; NM_001319948.2. [Q92876-2] DR RefSeq; NP_001306878.1; NM_001319949.2. [Q92876-2] DR RefSeq; NP_002765.1; NM_002774.4. [Q92876-1] DR RefSeq; XP_024307379.1; XM_024451611.2. [Q92876-2] DR PDB; 1GVL; X-ray; 1.80 A; A=21-243. DR PDB; 1L2E; X-ray; 1.75 A; A=22-244. DR PDB; 1LO6; X-ray; 1.56 A; A=22-244. DR PDB; 3VFE; X-ray; 1.88 A; A=22-244. DR PDB; 4D8N; X-ray; 1.68 A; A=22-244. DR PDB; 5NX1; X-ray; 1.85 A; A=22-244. DR PDB; 5NX3; X-ray; 2.30 A; A=22-244. DR PDB; 6QFF; X-ray; 1.64 A; A/B=22-243. DR PDB; 6QFG; X-ray; 1.68 A; A/B=22-244. DR PDB; 6QFH; X-ray; 1.65 A; A/B=22-243. DR PDB; 6QH9; X-ray; 2.27 A; A/B=22-244. DR PDB; 6QHA; X-ray; 1.82 A; A/B=22-244. DR PDB; 6QHB; X-ray; 1.84 A; A/B=22-244. DR PDB; 6QHC; X-ray; 1.87 A; A/B=22-244. DR PDB; 6SKB; X-ray; 1.84 A; A/B/C=12-244. DR PDB; 6SKC; X-ray; 2.18 A; A/B=22-244. DR PDB; 6SKD; X-ray; 2.26 A; A/B=22-244. DR PDB; 7QFT; X-ray; 1.47 A; A/B=22-244. DR PDB; 7QFV; X-ray; 1.56 A; A/B=22-244. DR PDB; 7QHZ; X-ray; 1.50 A; A=22-244. DR PDB; 7QI0; X-ray; 1.88 A; A/B=22-244. DR PDBsum; 1GVL; -. DR PDBsum; 1L2E; -. DR PDBsum; 1LO6; -. DR PDBsum; 3VFE; -. DR PDBsum; 4D8N; -. DR PDBsum; 5NX1; -. DR PDBsum; 5NX3; -. DR PDBsum; 6QFF; -. DR PDBsum; 6QFG; -. DR PDBsum; 6QFH; -. DR PDBsum; 6QH9; -. DR PDBsum; 6QHA; -. DR PDBsum; 6QHB; -. DR PDBsum; 6QHC; -. DR PDBsum; 6SKB; -. DR PDBsum; 6SKC; -. DR PDBsum; 6SKD; -. DR PDBsum; 7QFT; -. DR PDBsum; 7QFV; -. DR PDBsum; 7QHZ; -. DR PDBsum; 7QI0; -. DR AlphaFoldDB; Q92876; -. DR SMR; Q92876; -. DR BioGRID; 111634; 63. DR CORUM; Q92876; -. DR FunCoup; Q92876; 77. DR IntAct; Q92876; 191. DR MINT; Q92876; -. DR STRING; 9606.ENSP00000366047; -. DR BindingDB; Q92876; -. DR ChEMBL; CHEMBL4448; -. DR DrugBank; DB03127; Benzamidine. DR GuidetoPHARMACOLOGY; 2376; -. DR MEROPS; S01.236; -. DR GlyConnect; 2937; 2 N-Linked glycans (1 site). DR GlyCosmos; Q92876; 1 site, 18 glycans. DR GlyGen; Q92876; 1 site, 18 N-linked glycans (1 site). DR iPTMnet; Q92876; -. DR PhosphoSitePlus; Q92876; -. DR BioMuta; KLK6; -. DR DMDM; 3914480; -. DR jPOST; Q92876; -. DR MassIVE; Q92876; -. DR PaxDb; 9606-ENSP00000366047; -. DR PeptideAtlas; Q92876; -. DR ProteomicsDB; 75559; -. [Q92876-1] DR ProteomicsDB; 75560; -. [Q92876-2] DR Pumba; Q92876; -. DR Antibodypedia; 32402; 345 antibodies from 33 providers. DR DNASU; 5653; -. DR Ensembl; ENST00000310157.7; ENSP00000309148.1; ENSG00000167755.16. [Q92876-1] DR Ensembl; ENST00000376851.7; ENSP00000366047.2; ENSG00000167755.16. [Q92876-1] DR Ensembl; ENST00000391808.5; ENSP00000375684.1; ENSG00000167755.16. [Q92876-2] DR Ensembl; ENST00000594641.1; ENSP00000470482.1; ENSG00000167755.16. [Q92876-1] DR Ensembl; ENST00000597379.5; ENSP00000469630.1; ENSG00000167755.16. [Q92876-3] DR Ensembl; ENST00000599881.5; ENSP00000471948.1; ENSG00000167755.16. [Q92876-3] DR GeneID; 5653; -. DR KEGG; hsa:5653; -. DR MANE-Select; ENST00000310157.7; ENSP00000309148.1; NM_002774.4; NP_002765.1. DR UCSC; uc002pui.4; human. [Q92876-1] DR AGR; HGNC:6367; -. DR ClinPGx; PA30156; -. DR CTD; 5653; -. DR DisGeNET; 5653; -. DR GeneCards; KLK6; -. DR HGNC; HGNC:6367; KLK6. DR HPA; ENSG00000167755; Tissue enriched (brain). DR MIM; 602652; gene. DR OpenTargets; ENSG00000167755; -. DR VEuPathDB; HostDB:ENSG00000167755; -. DR eggNOG; KOG3627; Eukaryota. DR GeneTree; ENSGT01030000234551; -. DR HOGENOM; CLU_006842_1_1_1; -. DR InParanoid; Q92876; -. DR OMA; RHDNDIM; -. DR OrthoDB; 10059102at2759; -. DR PAN-GO; Q92876; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q92876; -. DR BRENDA; 3.4.21.104; 2681. DR BRENDA; 3.4.21.34; 2681. DR BRENDA; 3.4.21.B10; 2681. DR PathwayCommons; Q92876; -. DR SABIO-RK; Q92876; -. DR SignaLink; Q92876; -. DR Agora; ENSG00000167755; -. DR BioGRID-ORCS; 5653; 20 hits in 1159 CRISPR screens. DR ChiTaRS; KLK6; human. DR EvolutionaryTrace; Q92876; -. DR GeneWiki; KLK6; -. DR GenomeRNAi; 5653; -. DR Pharos; Q92876; Tchem. DR PRO; PR:Q92876; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q92876; protein. DR Bgee; ENSG00000167755; Expressed in C1 segment of cervical spinal cord and 145 other cell types or tissues. DR ExpressionAtlas; Q92876; baseline and differential. DR GO; GO:0001533; C:cornified envelope; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0045171; C:intercellular bridge; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0030141; C:secretory granule; IBA:GO_Central. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; NAS:UniProtKB. DR GO; GO:0007417; P:central nervous system development; NAS:UniProtKB. DR GO; GO:0030574; P:collagen catabolic process; NAS:UniProtKB. DR GO; GO:0042445; P:hormone metabolic process; NAS:UniProtKB. DR GO; GO:0042552; P:myelination; NAS:UniProtKB. DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0016540; P:protein autoprocessing; NAS:UniProtKB. DR GO; GO:0051604; P:protein maturation; IBA:GO_Central. DR GO; GO:0045595; P:regulation of cell differentiation; NAS:UniProtKB. DR GO; GO:0010975; P:regulation of neuron projection development; IEA:Ensembl. DR GO; GO:0009611; P:response to wounding; NAS:UniProtKB. DR GO; GO:0042246; P:tissue regeneration; NAS:UniProtKB. DR CDD; cd00190; Tryp_SPc; 1. DR FunFam; 2.40.10.10:FF:000088; kallikrein-6 isoform X1; 1. DR FunFam; 2.40.10.10:FF:000041; kallikrein-6 isoform X2; 1. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin. DR InterPro; IPR001314; Peptidase_S1A. DR InterPro; IPR001254; Trypsin_dom. DR InterPro; IPR018114; TRYPSIN_HIS. DR InterPro; IPR033116; TRYPSIN_SER. DR PANTHER; PTHR24271:SF19; KALLIKREIN-6; 1. DR PANTHER; PTHR24271; KALLIKREIN-RELATED; 1. DR Pfam; PF00089; Trypsin; 1. DR PRINTS; PR00722; CHYMOTRYPSIN. DR SMART; SM00020; Tryp_SPc; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS50240; TRYPSIN_DOM; 1. DR PROSITE; PS00134; TRYPSIN_HIS; 1. DR PROSITE; PS00135; TRYPSIN_SER; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autocatalytic cleavage; KW Cleavage on pair of basic residues; Cytoplasm; Direct protein sequencing; KW Disulfide bond; Endoplasmic reticulum; Glycoprotein; Hydrolase; Microsome; KW Mitochondrion; Nucleus; Protease; Proteomics identification; KW Reference proteome; Secreted; Serine protease; Signal; Zymogen. FT SIGNAL 1..16 FT /evidence="ECO:0000255" FT PROPEP 17..21 FT /note="Activation peptide" FT /evidence="ECO:0000255" FT /id="PRO_0000027940" FT CHAIN 22..244 FT /note="Kallikrein-6" FT /id="PRO_0000027941" FT DOMAIN 22..242 FT /note="Peptidase S1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT ACT_SITE 62 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:12016211" FT ACT_SITE 106 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:12016211" FT ACT_SITE 197 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:12016211" FT SITE 80..81 FT /note="Cleavage; by autolysis" FT CARBOHYD 134 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 28..157 FT DISULFID 47..63 FT DISULFID 131..231 FT DISULFID 138..203 FT DISULFID 168..182 FT DISULFID 193..218 FT VAR_SEQ 1..107 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15207701" FT /id="VSP_034403" FT VAR_SEQ 14..40 FT /note="AWAEEQNKLVHGGPCDKTSHPYQAALY -> GIFRSSWGSITFGKGRVPRSR FT VLLSGL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15207701" FT /id="VSP_034404" FT VAR_SEQ 41..244 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15207701" FT /id="VSP_034405" FT VARIANT 78 FT /note="R -> W (in dbSNP:rs61469141)" FT /id="VAR_061776" FT HELIX 27..29 FT /evidence="ECO:0007829|PDB:1GVL" FT STRAND 36..41 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 44..53 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 56..59 FT /evidence="ECO:0007829|PDB:7QFT" FT HELIX 61..63 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 69..73 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:1GVL" FT STRAND 85..94 FT /evidence="ECO:0007829|PDB:7QFT" FT TURN 100..103 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 108..114 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:7QI0" FT STRAND 137..144 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 146..149 FT /evidence="ECO:0007829|PDB:1GVL" FT STRAND 156..163 FT /evidence="ECO:0007829|PDB:7QFT" FT HELIX 165..171 FT /evidence="ECO:0007829|PDB:7QFT" FT TURN 173..175 FT /evidence="ECO:0007829|PDB:1LO6" FT STRAND 180..184 FT /evidence="ECO:0007829|PDB:7QFT" FT TURN 186..188 FT /evidence="ECO:0007829|PDB:7QFT" FT TURN 194..198 FT /evidence="ECO:0007829|PDB:1LO6" FT STRAND 200..203 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 206..213 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 216..218 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 221..223 FT /evidence="ECO:0007829|PDB:7QFT" FT STRAND 225..229 FT /evidence="ECO:0007829|PDB:7QFT" FT HELIX 230..233 FT /evidence="ECO:0007829|PDB:7QFT" FT HELIX 234..242 FT /evidence="ECO:0007829|PDB:7QFT" SQ SEQUENCE 244 AA; 26856 MW; AEA03F9145D87AAB CRC64; MKKLMVVLSL IAAAWAEEQN KLVHGGPCDK TSHPYQAALY TSGHLLCGGV LIHPLWVLTA AHCKKPNLQV FLGKHNLRQR ESSQEQSSVV RAVIHPDYDA ASHDQDIMLL RLARPAKLSE LIQPLPLERD CSANTTSCHI LGWGKTADGD FPDTIQCAYI HLVSREECEH AYPGQITQNM LCAGDEKYGK DSCQGDSGGP LVCGDHLRGL VSWGNIPCGS KEKPGVYTNV CRYTNWIQKT IQAK // ID LRRK2_HUMAN Reviewed; 2527 AA. AC Q5S007; A6NJU2; Q6ZS50; Q8NCX9; DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 20-APR-2010, sequence version 2. DT 28-JAN-2026, entry version 200. DE RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; DE EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}; DE EC=3.6.5.- {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815}; DE AltName: Full=Dardarin; GN Name=LRRK2; Synonyms=PARK8; 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], TISSUE SPECIFICITY, AND VARIANTS PARK8 RP VAL-1122; CYS-1441; CYS-1699 AND THR-2020. RC TISSUE=Brain; RX PubMed=15541309; DOI=10.1016/j.neuron.2004.11.005; RA Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., Lincoln S.J., RA Kachergus J.M., Hulihan M.M., Uitti R.J., Calne D.B., Stoessl A.J., RA Pfeiffer R.F., Patenge N., Carballo Carbajal I., Vieregge P., Asmus F., RA Mueller-Myhsok B., Dickson D.W., Meitinger T., Strom T.M., Wszolek Z.K., RA Gasser T.; RT "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic RT pathology."; RL Neuron 44:601-607(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2128-2527. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP DISEASE. RX PubMed=16081470; DOI=10.1093/brain/awh607; RA Adams J.R., van Netten H., Schulzer M., Mak E., McKenzie J., Strongosky A., RA Sossi V., Ruth T.J., Lee C.S., Farrer M., Gasser T., Uitti R.J., RA Calne D.B., Wszolek Z.K., Stoessl A.J.; RT "PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and RT evidence for presymptomatic compensation."; RL Brain 128:2777-2785(2005). RN [5] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT PARK8 THR-2020. RX PubMed=16321986; DOI=10.1093/hmg/ddi439; RA Gloeckner C.J., Kinkl N., Schumacher A., Braun R.J., O'Neill E., RA Meitinger T., Kolch W., Prokisch H., Ueffing M.; RT "The Parkinson disease causing LRRK2 mutation I2020T is associated with RT increased kinase activity."; RL Hum. Mol. Genet. 15:223-232(2006). RN [6] RP DISEASE. RX PubMed=16087219; DOI=10.1016/j.mad.2005.06.010; RA Toft M., Sando S.B., Melquist S., Ross O.A., White L.R., Aasly J.O., RA Farrer M.J.; RT "LRRK2 mutations are not common in Alzheimer's disease."; RL Mech. Ageing Dev. 126:1201-1205(2005). RN [7] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK8 CYS-1441 AND RP SER-2019. RX PubMed=16269541; DOI=10.1073/pnas.0507360102; RA West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 RT augment kinase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005). RN [8] RP SUBCELLULAR LOCATION, AND INTERACTION WITH PRKN. 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 [9] RP TISSUE SPECIFICITY. RX PubMed=16532471; DOI=10.1002/ana.20808; RA Galter D., Westerlund M., Carmine A., Lindqvist E., Sydow O., Olson L.; RT "LRRK2 expression linked to dopamine-innervated areas."; RL Ann. Neurol. 59:714-719(2006). RN [10] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17120249; DOI=10.1002/ana.21019; RA Biskup S., Moore D.J., Celsi F., Higashi S., West A.B., Andrabi S.A., RA Kurkinen K., Yu S.W., Savitt J.M., Waldvogel H.J., Faull R.L., Emson P.C., RA Torp R., Ottersen O.P., Dawson T.M., Dawson V.L.; RT "Localization of LRRK2 to membranous and vesicular structures in mammalian RT brain."; RL Ann. Neurol. 60:557-569(2006). RN [11] RP FUNCTION, CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699; SER-2019 RP AND THR-2020, AND VARIANT MET-1906. RX PubMed=17114044; DOI=10.1016/j.neuron.2006.10.008; RA MacLeod D., Dowman J., Hammond R., Leete T., Inoue K., Abeliovich A.; RT "The familial Parkinsonism gene LRRK2 regulates neurite process RT morphology."; RL Neuron 52:587-593(2006). RN [12] RP FUNCTION. RX PubMed=20949042; DOI=10.1371/journal.pone.0013191; RA Zach S., Felk S., Gillardon F.; RT "Signal transduction protein array analysis links LRRK2 to Ste20 kinases RT and PKC zeta that modulate neuronal plasticity."; RL PLoS ONE 5:E13191-E13191(2010). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRDX3, AND RP CHARACTERIZATION OF VARIANT PARK8 SER-2019. RX PubMed=21850687; DOI=10.1002/humu.21582; RA Angeles D.C., Gan B.H., Onstead L., Zhao Y., Lim K.L., Dachsel J., RA Melrose H., Farrer M., Wszolek Z.K., Dickson D.W., Tan E.K.; RT "Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 RT exacerbating oxidative stress-induced neuronal death."; RL Hum. Mutat. 32:1390-1397(2011). RN [14] RP FUNCTION, AND INTERACTION WITH TPCN2. RX PubMed=22012985; DOI=10.1093/hmg/ddr481; RA Gomez-Suaga P., Luzon-Toro B., Churamani D., Zhang L., Bloor-Young D., RA Patel S., Woodman P.G., Churchill G.C., Hilfiker S.; RT "Leucine-rich repeat kinase 2 regulates autophagy through a calcium- RT dependent pathway involving NAADP."; RL Hum. Mol. Genet. 21:511-525(2012). RN [15] RP SUBUNIT, AND AUTOPHOSPHORYLATION. RX PubMed=22952686; DOI=10.1371/journal.pone.0043472; RA Civiero L., Vancraenenbroeck R., Belluzzi E., Beilina A., Lobbestael E., RA Reyniers L., Gao F., Micetic I., De Maeyer M., Bubacco L., Baekelandt V., RA Cookson M.R., Greggio E., Taymans J.M.; RT "Biochemical characterization of highly purified leucine-rich repeat RT kinases 1 and 2 demonstrates formation of homodimers."; RL PLoS ONE 7:E43472-E43472(2012). RN [16] RP FUNCTION IN RETROGRADE TRANSPORT, INTERACTION WITH RAB29 AND VPS35, RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT PARK8 SER-2019, AND RP CHARACTERIZATION OF VARIANT MET-1906. RX PubMed=23395371; DOI=10.1016/j.neuron.2012.11.033; RA MacLeod D.A., Rhinn H., Kuwahara T., Zolin A., Di Paolo G., McCabe B.D., RA MacCabe B.D., Marder K.S., Honig L.S., Clark L.N., Small S.A., RA Abeliovich A.; RT "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and RT Parkinson's disease risk."; RL Neuron 77:425-439(2013). RN [17] RP WD REPEATS. RX PubMed=23776530; DOI=10.1371/journal.pone.0065705; RA Wang Y., Jiang F., Zhuo Z., Wu X.H., Wu Y.D.; RT "A method for WD40 repeat detection and secondary structure prediction."; RL PLoS ONE 8:E65705-E65705(2013). RN [18] 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 [19] RP FUNCTION, SUBCELLULAR LOCATION, ELECTRON MICROSCOPY, WD REPEATS, AND RP CHARACTERIZATION OF VARIANT ARG-2385. RX PubMed=24687852; DOI=10.1128/mcb.00914-13; RA Piccoli G., Onofri F., Cirnaru M.D., Kaiser C.J., Jagtap P., RA Kastenmuller A., Pischedda F., Marte A., von Zweydorf F., Vogt A., RA Giesert F., Pan L., Antonucci F., Kiel C., Zhang M., Weinkauf S., RA Sattler M., Sala C., Matteoli M., Ueffing M., Gloeckner C.J.; RT "Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein RT interactions mediated by its C-terminal WD40 domain."; RL Mol. Cell. Biol. 34:2147-2161(2014). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION, INTERACTION RP WITH RAB8A; RAB10 AND RAB12, CHARACTERIZATION OF VARIANTS PARK8 HIS-1441; RP CYS-1441; GLY-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND RP ARG-2385, AND MUTAGENESIS OF ASP-1994. RX PubMed=26824392; DOI=10.7554/elife.12813; RA Steger M., Tonelli F., Ito G., Davies P., Trost M., Vetter M., Wachter S., RA Lorentzen E., Duddy G., Wilson S., Baptista M.A., Fiske B.K., Fell M.J., RA Morrow J.A., Reith A.D., Alessi D.R., Mann M.; RT "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates RT a subset of Rab GTPases."; RL Elife 5:0-0(2016). RN [21] RP FUNCTION, INTERACTION WITH MAPT, SUBCELLULAR LOCATION, CHARACTERIZATION OF RP VARIANT PAR8 SER-2019, AND MUTAGENESIS OF LYS-1906; ASP-1994 AND ASP-2017. RX PubMed=26014385; DOI=10.1007/s12035-015-9209-z; RA Guerreiro P.S., Gerhardt E., Lopes da Fonseca T., Baehr M., Outeiro T.F., RA Eckermann K.; RT "LRRK2 Promotes Tau Accumulation, Aggregation and Release."; RL Mol. Neurobiol. 53:3124-3135(2016). RN [22] RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT MET-1906. RX PubMed=27830463; DOI=10.1007/s13238-016-0326-x; RA Yan R., Liu Z.; RT "LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by RT promoting Rip2 phosphorylation."; RL Protein Cell 8:55-66(2017). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, CHARACTERIZATION OF VARIANTS PARK8 RP GLY-1441; CYS-1699 AND SER-2019, AND MUTAGENESIS OF ASP-2017. RX PubMed=29125462; DOI=10.7554/elife.31012; RA Steger M., Diez F., Dhekne H.S., Lis P., Nirujogi R.S., Karayel O., RA Tonelli F., Martinez T.N., Lorentzen E., Pfeffer S.R., Alessi D.R., RA Mann M.; RT "Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation RT establishes a connection to ciliogenesis."; RL Elife 6:0-0(2017). RN [24] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, INTERACTION WITH APP, RP PHOSPHORYLATION AT SER-910 AND SER-935, CHARACTERIZATION OF VARIANTS PARK8 RP GLY-1441 AND SER-2019, AND MUTAGENESIS OF ASP-1994. RX PubMed=28720718; DOI=10.1126/scisignal.aam6790; RA Chen Z.C., Zhang W., Chua L.L., Chai C., Li R., Lin L., Cao Z., RA Angeles D.C., Stanton L.W., Peng J.H., Zhou Z.D., Lim K.L., Zeng L., RA Tan E.K.; RT "Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD RT activity and neurotoxicity in Parkinson's disease."; RL Sci. Signal. 10:0-0(2017). RN [25] {ECO:0000305} RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS PARK8 RP CYS-1441; GLY-1441; CYS-1699; SER-2019 AND THR-2020, AND CHARACTERIZATION RP OF VARIANT MET-1906. RX PubMed=30209220; DOI=10.1073/pnas.1812196115; RA Eguchi T., Kuwahara T., Sakurai M., Komori T., Fujimoto T., Ito G., RA Yoshimura S.I., Harada A., Fukuda M., Koike M., Iwatsubo T.; RT "LRRK2 and its substrate Rab GTPases are sequentially targeted onto RT stressed lysosomes and maintain their homeostasis."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E9115-E9124(2018). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, TISSUE SPECIFICITY, RP CHARACTERIZATION OF VARIANT PARK8 SER-2019, AND PHOSPHORYLATION AT SER-935. RX PubMed=29127255; DOI=10.1042/bcj20170803; RA Fan Y., Howden A.J.M., Sarhan A.R., Lis P., Ito G., Martinez T.N., RA Brockmann K., Gasser T., Alessi D.R., Sammler E.M.; RT "Interrogating Parkinson's disease LRRK2 kinase pathway activity by RT assessing Rab10 phosphorylation in human neutrophils."; RL Biochem. J. 475:23-44(2018). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, AND VARIANTS PARK8 GLY-1441 AND SER-2019. RX PubMed=30398148; DOI=10.7554/elife.40202; RA Dhekne H.S., Yanatori I., Gomez R.C., Tonelli F., Diez F., Schuele B., RA Steger M., Alessi D.R., Pfeffer S.R.; RT "A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and RT Sonic hedgehog signaling in the brain."; RL Elife 7:0-0(2018). RN [28] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP PHOSPHORYLATION AT SER-910; SER-935; SER-955; SER-973 AND SER-1292, RP CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; CYS-1699; RP HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385, AND MUTAGENESIS OF RP CYS-727; LEU-728; LEU-729; LEU-760; LEU-761; LEU-762; LEU-789; LEU-790; RP LEU-791; THR-1348; ARG-1441; TYR-1699; ASP-2017 AND GLY-2019. RX PubMed=29212815; DOI=10.15252/embj.201798099; RA Purlyte E., Dhekne H.S., Sarhan A.R., Gomez R., Lis P., Wightman M., RA Martinez T.N., Tonelli F., Pfeffer S.R., Alessi D.R.; RT "Rab29 activation of the Parkinson's disease-associated LRRK2 kinase."; RL EMBO J. 37:1-18(2018). RN [29] RP ERRATUM OF PUBMED:29212815. RX PubMed=30647193; DOI=10.15252/embj.2018101237; RA Purlyte E., Dhekne H.S., Sarhan A.R., Gomez R., Lis P., Wightman M., RA Martinez T.N., Tonelli F., Pfeffer S.R., Alessi D.R.; RL EMBO J. 38:0-0(2019). RN [30] RP SUBCELLULAR LOCATION, AND UBIQUITINATION BY TRIM1. RX PubMed=35266954; DOI=10.1083/jcb.202010065; RA Stormo A.E.D., Shavarebi F., FitzGibbon M., Earley E.M., Ahrendt H., RA Lum L.S., Verschueren E., Swaney D.L., Skibinski G., Ravisankar A., RA van Haren J., Davis E.J., Johnson J.R., Von Dollen J., Balen C., Porath J., RA Crosio C., Mirescu C., Iaccarino C., Dauer W.T., Nichols R.J., Wittmann T., RA Cox T.C., Finkbeiner S., Krogan N.J., Oakes S.A., Hiniker A.; RT "The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, RT degradation, and toxicity."; RL J. Cell Biol. 221:0-0(2022). RN [31] {ECO:0000305} RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=38227290; DOI=10.1083/jcb.202302067; RA Eguchi T., Sakurai M., Wang Y., Saito C., Yoshii G., Wileman T., RA Mizushima N., Kuwahara T., Iwatsubo T.; RT "The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal RT stress response."; RL J. Cell Biol. 223:0-0(2024). RN [32] {ECO:0007744|PDB:2ZEJ, ECO:0007744|PDB:3D6T} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1333-1516 IN COMPLEX WITH GDP, RP FUNCTION, GTPASE ACTIVITY, ACTIVITY REGULATION, SUBUNIT, DOMAIN ROC, AND RP MUTAGENESIS OF THR-1343 AND ARG-1398. RX PubMed=18230735; DOI=10.1073/pnas.0709098105; RA Deng J., Lewis P.A., Greggio E., Sluch E., Beilina A., Cookson M.R.; RT "Structure of the ROC domain from the Parkinson's disease-associated RT leucine-rich repeat kinase 2 reveals a dimeric GTPase."; RL Proc. Natl. Acad. Sci. U.S.A. 105:1499-1504(2008). RN [33] {ECO:0007744|PDB:5MY9, ECO:0007744|PDB:5MYC} RP X-RAY CRYSTALLOGRAPHY (1.33 ANGSTROMS) OF 929-941 IN COMPLEX WITH SFN, RP INTERACTION WITH YWHAG, PHOSPHORYLATION AT SER-910; SER-935; SER-955; RP SER-973 AND SER-1444, AND CHARACTERIZATION OF VARIANT PARK8 CYS-1441. RX PubMed=28202711; DOI=10.1042/bcj20161078; RA Stevers L.M., de Vries R.M., Doveston R.G., Milroy L.G., Brunsveld L., RA Ottmann C.; RT "Structural interface between LRRK2 and 14-3-3 protein."; RL Biochem. J. 474:1273-1287(2017). RN [34] {ECO:0007744|PDB:6DLO, ECO:0007744|PDB:6DLP} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 2142-2527, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, DOMAIN, PHOSPHORYLATION AT SER-935 AND SER-1292, RP CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; SER-2019; ASP-2175; TYR-2189; RP ILE-2356; ARG-2385; MET-2390 AND ILE-2439, AND MUTAGENESIS OF ASP-2017; RP LEU-2343; PHE-2344; SER-2345; TYR-2346; HIS-2391; ARG-2394; GLU-2395; RP MET-2408 AND SER-2409. RX PubMed=30635421; DOI=10.1073/pnas.1817889116; RA Zhang P., Fan Y., Ru H., Wang L., Magupalli V.G., Taylor S.S., Alessi D.R., RA Wu H.; RT "Crystal structure of the WD40 domain dimer of LRRK2."; RL Proc. Natl. Acad. Sci. U.S.A. 116:1579-1584(2019). RN [35] {ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9, ECO:0007744|PDB:8SMC} RP STRUCTURE BY ELECTRON MICROSCOPY (3.48 ANGSTROMS) IN COMPLEX WITH RAB29; RP ATP AND GDP, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT, RP INTERACTION WITH RAB29 AND RAB32, SUBCELLULAR LOCATION, DOMAIN, RP AUTOPHOSPHORYLATION AT SER-1292, LRR REPEATS, WD REPEATS, AND MUTAGENESIS RP OF ARG-399; LEU-403; PRO-1588; ASN-1710; TRP-1791 AND ASP-2017. RX PubMed=38127736; DOI=10.1126/science.adi9926; RA Zhu H., Tonelli F., Turk M., Prescott A., Alessi D.R., Sun J.; RT "Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2."; RL Science 382:1404-1411(2023). RN [36] RP VARIANTS PARK8 GLY-1441 AND CYS-1699, AND TISSUE SPECIFICITY. RX PubMed=15541308; DOI=10.1016/j.neuron.2004.10.023; RA Paisan-Ruiz C., Jain S., Evans E.W., Gilks W.P., Simon J., van der Brug M., RA Lopez de Munain A., Aparicio S., Gil A.M., Khan N.L., Johnson J., RA Martinez J.R., Nicholl D., Carrera I.M., Pena A.S., de Silva R., Lees A.J., RA Marti-Masso J.F., Perez-Tur J., Wood N.W., Singleton A.B.; RT "Cloning of the gene containing mutations that cause PARK8-linked RT Parkinson's disease."; RL Neuron 44:595-600(2004). RN [37] RP VARIANT PARK8 SER-2019. RX PubMed=15726496; DOI=10.1086/429256; RA Kachergus J.M., Mata I.F., Hulihan M., Taylor J.P., Lincoln S., Aasly J.O., RA Gibson J.M., Ross O.A., Lynch T., Wiley J., Payami H., Nutt J., RA Maraganore D.M., Czyzewski K., Styczynska M., Wszolek Z.K., Farrer M.J., RA Toft M.; RT "Identification of a novel LRRK2 mutation linked to autosomal dominant RT parkinsonism: evidence of a common founder across European populations."; RL Am. J. Hum. Genet. 76:672-680(2005). RN [38] RP VARIANT PARK8 SER-2019. RX PubMed=15732108; DOI=10.1002/ana.20401; RA Hernandez D.G., Paisan-Ruiz C., McInerney-Leo A., Jain S., RA Meyer-Lindenberg A., Evans E.W., Berman K.F., Johnson J., Auburger G., RA Schaeffer A.A., Lopez G.J., Nussbaum R.L., Singleton A.B.; RT "Clinical and positron emission tomography of Parkinson's disease caused by RT LRRK2."; RL Ann. Neurol. 57:453-456(2005). RN [39] RP VARIANT PARK8/PD SER-2019. RX PubMed=15852371; DOI=10.1002/ana.20456; RA Aasly J.O., Toft M., Fernandez-Mata I., Kachergus J.M., Hulihan M., RA White L.R., Farrer M.J.; RT "Clinical features of LRRK2-associated Parkinson's disease in central RT Norway."; RL Ann. Neurol. 57:762-765(2005). RN [40] RP VARIANT PARK8 SER-2019. RX PubMed=16240353; DOI=10.1002/ana.20636; RG French Parkinson's disease genetics study group; RA Lesage S., Ibanez P., Lohmann E., Pollak P., Tison F., Tazir M., RA Leutenegger A.-L., Guimaraes J., Bonnet A.-M., Agid Y., Duerr A., Brice A.; RT "G2019S LRRK2 mutation in French and North African families with RT Parkinson's disease."; RL Ann. Neurol. 58:784-787(2005). RN [41] RP VARIANT PARK8 THR-2020. RX PubMed=15880653; DOI=10.1002/ana.20484; RA Funayama M., Hasegawa K., Ohta E., Kawashima N., Komiyama M., Kowa H., RA Tsuji S., Obata F.; RT "An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 RT family."; RL Ann. Neurol. 57:918-921(2005). RN [42] RP VARIANT PARK8 SER-2019. RX PubMed=15929036; DOI=10.1002/ana.20510; RA Deng H., Le W., Guo Y., Hunter C.B., Xie W., Jankovic J.; RT "Genetic and clinical identification of Parkinson's disease patients with RT LRRK2 G2019S mutation."; RL Ann. Neurol. 57:933-934(2005). RN [43] RP VARIANTS PARK8 MET-793; ARG-930; CYS-1096; THR-1228; SER-2019 AND THR-2020, RP AND VARIANT LYS-551. RX PubMed=16251215; DOI=10.1093/brain/awh666; RA Berg D., Schweitzer K., Leitner P., Zimprich A., Lichtner P., Belcredi P., RA Bruessel T., Schulte C., Maass S., Naegele T.; RT "Type and frequency of mutations in the LRRK2 gene in familial and sporadic RT Parkinson's disease."; RL Brain 128:3000-3011(2005). RN [44] RP VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356. RX PubMed=16272164; DOI=10.1093/brain/awh667; RA Khan N.L., Jain S., Lynch J.M., Pavese N., Abou-Sleiman P.M., Holton J.L., RA Healy D.G., Gilks W.P., Sweeney M.G., Ganguly M., Gibbons V., Gandhi S., RA Vaughan J., Eunson L.H., Katzenschlager R., Gayton J., Lennox G., RA Revesz T., Nicholl D., Bhatia K.P., Quinn N., Brooks D., Lees A.J., RA Davis M.B., Piccini P., Singleton A.B., Wood N.W.; RT "Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial RT Parkinson's disease: clinical, pathological, olfactory and functional RT imaging and genetic data."; RL Brain 128:2786-2796(2005). RN [45] RP VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019. RX PubMed=16333314; DOI=10.1038/sj.ejhg.5201539; RA Di Fonzo A., Tassorelli C., De Mari M., Chien H.F., Ferreira J., Rohe C.F., RA Riboldazzi G., Antonini A., Albani G., Mauro A., Marconi R., Abbruzzese G., RA Lopiano L., Fincati E., Guidi M., Marini P., Stocchi F., Onofrj M., RA Toni V., Tinazzi M., Fabbrini G., Lamberti P., Vanacore N., Meco G., RA Leitner P., Uitti R.J., Wszolek Z.K., Gasser T., Simons E.J., RA Breedveld G.J., Goldwurm S., Pezzoli G., Sampaio C., Barbosa E., RA Martignoni E., Oostra B.A., Bonifati V.; RT "Comprehensive analysis of the LRRK2 gene in sixty families with RT Parkinson's disease."; RL Eur. J. Hum. Genet. 14:322-331(2006). RN [46] RP VARIANT PARK8 SER-2019. RX PubMed=16272257; DOI=10.1136/jmg.2005.035568; RA Goldwurm S., Di Fonzo A., Simons E.J., Rohe C.F., Zini M., Canesi M., RA Tesei S., Zecchinelli A., Antonini A., Mariani C., Meucci N., Sacilotto G., RA Sironi F., Salani G., Ferreira J., Chien H.F., Fabrizio E., Vanacore N., RA Dalla Libera A., Stocchi F., Diroma C., Lamberti P., Sampaio C., Meco G., RA Barbosa E., Bertoli-Avella A.M., Breedveld G.J., Oostra B.A., Pezzoli G., RA Bonifati V.; RT "The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late RT onset Parkinson's disease and originates from a common ancestor."; RL J. Med. Genet. 42:E65-E65(2005). RN [47] RP VARIANT PARK8 SER-2019. RX PubMed=15680455; DOI=10.1016/s0140-6736(05)17828-3; RG The Parkinson study group-PROGENI investigators; RA Nichols W.C., Pankratz N., Hernandez D., Paisan-Ruiz C., Jain S., RA Halter C.A., Michaels V.E., Reed T., Rudolph A., Shults C.W., Singleton A., RA Foroud T.; RT "Genetic screening for a single common LRRK2 mutation in familial RT Parkinson's disease."; RL Lancet 365:410-412(2005). RN [48] RP VARIANT PARK8 SER-2019. RX PubMed=15680456; DOI=10.1016/s0140-6736(05)17829-5; RG The Italian Parkinson genetics network; RA Di Fonzo A., Rohe C.F., Ferreira J., Chien H.F., Vacca L., Stocchi F., RA Guedes L., Fabrizio E., Manfredi M., Vanacore N., Goldwurm S., RA Breedveld G.J., Sampaio C., Meco G., Barbosa E., Oostra B.A., Bonifati V.; RT "A frequent LRRK2 gene mutation associated with autosomal dominant RT Parkinson's disease."; RL Lancet 365:412-415(2005). RN [49] RP VARIANT PARK8 SER-2019. RX PubMed=15680457; DOI=10.1016/s0140-6736(05)17830-1; RA Gilks W.P., Abou-Sleiman P.M., Gandhi S., Jain S., Singleton A., Lees A.J., RA Shaw K., Bhatia K.P., Bonifati V., Quinn N.P., Lynch J.M., Healy D.G., RA Holton J.L., Revesz T., Wood N.W.; RT "A common LRRK2 mutation in idiopathic Parkinson's disease."; RL Lancet 365:415-416(2005). RN [50] RP VARIANT PARK8 SER-2019. RX PubMed=15811454; DOI=10.1016/s0140-6736(05)74809-1; RA Toft M., Mata I.F., Kachergus J.M., Ross O.A., Farrer M.J.; RT "LRRK2 mutations and Parkinsonism."; RL Lancet 365:1229-1230(2005). RN [51] RP VARIANT SER-2019. RX PubMed=16001413; DOI=10.1002/mds.20618; RA Kay D.M., Kramer P., Higgins D.S., Zabetian C.P., Payami H.; RT "Escaping Parkinson's disease: a neurologically healthy octogenarian with RT the LRRK2 G2019S mutation."; RL Mov. Disord. 20:1077-1078(2005). RN [52] RP VARIANT PARK8 SER-2019. RX PubMed=16250030; DOI=10.1002/mds.20751; RA Kay D.M., Zabetian C.P., Factor S.A., Nutt J.G., Samii A., Griffith A., RA Bird T.D., Kramer P., Higgins D.S., Payami H.; RT "Parkinson's disease and LRRK2: frequency of a common mutation in U.S. RT movement disorder clinics."; RL Mov. Disord. 21:519-523(2006). RN [53] RP VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; GLU-1598; RP PRO-1628; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND ARG-2385, RP AND VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; ALA-1262; RP HIS-1398; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397. RX PubMed=16172858; DOI=10.1007/s10048-005-0005-1; RA Mata I.F., Kachergus J.M., Taylor J.P., Lincoln S., Aasly J., Lynch T., RA Hulihan M.M., Cobb S.A., Wu R.-M., Lu C.-S., Lahoz C., Wszolek Z.K., RA Farrer M.J.; RT "Lrrk2 pathogenic substitutions in Parkinson's disease."; RL Neurogenetics 6:171-177(2005). RN [54] RP VARIANTS PARK8 VAL-1371 AND SER-2019, AND VARIANTS HIS-1398 AND THR-2397. RX PubMed=16157901; DOI=10.1212/01.wnl.0000167552.79769.b3; RA Paisan-Ruiz C., Lang A.E., Kawarai T., Sato C., Salehi-Rad S., Fisman G.K., RA Al-Khairallah T., St George-Hyslop P.H., Singleton A., Rogaeva E.; RT "LRRK2 gene in Parkinson disease: mutation analysis and case control RT association study."; RL Neurology 65:696-700(2005). RN [55] RP VARIANT PARK8 GLN-1067. RX PubMed=16247070; DOI=10.1212/01.wnl.0000180517.70572.37; RA Skipper L., Shen H., Chua E., Bonnard C., Kolatkar P., Tan L.C.S., RA Jamora R.D., Puvan K., Puong K.Y., Zhao Y., Pavanni R., Wong M.C., Yuen Y., RA Farrer M., Liu J.J., Tan E.K.; RT "Analysis of LRRK2 functional domains in nondominant Parkinson disease."; RL Neurology 65:1319-1321(2005). RN [56] RP VARIANTS PARK8 MET-793; THR-1869 AND SER-2019. RX PubMed=16157908; DOI=10.1212/01.wnl.0000169023.51764.b0; RA Farrer M., Stone J., Mata I.F., Lincoln S., Kachergus J., Hulihan M., RA Strain K.J., Maraganore D.M.; RT "LRRK2 mutations in Parkinson disease."; RL Neurology 65:738-740(2005). RN [57] RP VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019. RX PubMed=16157909; DOI=10.1212/01.wnl.0000172630.22804.73; RA Zabetian C.P., Samii A., Mosley A.D., Roberts J.W., Leis B.C., Yearout D., RA Raskind W.H., Griffith A.; RT "A clinic-based study of the LRRK2 gene in Parkinson disease yields new RT mutations."; RL Neurology 65:741-744(2005). RN [58] RP VARIANT PARK8 GLY-1441. RX PubMed=15925109; DOI=10.1016/j.neulet.2005.03.033; RA Mata I.F., Taylor J.P., Kachergus J., Hulihan M., Huerta C., Lahoz C., RA Blazquez M., Guisasola L.M., Salvador C., Ribacoba R., Martinez C., RA Farrer M., Alvarez V.; RT "LRRK2 R1441G in Spanish patients with Parkinson's disease."; RL Neurosci. Lett. 382:309-311(2005). RN [59] RP VARIANT PARK8 SER-2019. RX PubMed=16298482; DOI=10.1016/j.neulet.2005.10.083; RA Infante J., Rodriguez E., Combarros O., Mateo I., Fontalba A., Pascual J., RA Oterino A., Polo J.M., Leno C., Berciano J.; RT "LRRK2 G2019S is a common mutation in Spanish patients with late-onset RT Parkinson's disease."; RL Neurosci. Lett. 395:224-226(2006). RN [60] RP VARIANT PARK8 SER-2019. RX PubMed=16102999; DOI=10.1016/j.parkreldis.2005.05.004; RA Gosal D., Ross O.A., Wiley J., Irvine G.B., Johnston J.A., Toft M., RA Mata I.F., Kachergus J., Hulihan M., Taylor J.P., Lincoln S.J., RA Farrer M.J., Lynch T., Mark Gibson J.; RT "Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link RT between familial and idiopathic PD."; RL Parkinsonism Relat. Disord. 11:349-352(2005). RN [61] RP VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019. RX PubMed=16533964; DOI=10.1001/archneur.63.3.377; RA Gaig C., Ezquerra M., Marti M.J., Munoz E., Valldeoriola F., Tolosa E.; RT "LRRK2 mutations in Spanish patients with Parkinson disease: frequency, RT clinical features, and incomplete penetrance."; RL Arch. Neurol. 63:377-382(2006). RN [62] RP CHARACTERIZATION OF VARIANT ARG-2385, AND ASSOCIATION WITH PARKINSON RP DISEASE. RX PubMed=17019612; DOI=10.1007/s00439-006-0268-0; RA Tan E.K., Zhao Y., Skipper L., Tan M.G., Di Fonzo A., Sun L., RA Fook-Chong S., Tang S., Chua E., Yuen Y., Tan L., Pavanni R., Wong M.C., RA Kolatkar P., Lu C.S., Bonifati V., Liu J.J.; RT "The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: RT genetic and functional evidence."; RL Hum. Genet. 120:857-863(2007). RN [63] RP VARIANTS [LARGE SCALE ANALYSIS] PRO-119; VAL-419; LYS-551; VAL-723; RP HIS-1398; GLN-1514; SER-1542; GLN-1550 AND PRO-1723. 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 [64] RP VARIANTS PARK8 VAL-712; LEU-1728; HIS-1728; SER-2019; MET-2141; HIS-2143 RP AND HIS-2466, AND VARIANTS SER-228; VAL-716; GLU-871; PHE-1870 AND RP LYS-2395. RX PubMed=18213618; DOI=10.1002/humu.20668; RA Paisan-Ruiz C., Nath P., Washecka N., Gibbs J.R., Singleton A.B.; RT "Comprehensive analysis of LRRK2 in publicly available Parkinson's disease RT cases and neurologically normal controls."; RL Hum. Mutat. 29:485-490(2008). RN [65] RP VARIANT ILE-1359. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [66] RP VARIANTS PARK8 PRO-1628 AND ARG-2385. RX PubMed=21641266; DOI=10.1016/j.parkreldis.2010.11.008; RA Bardien S., Lesage S., Brice A., Carr J.; RT "Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated RT Parkinson's disease."; RL Parkinsonism Relat. Disord. 17:501-508(2011). RN [67] RP VARIANTS LYS-551; VAL-723; HIS-1398; GLN-1514; SER-1542; PRO-1628; RP THR-1646; THR-1647; ASP-2081 AND THR-2397. RX PubMed=22415848; DOI=10.1002/humu.22075; RA Rubio J.P., Topp S., Warren L., St Jean P.L., Wegmann D., Kessner D., RA Novembre J., Shen J., Fraser D., Aponte J., Nangle K., Cardon L.R., RA Ehm M.G., Chissoe S.L., Whittaker J.C., Nelson M.R., Mooser V.E.; RT "Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence RT of purifying selection and independent origin of the p.Arg1628Pro mutation RT in Europe."; RL Hum. Mutat. 33:1087-1098(2012). RN [68] RP VARIANT PARK8 SER-2019. 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 [69] RP CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; CYS-1699 AND SER-2019, RP CHARACTERIZATION OF VARIANT ARG-2385, FUNCTION, SUBCELLULAR LOCATION, RP INTERACTION WITH SEC16A, AND MUTAGENESIS OF LYS-1347 AND ASP-1994. RX PubMed=25201882; DOI=10.15252/embj.201487807; RA Cho H.J., Yu J., Xie C., Rudrabhatla P., Chen X., Wu J., Parisiadou L., RA Liu G., Sun L., Ma B., Ding J., Liu Z., Cai H.; RT "Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow RT ER-Golgi export."; RL EMBO J. 33:2314-2331(2014). CC -!- FUNCTION: Serine/threonine-protein kinase which phosphorylates a broad CC range of proteins involved in multiple processes such as neuronal CC plasticity, innate immunity, autophagy, and vesicle trafficking CC (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, CC PubMed:23395371, PubMed:24687852, PubMed:25201882, PubMed:26014385, CC PubMed:26824392, PubMed:27830463, PubMed:28720718, PubMed:29125462, CC PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421). Is CC a key regulator of RAB GTPases by regulating the GTP/GDP exchange and CC interaction partners of RABs through phosphorylation (PubMed:26824392, CC PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, CC PubMed:30398148, PubMed:30635421). Phosphorylates RAB3A, RAB3B, RAB3C, CC RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB29, RAB35, CC and RAB43 (PubMed:23395371, PubMed:26824392, PubMed:28720718, CC PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, CC PubMed:30635421, PubMed:38127736). Regulates the RAB3IP-catalyzed CC GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on CC RAB8A (PubMed:26824392). Inhibits the interaction between RAB8A and CC GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A CC (PubMed:26824392). Regulates primary ciliogenesis through CC phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the CC brain (PubMed:29125462, PubMed:30398148). Together with RAB29, plays a CC role in the retrograde trafficking pathway for recycling proteins, such CC as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi CC apparatus in a retromer-dependent manner (PubMed:23395371). Regulates CC neuronal process morphology in the intact central nervous system (CNS) CC (PubMed:17114044). Plays a role in synaptic vesicle trafficking CC (PubMed:24687852). Plays an important role in recruiting SEC16A to CC endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi CC vesicle-mediated transport and ERES organization (PubMed:25201882). CC Positively regulates autophagy through a calcium-dependent activation CC of the CaMKK/AMPK signaling pathway (PubMed:22012985). The process CC involves activation of nicotinic acid adenine dinucleotide phosphate CC (NAADP) receptors, increase in lysosomal pH, and calcium release from CC lysosomes (PubMed:22012985). Phosphorylates PRDX3 (PubMed:21850687). By CC phosphorylating APP on 'Thr-743', which promotes the production and the CC nuclear translocation of the APP intracellular domain (AICD), regulates CC dopaminergic neuron apoptosis (PubMed:28720718). Acts as a positive CC regulator of innate immunity by mediating phosphorylation of RIPK2 CC downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation CC (PubMed:27830463). Independent of its kinase activity, inhibits the CC proteasomal degradation of MAPT, thus promoting MAPT oligomerization CC and secretion (PubMed:26014385). In addition, has GTPase activity via CC its Roc domain which regulates LRRK2 kinase activity (PubMed:18230735, CC PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815). CC Recruited by RAB29/RAB7L1 to overloaded lysosomes where it CC phosphorylates and stabilizes RAB8A and RAB10 which promote lysosomal CC content release and suppress lysosomal enlargement through the EHBP1 CC and EHBP1L1 effector proteins (PubMed:30209220, PubMed:38227290). CC {ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18230735, CC ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, CC ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:25201882, CC ECO:0000269|PubMed:26014385, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:27830463, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, CC ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421, CC ECO:0000269|PubMed:38127736, ECO:0000269|PubMed:38227290}. 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:26824392, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, CC ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736}; 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:26824392, ECO:0000269|PubMed:27830463, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:38127736}; CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; CC Evidence={ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:38127736}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462}; CC -!- ACTIVITY REGULATION: Kinase activity is regulated by the GTPase CC activity of the ROC domain (PubMed:18230735, PubMed:29212815). GTP- CC bound LRRK2 kinase activity is stimulated by RAB29 (PubMed:29212815, CC PubMed:38127736). Phosphorylation of RAB10 'Thr-73' is stimulated by CC RAB29 and RAB32 (PubMed:38127736). Inhibited by small molecule CC inhibitor MLi-2 (PubMed:26824392, PubMed:29127255). CC {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:38127736}. CC -!- SUBUNIT: Homodimer (PubMed:18230735, PubMed:22952686, PubMed:30635421, CC PubMed:38127736). Homotetramer; when activated by GTP-bound RAB29 CC (PubMed:38127736). Interacts with PRKN, PRDX3, and TPCN2 CC (PubMed:16352719, PubMed:21850687, PubMed:22012985). Interacts with CC VPS35 (PubMed:23395371). Interacts (via N-terminus) with RAB29; this CC interaction is direct and stimulates kinase activity (PubMed:23395371, CC PubMed:38127736). Interacts (via ROC domain) with SEC16A CC (PubMed:25201882). Interacts with APP; interaction promotes CC phosphorylation of 'Thr-743' of APP (PubMed:28720718). Interacts with CC MAPT (PubMed:26014385). Interacts with RAB8A, RAB10, and RAB12 CC (PubMed:26824392). Interacts (via N-terminus) with RAB32 CC (PubMed:38127736). Interacts with YWHAG; this interaction is dependent CC on phosphorylation of Ser-910 and either Ser-935 or Ser-1444 CC (PubMed:28202711). Interacts with SFN; this interaction is dependent on CC phosphorylation of Ser-910 and/or Ser-935 (PubMed:28202711). CC {ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:18230735, CC ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22012985, CC ECO:0000269|PubMed:22952686, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26014385, CC ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:30635421, CC ECO:0000269|PubMed:38127736}. CC -!- INTERACTION: CC Q5S007; Q9UKV8: AGO2; NbExp=3; IntAct=EBI-5323863, EBI-528269; CC Q5S007; O43865: AHCYL1; NbExp=3; IntAct=EBI-5323863, EBI-2371423; CC Q5S007; P31749: AKT1; NbExp=6; IntAct=EBI-5323863, EBI-296087; CC Q5S007; Q8N8V4: ANKS4B; NbExp=2; IntAct=EBI-5323863, EBI-9658517; CC Q5S007; O00203: AP3B1; NbExp=2; IntAct=EBI-5323863, EBI-1044383; CC Q5S007; Q8N6T3-2: ARFGAP1; NbExp=6; IntAct=EBI-5323863, EBI-6288865; CC Q5S007; Q14155: ARHGEF7; NbExp=7; IntAct=EBI-5323863, EBI-717515; CC Q5S007; O95816: BAG2; NbExp=3; IntAct=EBI-5323863, EBI-355275; CC Q5S007; O95817: BAG3; NbExp=2; IntAct=EBI-5323863, EBI-747185; CC Q5S007; Q9UL15: BAG5; NbExp=12; IntAct=EBI-5323863, EBI-356517; CC Q5S007; P10415-1: BCL2; NbExp=2; IntAct=EBI-5323863, EBI-4370304; CC Q5S007; Q13191: CBLB; NbExp=4; IntAct=EBI-5323863, EBI-744027; CC Q5S007; Q16543: CDC37; NbExp=10; IntAct=EBI-5323863, EBI-295634; CC Q5S007; P60953: CDC42; NbExp=3; IntAct=EBI-5323863, EBI-81752; CC Q5S007; Q9UKI2: CDC42EP3; NbExp=2; IntAct=EBI-5323863, EBI-723480; CC Q5S007; Q9Y6A4: CFAP20; NbExp=3; IntAct=EBI-5323863, EBI-1046872; CC Q5S007; P05060: CHGB; NbExp=3; IntAct=EBI-5323863, EBI-712619; CC Q5S007; Q9ULV4: CORO1C; NbExp=3; IntAct=EBI-5323863, EBI-351384; CC Q5S007; P48729-1: CSNK1A1; NbExp=2; IntAct=EBI-5323863, EBI-10106282; CC Q5S007; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-5323863, EBI-9087876; CC Q5S007; Q9NWM3: CUEDC1; NbExp=2; IntAct=EBI-5323863, EBI-5838167; CC Q5S007; P53355: DAPK1; NbExp=2; IntAct=EBI-5323863, EBI-358616; CC Q5S007; Q05193: DNM1; NbExp=4; IntAct=EBI-5323863, EBI-713135; CC Q5S007; O00429: DNM1L; NbExp=16; IntAct=EBI-5323863, EBI-724571; CC Q5S007; O00429-3: DNM1L; NbExp=2; IntAct=EBI-5323863, EBI-6896746; CC Q5S007; O14640-2: DVL1; NbExp=7; IntAct=EBI-5323863, EBI-6504027; CC Q5S007; O14641: DVL2; NbExp=5; IntAct=EBI-5323863, EBI-740850; CC Q5S007; Q92997: DVL3; NbExp=4; IntAct=EBI-5323863, EBI-739789; CC Q5S007; P30084: ECHS1; NbExp=4; IntAct=EBI-5323863, EBI-719602; CC Q5S007; Q05639: EEF1A2; NbExp=3; IntAct=EBI-5323863, EBI-354943; CC Q5S007; Q13158: FADD; NbExp=4; IntAct=EBI-5323863, EBI-494804; CC Q5S007; O14976: GAK; NbExp=11; IntAct=EBI-5323863, EBI-714707; CC Q5S007; P49841: GSK3B; NbExp=7; IntAct=EBI-5323863, EBI-373586; CC Q5S007; P11142: HSPA8; NbExp=6; IntAct=EBI-5323863, EBI-351896; CC Q5S007; Q71RC2: LARP4; NbExp=3; IntAct=EBI-5323863, EBI-2878091; CC Q5S007; Q4G0J3: LARP7; NbExp=3; IntAct=EBI-5323863, EBI-2371923; CC Q5S007; P07195: LDHB; NbExp=2; IntAct=EBI-5323863, EBI-358748; CC Q5S007; O75581: LRP6; NbExp=4; IntAct=EBI-5323863, EBI-910915; CC Q5S007; Q38SD2: LRRK1; NbExp=5; IntAct=EBI-5323863, EBI-1050422; CC Q5S007; Q5S007: LRRK2; NbExp=68; IntAct=EBI-5323863, EBI-5323863; CC Q5S007; PRO_0000018605 [P46821]: MAP1B; NbExp=5; IntAct=EBI-5323863, EBI-9517186; CC Q5S007; P46734: MAP2K3; NbExp=5; IntAct=EBI-5323863, EBI-602462; CC Q5S007; P52564: MAP2K6; NbExp=4; IntAct=EBI-5323863, EBI-448135; CC Q5S007; O14733: MAP2K7; NbExp=3; IntAct=EBI-5323863, EBI-492605; CC Q5S007; P10636-2: MAPT; NbExp=3; IntAct=EBI-5323863, EBI-7796412; CC Q5S007; P10636-8: MAPT; NbExp=9; IntAct=EBI-5323863, EBI-366233; CC Q5S007; P42679: MATK; NbExp=2; IntAct=EBI-5323863, EBI-751664; CC Q5S007; O95140: MFN2; NbExp=3; IntAct=EBI-5323863, EBI-3324756; CC Q5S007; P49406: MRPL19; NbExp=3; IntAct=EBI-5323863, EBI-1188518; CC Q5S007; P26038: MSN; NbExp=19; IntAct=EBI-5323863, EBI-528768; CC Q5S007; Q7L592: NDUFAF7; NbExp=2; IntAct=EBI-5323863, EBI-2555519; CC Q5S007; Q96PY6: NEK1; NbExp=2; IntAct=EBI-5323863, EBI-373615; CC Q5S007; Q13469: NFATC2; NbExp=3; IntAct=EBI-5323863, EBI-716258; CC Q5S007; Q8WUM0: NUP133; NbExp=4; IntAct=EBI-5323863, EBI-295695; CC Q5S007; O60313: OPA1; NbExp=5; IntAct=EBI-5323863, EBI-1054131; CC Q5S007; Q9NQU5: PAK6; NbExp=2; IntAct=EBI-5323863, EBI-1053685; CC Q5S007; P62136: PPP1CA; NbExp=6; IntAct=EBI-5323863, EBI-357253; CC Q5S007; Q12972: PPP1R8; NbExp=3; IntAct=EBI-5323863, EBI-716633; CC Q5S007; P63151: PPP2R2A; NbExp=4; IntAct=EBI-5323863, EBI-1048931; CC Q5S007; P30048: PRDX3; NbExp=14; IntAct=EBI-5323863, EBI-748336; CC Q5S007; P17612: PRKACA; NbExp=6; IntAct=EBI-5323863, EBI-476586; CC Q5S007; O60260: PRKN; NbExp=3; IntAct=EBI-5323863, EBI-716346; CC Q5S007; P61026: RAB10; NbExp=7; IntAct=EBI-5323863, EBI-726075; CC Q5S007; Q6IQ22: RAB12; NbExp=2; IntAct=EBI-5323863, EBI-4289591; CC Q5S007; Q9H0U4: RAB1B; NbExp=5; IntAct=EBI-5323863, EBI-1045214; CC Q5S007; O14966: RAB29; NbExp=15; IntAct=EBI-5323863, EBI-372165; CC Q5S007; Q13637: RAB32; NbExp=12; IntAct=EBI-5323863, EBI-9837586; CC Q5S007; P57729: RAB38; NbExp=4; IntAct=EBI-5323863, EBI-6552718; CC Q5S007; P61020: RAB5B; NbExp=9; IntAct=EBI-5323863, EBI-399401; CC Q5S007; P61006: RAB8A; NbExp=9; IntAct=EBI-5323863, EBI-722293; CC Q5S007; P63000: RAC1; NbExp=5; IntAct=EBI-5323863, EBI-413628; CC Q5S007; P41220: RGS2; NbExp=6; IntAct=EBI-5323863, EBI-712388; CC Q5S007; P62906: RPL10A; NbExp=4; IntAct=EBI-5323863, EBI-356860; CC Q5S007; P26373: RPL13; NbExp=4; IntAct=EBI-5323863, EBI-356849; CC Q5S007; P50914: RPL14; NbExp=2; IntAct=EBI-5323863, EBI-356746; CC Q5S007; P62750: RPL23A; NbExp=2; IntAct=EBI-5323863, EBI-353254; CC Q5S007; P62888: RPL30; NbExp=3; IntAct=EBI-5323863, EBI-353116; CC Q5S007; P49207: RPL34; NbExp=3; IntAct=EBI-5323863, EBI-1051893; CC Q5S007; Q9BUL9: RPP25; NbExp=3; IntAct=EBI-5323863, EBI-366570; CC Q5S007; P62280: RPS11; NbExp=5; IntAct=EBI-5323863, EBI-1047710; CC Q5S007; P62277: RPS13; NbExp=3; IntAct=EBI-5323863, EBI-351850; CC Q5S007; P62841: RPS15; NbExp=9; IntAct=EBI-5323863, EBI-372635; CC Q5S007; P62249: RPS16; NbExp=4; IntAct=EBI-5323863, EBI-352480; CC Q5S007; P62269: RPS18; NbExp=3; IntAct=EBI-5323863, EBI-352451; CC Q5S007; P15880: RPS2; NbExp=4; IntAct=EBI-5323863, EBI-443446; CC Q5S007; P60866: RPS20; NbExp=4; IntAct=EBI-5323863, EBI-353105; CC Q5S007; P62266: RPS23; NbExp=2; IntAct=EBI-5323863, EBI-353072; CC Q5S007; P42677: RPS27; NbExp=4; IntAct=EBI-5323863, EBI-356336; CC Q5S007; P23396: RPS3; NbExp=4; IntAct=EBI-5323863, EBI-351193; CC Q5S007; O15027: SEC16A; NbExp=8; IntAct=EBI-5323863, EBI-357515; CC Q5S007; P60896: SEM1; NbExp=3; IntAct=EBI-5323863, EBI-79819; CC Q5S007; P31947: SFN; NbExp=5; IntAct=EBI-5323863, EBI-476295; CC Q5S007; Q99961: SH3GL1; NbExp=3; IntAct=EBI-5323863, EBI-697911; CC Q5S007; Q99962: SH3GL2; NbExp=4; IntAct=EBI-5323863, EBI-77938; CC Q5S007; P12235: SLC25A4; NbExp=2; IntAct=EBI-5323863, EBI-359074; CC Q5S007; P05141: SLC25A5; NbExp=2; IntAct=EBI-5323863, EBI-355133; CC Q5S007; P12236: SLC25A6; NbExp=2; IntAct=EBI-5323863, EBI-356254; CC Q5S007; O95295: SNAPIN; NbExp=5; IntAct=EBI-5323863, EBI-296723; CC Q5S007; P37840: SNCA; NbExp=6; IntAct=EBI-5323863, EBI-985879; CC Q5S007; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-5323863, EBI-7067260; CC Q5S007; Q13501: SQSTM1; NbExp=18; IntAct=EBI-5323863, EBI-307104; CC Q5S007; Q9UNE7: STUB1; NbExp=4; IntAct=EBI-5323863, EBI-357085; CC Q5S007; Q9UNE7-1: STUB1; NbExp=2; IntAct=EBI-5323863, EBI-15687717; CC Q5S007; Q9BQ70: TCF25; NbExp=3; IntAct=EBI-5323863, EBI-745182; CC Q5S007; Q6P3X3: TTC27; NbExp=3; IntAct=EBI-5323863, EBI-1057046; CC Q5S007; P07437: TUBB; NbExp=6; IntAct=EBI-5323863, EBI-350864; CC Q5S007; Q13885: TUBB2A; NbExp=3; IntAct=EBI-5323863, EBI-711595; CC Q5S007; P04350: TUBB4A; NbExp=6; IntAct=EBI-5323863, EBI-355007; CC Q5S007; P68371: TUBB4B; NbExp=3; IntAct=EBI-5323863, EBI-351356; CC Q5S007; Q9BUF5: TUBB6; NbExp=3; IntAct=EBI-5323863, EBI-356735; CC Q5S007; Q53GS9: USP39; NbExp=3; IntAct=EBI-5323863, EBI-1044822; CC Q5S007; P21796: VDAC1; NbExp=3; IntAct=EBI-5323863, EBI-354158; CC Q5S007; Q9Y6I7: WSB1; NbExp=5; IntAct=EBI-5323863, EBI-1171494; CC Q5S007; P31946: YWHAB; NbExp=5; IntAct=EBI-5323863, EBI-359815; CC Q5S007; P62258: YWHAE; NbExp=8; IntAct=EBI-5323863, EBI-356498; CC Q5S007; P61981: YWHAG; NbExp=26; IntAct=EBI-5323863, EBI-359832; CC Q5S007; Q04917: YWHAH; NbExp=6; IntAct=EBI-5323863, EBI-306940; CC Q5S007; P27348: YWHAQ; NbExp=10; IntAct=EBI-5323863, EBI-359854; CC Q5S007; P63104: YWHAZ; NbExp=11; IntAct=EBI-5323863, EBI-347088; CC Q5S007; O95218: ZRANB2; NbExp=2; IntAct=EBI-5323863, EBI-1051583; CC Q5S007; Q62848: Arfgap1; Xeno; NbExp=7; IntAct=EBI-5323863, EBI-4398879; CC Q5S007; O55143: Atp2a2; Xeno; NbExp=13; IntAct=EBI-5323863, EBI-770763; CC Q5S007; P30275: Ckmt1; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-773103; CC Q5S007; P39053: Dnm1; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-397785; CC Q5S007; P02687: MBP; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-908215; CC Q5S007; Q811U4: Mfn1; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-9029118; CC Q5S007; P00634: phoA; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-552958; CC Q5S007; P12369: Prkar2b; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-6096160; CC Q5S007; Q63481: Rab29; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-6513837; CC Q5S007; P61021: Rab5b; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-8320093; CC Q5S007; Q58A65: Spag9; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-6530207; CC Q5S007; Q9WUD1: Stub1; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-773027; CC Q5S007; P61983: Ywhag; Xeno; NbExp=6; IntAct=EBI-5323863, EBI-359821; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle {ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:26014385}. Perikaryon CC {ECO:0000269|PubMed:17120249}. Golgi apparatus membrane CC {ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:38127736}; Peripheral membrane protein CC {ECO:0000269|PubMed:16321986}. Cell projection, axon CC {ECO:0000269|PubMed:17120249}. Cell projection, dendrite CC {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:21850687}. Endoplasmic CC reticulum membrane {ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:25201882}; Peripheral membrane protein CC {ECO:0000269|PubMed:16321986}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle membrane {ECO:0000269|PubMed:24687852}. Endosome CC {ECO:0000250|UniProtKB:Q5S006}. Lysosome {ECO:0000269|PubMed:17120249, CC ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:38227290}. CC Mitochondrion outer membrane {ECO:0000269|PubMed:16269541, CC ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:17120249, CC ECO:0000269|PubMed:29212815}; Peripheral membrane protein CC {ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}. Cytoplasm, CC cytoskeleton {ECO:0000269|PubMed:35266954}. Cytoplasmic vesicle, CC phagosome {ECO:0000250|UniProtKB:Q5S006}. Note=Colocalized with RAB29 CC along tubular structures emerging from Golgi apparatus CC (PubMed:23395371, PubMed:38127736). Localizes to endoplasmic reticulum CC exit sites (ERES), also known as transitional endoplasmic reticulum CC (tER) (PubMed:25201882). Detected on phagosomes and stressed lysosomes CC but not detected on autophagosomes induced by starvation (By CC similarity). Recruitment to stressed lysosomes is dependent on the ATG8 CC conjugation system composed of ATG5, ATG12 and ATG16L1 and leads to CC lysosomal stress-induced activation of LRRK2 (By similarity). CC {ECO:0000250|UniProtKB:Q5S006, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:38127736}. CC -!- TISSUE SPECIFICITY: Expressed in pyramidal neurons in all cortical CC laminae of the visual cortex, in neurons of the substantia nigra pars CC compacta and caudate putamen (at protein level). Expressed in CC neutrophils (at protein level) (PubMed:29127255). Expressed in the CC brain. Expressed throughout the adult brain, but at a lower level than CC in heart and liver. Also expressed in placenta, lung, skeletal muscle, CC kidney and pancreas. In the brain, expressed in the cerebellum, CC cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, CC temporal lobe and putamen. Expression is particularly high in brain CC dopaminoceptive areas. {ECO:0000269|PubMed:15541308, CC ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:16532471, CC ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29127255}. CC -!- DOMAIN: The seven-bladed WD repeat region is critical for synaptic CC vesicle trafficking and mediates interaction with multiple vesicle- CC associated presynaptic proteins (PubMed:24687852). It also mediates CC homodimerization and regulates kinase activity (PubMed:30635421). CC {ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:30635421}. CC -!- DOMAIN: The COR domain mediates homodimerization; it also mediates CC homotetramerization via interaction with the protein kinase domain. CC {ECO:0000269|PubMed:38127736}. CC -!- DOMAIN: The Roc domain mediates homodimerization and regulates kinase CC activity. {ECO:0000269|PubMed:18230735}. CC -!- PTM: Autophosphorylated at Ser-1292; autophosphorylation is stimulated CC by RAB29 (PubMed:28202711, PubMed:28720718, PubMed:29127255, CC PubMed:29212815, PubMed:30635421, PubMed:38127736). Phosphorylation of CC Ser-910 and either Ser-935 or Ser-1444 facilitates interaction with CC YWHAG (PubMed:28202711). Phosphorylation of Ser-910 and/or Ser-935 CC facilitates interaction with SFN (PubMed:28202711). CC {ECO:0000269|PubMed:28202711, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736}. CC -!- PTM: Ubiquitinated by TRIM1; undergoes 'Lys-48'-linked CC polyubiquitination leading to proteasomal degradation. CC {ECO:0000269|PubMed:35266954}. CC -!- DISEASE: Parkinson disease 8 (PARK8) [MIM:607060]: A slowly progressive CC neurodegenerative disorder characterized by bradykinesia, rigidity, CC resting tremor, postural instability, neuronal loss in the substantia CC nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy CC bodies in some patients. {ECO:0000269|PubMed:15541308, CC ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, CC ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, CC ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, CC ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, CC ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, CC ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, CC ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, CC ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, CC ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, CC ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, CC ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, CC ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, CC ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16333314, CC ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, CC ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:21641266, CC ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, CC ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, CC ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, CC ECO:0000269|PubMed:30635421}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY792511; AAV63975.1; -; mRNA. DR EMBL; AC079630; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC084290; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC107023; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL834529; CAD39185.1; -; mRNA. DR CCDS; CCDS31774.1; -. DR PDB; 2ZEJ; X-ray; 2.00 A; A/B=1333-1516. DR PDB; 3D6T; X-ray; 2.43 A; B=1335-1505. DR PDB; 5MY9; X-ray; 1.33 A; P=929-941. DR PDB; 5MYC; X-ray; 1.46 A; P=904-941. DR PDB; 6DLO; X-ray; 2.70 A; A/B=2142-2527. DR PDB; 6DLP; X-ray; 4.00 A; A/B=2142-2527. DR PDB; 6OJE; X-ray; 1.95 A; A/B=1329-1520. DR PDB; 6OJF; X-ray; 1.60 A; A/B=1329-1520. DR PDB; 6VNO; EM; 3.50 A; A=1327-2527. DR PDB; 6VP6; EM; 3.47 A; A/B/C=1327-2527. DR PDB; 6VP7; EM; 3.50 A; A=1327-2527. DR PDB; 6VP8; EM; 3.50 A; A=1330-2527, B=1670-1950, C=2140-2498. DR PDB; 6XAF; X-ray; 1.97 A; A/B=1329-1520. DR PDB; 6XR4; EM; 14.00 A; A/B=1-2527. DR PDB; 7LHT; EM; 3.50 A; A/B=1-2527. DR PDB; 7LHW; EM; 3.70 A; A=1-2527. DR PDB; 7LI3; EM; 3.80 A; A=1-2527. DR PDB; 7LI4; EM; 3.10 A; A=1-2527. DR PDB; 7THY; EM; 5.20 A; A=1332-1525. DR PDB; 7THZ; EM; 5.00 A; A=1332-1525. DR PDB; 8FO2; EM; 4.13 A; E=1-2527. DR PDB; 8FO7; EM; 3.52 A; C=1327-2527. DR PDB; 8FO8; EM; 3.88 A; C/E=1-2527. DR PDB; 8FO9; EM; 3.48 A; A/C/E/F=1-2527. DR PDB; 8SMC; EM; 4.02 A; C=1327-2527. DR PDB; 8TXZ; EM; 3.05 A; A=1334-2527. DR PDB; 8TYQ; EM; 2.99 A; A=1-2527. DR PDB; 8TZB; EM; 3.10 A; A=1-2527. DR PDB; 8TZC; EM; 2.70 A; A=1333-2527. DR PDB; 8TZE; EM; 2.90 A; A=1-2527. DR PDB; 8TZF; EM; 3.40 A; A=1-2527. DR PDB; 8TZG; EM; 2.70 A; A=1333-2522. DR PDB; 8TZH; EM; 3.90 A; A=1-2527. DR PDB; 8U1B; EM; 3.70 A; A=1334-2527. DR PDB; 8U7H; EM; 3.80 A; C=1327-2527. DR PDB; 8U7L; EM; 3.60 A; A/B=1-2527. DR PDB; 8U8A; EM; 3.40 A; B/C=1-2527. DR PDB; 8U8B; EM; 3.70 A; A/B=1-2527. DR PDB; 8VH4; EM; 4.10 A; A=1-2527. DR PDB; 8VH5; EM; 4.00 A; A/C=1-2527. DR PDB; 9C76; X-ray; 2.30 A; A/B=1329-1516. DR PDB; 9CHO; EM; 7.80 A; A=543-2527. DR PDB; 9CI3; EM; 3.96 A; A=1-2527. DR PDB; 9DMI; EM; 3.35 A; A=1333-2527. DR PDBsum; 2ZEJ; -. DR PDBsum; 3D6T; -. DR PDBsum; 5MY9; -. DR PDBsum; 5MYC; -. DR PDBsum; 6DLO; -. DR PDBsum; 6DLP; -. DR PDBsum; 6OJE; -. DR PDBsum; 6OJF; -. DR PDBsum; 6VNO; -. DR PDBsum; 6VP6; -. DR PDBsum; 6VP7; -. DR PDBsum; 6VP8; -. DR PDBsum; 6XAF; -. DR PDBsum; 6XR4; -. DR PDBsum; 7LHT; -. DR PDBsum; 7LHW; -. DR PDBsum; 7LI3; -. DR PDBsum; 7LI4; -. DR PDBsum; 7THY; -. DR PDBsum; 7THZ; -. DR PDBsum; 8FO2; -. DR PDBsum; 8FO7; -. DR PDBsum; 8FO8; -. DR PDBsum; 8FO9; -. DR PDBsum; 8SMC; -. DR PDBsum; 8TXZ; -. DR PDBsum; 8TYQ; -. DR PDBsum; 8TZB; -. DR PDBsum; 8TZC; -. DR PDBsum; 8TZE; -. DR PDBsum; 8TZF; -. DR PDBsum; 8TZG; -. DR PDBsum; 8TZH; -. DR PDBsum; 8U1B; -. DR PDBsum; 8U7H; -. DR PDBsum; 8U7L; -. DR PDBsum; 8U8A; -. DR PDBsum; 8U8B; -. DR PDBsum; 8VH4; -. DR PDBsum; 8VH5; -. DR PDBsum; 9C76; -. DR PDBsum; 9CHO; -. DR PDBsum; 9CI3; -. DR PDBsum; 9DMI; -. DR AlphaFoldDB; Q5S007; -. DR EMDB; EMD-20825; -. DR EMDB; EMD-20826; -. DR EMDB; EMD-21250; -. DR EMDB; EMD-21306; -. DR EMDB; EMD-21309; -. DR EMDB; EMD-21310; -. DR EMDB; EMD-21311; -. DR EMDB; EMD-21312; -. DR EMDB; EMD-23350; -. DR EMDB; EMD-23352; -. DR EMDB; EMD-23359; -. DR EMDB; EMD-23360; -. DR EMDB; EMD-25649; -. DR EMDB; EMD-25658; -. DR EMDB; EMD-25664; -. DR EMDB; EMD-25674; -. DR EMDB; EMD-25897; -. DR EMDB; EMD-25906; -. DR EMDB; EMD-25907; -. DR EMDB; EMD-29339; -. DR EMDB; EMD-29340; -. DR EMDB; EMD-29341; -. DR EMDB; EMD-29342; -. DR EMDB; EMD-41709; -. DR EMDB; EMD-41728; -. DR EMDB; EMD-41753; -. DR EMDB; EMD-41754; -. DR EMDB; EMD-41756; -. DR EMDB; EMD-41757; -. DR EMDB; EMD-41758; -. DR EMDB; EMD-41759; -. DR EMDB; EMD-41794; -. DR EMDB; EMD-41795; -. DR EMDB; EMD-41798; -. DR EMDB; EMD-41799; -. DR EMDB; EMD-41806; -. DR EMDB; EMD-41985; -. DR EMDB; EMD-42019; -. DR EMDB; EMD-42020; -. DR EMDB; EMD-43234; -. DR EMDB; EMD-43235; -. DR EMDB; EMD-45591; -. DR EMDB; EMD-45593; -. DR EMDB; EMD-45594; -. DR EMDB; EMD-45595; -. DR EMDB; EMD-45596; -. DR EMDB; EMD-45609; -. DR EMDB; EMD-47004; -. DR EMDB; EMD-47006; -. DR EMDB; EMD-47025; -. DR SMR; Q5S007; -. DR BioGRID; 125700; 512. DR CORUM; Q5S007; -. DR DIP; DIP-29684N; -. DR FunCoup; Q5S007; 660. DR IntAct; Q5S007; 2316. DR MINT; Q5S007; -. DR STRING; 9606.ENSP00000298910; -. DR BindingDB; Q5S007; -. DR ChEMBL; CHEMBL1075104; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q5S007; -. DR GuidetoPHARMACOLOGY; 2059; -. DR TCDB; 8.A.23.1.54; the basigin (basigin) family. DR GlyGen; Q5S007; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q5S007; -. DR PhosphoSitePlus; Q5S007; -. DR BioMuta; LRRK2; -. DR DMDM; 294862450; -. DR jPOST; Q5S007; -. DR MassIVE; Q5S007; -. DR PaxDb; 9606-ENSP00000298910; -. DR PeptideAtlas; Q5S007; -. DR ProteomicsDB; 63755; -. DR ABCD; Q5S007; 2 sequenced antibodies. DR Antibodypedia; 2109; 881 antibodies from 47 providers. DR DNASU; 120892; -. DR Ensembl; ENST00000298910.12; ENSP00000298910.7; ENSG00000188906.18. DR GeneID; 120892; -. DR KEGG; hsa:120892; -. DR MANE-Select; ENST00000298910.12; ENSP00000298910.7; NM_198578.4; NP_940980.4. DR UCSC; uc001rmg.5; human. DR AGR; HGNC:18618; -. DR ClinPGx; PA134968052; -. DR CTD; 120892; -. DR DisGeNET; 120892; -. DR GeneCards; LRRK2; -. DR GeneReviews; LRRK2; -. DR HGNC; HGNC:18618; LRRK2. DR HPA; ENSG00000188906; Tissue enriched (lung). DR MalaCards; LRRK2; -. DR MIM; 168600; phenotype. DR MIM; 607060; phenotype. DR MIM; 609007; gene. DR OpenTargets; ENSG00000188906; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000188906; -. DR eggNOG; KOG0192; Eukaryota. DR eggNOG; KOG0618; Eukaryota. DR eggNOG; KOG0619; Eukaryota. DR GeneTree; ENSGT00940000158267; -. DR HOGENOM; CLU_000815_0_0_1; -. DR InParanoid; Q5S007; -. DR OMA; FIVECMV; -. DR OrthoDB; 8940716at2759; -. DR PAN-GO; Q5S007; 31 GO annotations based on evolutionary models. DR PhylomeDB; Q5S007; -. DR PathwayCommons; Q5S007; -. DR Reactome; R-HSA-8857538; PTK6 promotes HIF1A stabilization. DR SignaLink; Q5S007; -. DR SIGNOR; Q5S007; -. DR Agora; ENSG00000188906; -. DR BioGRID-ORCS; 120892; 21 hits in 1183 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR ChiTaRS; LRRK2; human. DR EvolutionaryTrace; Q5S007; -. DR GeneWiki; LRRK2; -. DR GenomeRNAi; 120892; -. DR Pharos; Q5S007; Tchem. DR PRO; PR:Q5S007; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q5S007; protein. DR Bgee; ENSG00000188906; Expressed in buccal mucosa cell and 154 other cell types or tissues. DR ExpressionAtlas; Q5S007; baseline and differential. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0099400; C:caveola neck; IDA:ParkinsonsUK-UCL. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0032473; C:cytoplasmic side of mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0032839; C:dendrite cytoplasm; IDA:BHF-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0070971; C:endoplasmic reticulum exit site; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; ISS:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005798; C:Golgi-associated vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0030426; C:growth cone; IDA:ParkinsonsUK-UCL. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; ISS:UniProtKB. DR GO; GO:0005902; C:microvillus; IDA:ParkinsonsUK-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0097487; C:multivesicular body, internal vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:BHF-UCL. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0043204; C:perikaryon; IDA:UniProtKB. DR GO; GO:0045335; C:phagocytic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0099523; C:presynaptic cytosol; IEA:Ensembl. DR GO; GO:1990904; C:ribonucleoprotein complex; IEA:Ensembl. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043195; C:terminal bouton; TAS:ParkinsonsUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:1990909; C:Wnt signalosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:1904713; F:beta-catenin destruction complex binding; NAS:ParkinsonsUK-UCL. DR GO; GO:0030276; F:clathrin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0039706; F:co-receptor binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0034211; F:GTP-dependent protein kinase activity; IDA:BHF-UCL. DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB. DR GO; GO:0003924; F:GTPase activity; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IDA:BHF-UCL. DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IMP:UniProtKB. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:BHF-UCL. DR GO; GO:0008017; F:microtubule binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0036479; F:peroxidase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0051018; F:protein kinase A binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. 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:0030159; F:signaling receptor complex adaptor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0031267; F:small GTPase binding; IPI:BHF-UCL. DR GO; GO:0000149; F:SNARE binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0017075; F:syntaxin-1 binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IPI:UniProtKB. DR GO; GO:0015631; F:tubulin binding; IDA:BHF-UCL. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0019722; P:calcium-mediated signaling; IMP:ParkinsonsUK-UCL. DR GO; GO:0060070; P:canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1904644; P:cellular response to curcumin; IEA:Ensembl. DR GO; GO:1903351; P:cellular response to dopamine; IMP:ParkinsonsUK-UCL. 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:0034614; P:cellular response to reactive oxygen species; IMP:ParkinsonsUK-UCL. DR GO; GO:0009267; P:cellular response to starvation; IMP:ParkinsonsUK-UCL. DR GO; GO:0008340; P:determination of adult lifespan; IMP:BHF-UCL. DR GO; GO:0006897; P:endocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:0007029; P:endoplasmic reticulum organization; IMP:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; ISS:ParkinsonsUK-UCL. DR GO; GO:0035640; P:exploration behavior; IMP:BHF-UCL. DR GO; GO:0007030; P:Golgi organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0046039; P:GTP metabolic process; IDA:BHF-UCL. DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:BHF-UCL. DR GO; GO:0008104; P:intracellular protein localization; ISS:ParkinsonsUK-UCL. DR GO; GO:0035556; P:intracellular signal transduction; ISS:ParkinsonsUK-UCL. DR GO; GO:0007254; P:JNK cascade; IDA:BHF-UCL. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0007040; P:lysosome organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB. DR GO; GO:0051646; P:mitochondrion localization; IMP:ParkinsonsUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; ISS:ParkinsonsUK-UCL. DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:MGI. DR GO; GO:1902823; P:negative regulation of late endosome to lysosome transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:1905504; P:negative regulation of motile cilium assembly; TAS:UniProt. DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IEA:Ensembl. DR GO; GO:0010955; P:negative regulation of protein processing; IDA:ParkinsonsUK-UCL. DR GO; GO:1903217; P:negative regulation of protein processing involved in protein targeting to mitochondrion; IC:ParkinsonsUK-UCL. DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0007528; P:neuromuscular junction development; IMP:BHF-UCL. DR GO; GO:0140058; P:neuron projection arborization; IEA:Ensembl. DR GO; GO:0048812; P:neuron projection morphogenesis; IMP:UniProtKB. DR GO; GO:0021772; P:olfactory bulb development; IMP:ParkinsonsUK-UCL. DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IGI:ParkinsonsUK-UCL. DR GO; GO:0060161; P:positive regulation of dopamine receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:ParkinsonsUK-UCL. DR GO; GO:1903980; P:positive regulation of microglial cell activation; IEA:Ensembl. DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:BHF-UCL. DR GO; GO:1902499; P:positive regulation of protein autoubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:1900244; P:positive regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:0070973; P:protein localization to endoplasmic reticulum exit site; IMP:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; IMP:ParkinsonsUK-UCL. DR GO; GO:1905289; P:regulation of CAMKK-AMPK signaling cascade; IMP:ParkinsonsUK-UCL. DR GO; GO:0141161; P:regulation of cAMP/PKA signal transduction; ISS:ParkinsonsUK-UCL. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; IBA:GO_Central. DR GO; GO:0031344; P:regulation of cell projection organization; IBA:GO_Central. DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IMP:ParkinsonsUK-UCL. DR GO; GO:0060159; P:regulation of dopamine receptor signaling pathway; ISS:ParkinsonsUK-UCL. DR GO; GO:0060628; P:regulation of ER to Golgi vesicle-mediated transport; ISS:UniProtKB. DR GO; GO:0035564; P:regulation of kidney size; ISS:BHF-UCL. DR GO; GO:0040012; P:regulation of locomotion; IMP:BHF-UCL. DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IMP:ParkinsonsUK-UCL. DR GO; GO:0042391; P:regulation of membrane potential; IMP:BHF-UCL. DR GO; GO:0051900; P:regulation of mitochondrial depolarization; IMP:ParkinsonsUK-UCL. DR GO; GO:0090140; P:regulation of mitochondrial fission; TAS:ParkinsonsUK-UCL. DR GO; GO:1902692; P:regulation of neuroblast proliferation; IMP:ParkinsonsUK-UCL. DR GO; GO:0014041; P:regulation of neuron maturation; IMP:ParkinsonsUK-UCL. DR GO; GO:0031647; P:regulation of protein stability; IMP:UniProtKB. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1905279; P:regulation of retrograde transport, endosome to Golgi; IGI:ParkinsonsUK-UCL. DR GO; GO:0035542; P:regulation of SNARE complex assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; ISS:ParkinsonsUK-UCL. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IBA:GO_Central. DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; ISS:ParkinsonsUK-UCL. DR GO; GO:0006979; P:response to oxidative stress; IMP:BHF-UCL. DR GO; GO:0007266; P:Rho protein signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl. DR GO; GO:0021756; P:striatum development; IEA:Ensembl. DR GO; GO:0022028; P:tangential migration from the subventricular zone to the olfactory bulb; IMP:ParkinsonsUK-UCL. DR GO; GO:1904887; P:Wnt signalosome assembly; IPI:ParkinsonsUK-UCL. DR CDD; cd09914; RocCOR; 1. DR CDD; cd14068; STKc_LRRK2; 1. DR FunFam; 1.10.510.10:FF:001216; Leucine-rich repeat kinase 2; 1. DR FunFam; 1.25.40.20:FF:000219; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 2.130.10.10:FF:000481; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.30.200.20:FF:000313; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.30.70.1390:FF:000001; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.40.50.300:FF:000656; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.80.10.10:FF:000110; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 1.25.10.10:FF:000215; leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.80.10.10:FF:000179; leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 1.25.10.10:FF:000232; leucine-rich repeat serine/threonine-protein kinase 2 isoform X1; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 2. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 2. DR Gene3D; 3.30.70.1390; ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR056593; ANK_LRRK2. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR056597; ARM_LRRK2. DR InterPro; IPR056602; Beta-prop_LRRK2. DR InterPro; IPR032171; COR-A. DR InterPro; IPR057263; COR-B. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR020859; ROC. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR051420; Ser_Thr_Kinases_DiverseReg. DR InterPro; IPR005225; Small_GTP-bd. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR InterPro; IPR036322; WD40_repeat_dom_sf. DR NCBIfam; TIGR00231; small_GTP; 1. DR PANTHER; PTHR48005; LEUCINE RICH REPEAT KINASE 2; 1. DR PANTHER; PTHR48005:SF13; SERINE_THREONINE-PROTEIN KINASE DDB_G0278509-RELATED; 1. DR Pfam; PF23745; ANK_LRRK2; 1. DR Pfam; PF23744; ARM_LRRK2; 1. DR Pfam; PF23748; Beta-prop_LRRK2; 1. DR Pfam; PF16095; COR-A; 1. DR Pfam; PF25497; COR-B; 1. DR Pfam; PF13855; LRR_8; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF08477; Roc; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00364; LRR_BAC; 8. DR SMART; SM00369; LRR_TYP; 7. DR SMART; SM00175; RAB; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF48371; ARM repeat; 2. DR SUPFAM; SSF52058; L domain-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF50978; WD40 repeat-like; 1. DR PROSITE; PS51450; LRR; 11. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS51424; ROC; 1. PE 1: Evidence at protein level; KW 3D-structure; ATP-binding; Autophagy; Cell projection; Coiled coil; KW Cytoplasm; Cytoplasmic vesicle; Cytoskeleton; Differentiation; KW Disease variant; Endoplasmic reticulum; Endosome; Golgi apparatus; KW GTP-binding; GTPase activation; Hydrolase; Kinase; Leucine-rich repeat; KW Lysosome; Membrane; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleotide-binding; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Synapse; Transferase; Ubl conjugation; KW WD repeat. FT CHAIN 1..2527 FT /note="Leucine-rich repeat serine/threonine-protein kinase FT 2" FT /id="PRO_0000086238" FT REPEAT 983..1004 FT /note="LRR 1" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1012..1033 FT /note="LRR 2" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1036..1057 FT /note="LRR 3" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1059..1080 FT /note="LRR 4" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1084..1105 FT /note="LRR 5" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1108..1129 FT /note="LRR 6" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1130..1150 FT /note="LRR 7" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1156..1171 FT /note="LRR 8" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1174..1196 FT /note="LRR 9" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1197..1218 FT /note="LRR 10" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1221..1245 FT /note="LRR 11" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1246..1267 FT /note="LRR 12" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1269..1291 FT /note="LRR 13" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT DOMAIN 1328..1511 FT /note="Roc" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT DOMAIN 1546..1740 FT /note="COR" FT /evidence="ECO:0000255" FT DOMAIN 1879..2138 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REPEAT 2139..2183 FT /note="WD 1" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2188..2228 FT /note="WD 2" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2233..2276 FT /note="WD 3" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2281..2327 FT /note="WD 4" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2333..2377 FT /note="WD 5" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2402..2438 FT /note="WD 6" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2443..2497 FT /note="WD 7" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REGION 1..969 FT /note="Required for RAB29-mediated activation" FT /evidence="ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:38127736" FT COILED 319..348 FT /evidence="ECO:0000255" FT ACT_SITE 1994 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 1341..1348 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758, FT ECO:0000269|PubMed:18230735" FT BINDING 1885 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1887 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1888 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1891 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8" FT BINDING 1893 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1904 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1906 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 1947 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8" FT BINDING 1948 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1950 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1954 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1957 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1998 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 2001 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2016 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2017 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2098..2121 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT BINDING 2295..2298 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT MOD_RES 910 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29212815" FT MOD_RES 935 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29127255, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30635421" FT MOD_RES 955 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815" FT MOD_RES 973 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815" FT MOD_RES 1292 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736" FT MOD_RES 1444 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711" FT VARIANT 50 FT /note="R -> H (in dbSNP:rs2256408)" FT /id="VAR_024931" FT VARIANT 119 FT /note="L -> P (in dbSNP:rs33995463)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846" FT /id="VAR_024932" FT VARIANT 228 FT /note="C -> S (in dbSNP:rs56108242)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054740" FT VARIANT 419 FT /note="A -> V (in dbSNP:rs34594498)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_033903" FT VARIANT 551 FT /note="N -> K (in dbSNP:rs7308720)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024933" FT VARIANT 712 FT /note="M -> V (in PARK8; dbSNP:rs199566791)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054741" FT VARIANT 716 FT /note="A -> V (in dbSNP:rs281865043)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054742" FT VARIANT 723 FT /note="I -> V (in dbSNP:rs10878307)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024934" FT VARIANT 755 FT /note="P -> L (in dbSNP:rs34410987)" FT /id="VAR_033904" FT VARIANT 793 FT /note="R -> M (in PARK8; uncertain significance; FT dbSNP:rs35173587)" FT /evidence="ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16251215" FT /id="VAR_024935" FT VARIANT 871 FT /note="K -> E (in dbSNP:rs281865044)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054743" FT VARIANT 930 FT /note="Q -> R (in PARK8; uncertain significance; FT dbSNP:rs281865045)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024936" FT VARIANT 944 FT /note="D -> Y (in dbSNP:rs17519916)" FT /id="VAR_024937" FT VARIANT 1067 FT /note="R -> Q (in PARK8; dbSNP:rs111341148)" FT /evidence="ECO:0000269|PubMed:16247070" FT /id="VAR_024938" FT VARIANT 1096 FT /note="S -> C (in PARK8; uncertain significance; FT dbSNP:rs76535406)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024939" FT VARIANT 1122 FT /note="I -> V (in PARK8; dbSNP:rs34805604)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16172858" FT /id="VAR_024940" FT VARIANT 1228 FT /note="S -> T (in PARK8; dbSNP:rs60185966)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024941" FT VARIANT 1262 FT /note="P -> A (in dbSNP:rs4640000)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024942" FT VARIANT 1359 FT /note="K -> I (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064728" FT VARIANT 1371 FT /note="I -> V (in PARK8; uncertain significance; FT dbSNP:rs17466213)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16333314" FT /id="VAR_024943" FT VARIANT 1375 FT /note="D -> E (in dbSNP:rs28365226)" FT /id="VAR_047022" FT VARIANT 1398 FT /note="R -> H (in dbSNP:rs7133914)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024944" FT VARIANT 1441 FT /note="R -> C (in PARK8; shows an increase in activity in FT both autophosphorylation and phosphorylation of a generic FT substrate; loss of interaction with SEC16A; shows an FT increase in activity in phosphorylation of RAB10; decreases FT phosphorylation-dependent binding to YWHAG; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs33939927)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16333314, FT ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220" FT /id="VAR_024945" FT VARIANT 1441 FT /note="R -> G (in PARK8; shows a progressive reduction in FT neurite length and branching; shows an increase in activity FT in phosphorylation of RAB8A and RAB10; decreases FT phosphorylation-dependent binding to YWHAG; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs33939927)" FT /evidence="ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024946" FT VARIANT 1441 FT /note="R -> H (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; decreases FT phosphorylation-dependent binding to YWHAG; FT dbSNP:rs34995376)" FT /evidence="ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815" FT /id="VAR_024947" FT VARIANT 1514 FT /note="R -> Q (in PARK8; uncertain significance; FT dbSNP:rs35507033)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024948" FT VARIANT 1542 FT /note="P -> S (in PARK8; uncertain significance; FT dbSNP:rs33958906)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024949" FT VARIANT 1550 FT /note="R -> Q (in an ovarian mucinous carcinoma sample; FT somatic mutation; dbSNP:rs200212150)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040678" FT VARIANT 1598 FT /note="V -> E (in PARK8; uncertain significance; FT dbSNP:rs721710)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024950" FT VARIANT 1628 FT /note="R -> P (in PARK8; uncertain significance; FT dbSNP:rs33949390)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:21641266, ECO:0000269|PubMed:22415848" FT /id="VAR_024951" FT VARIANT 1646 FT /note="M -> T (in dbSNP:rs35303786)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024952" FT VARIANT 1647 FT /note="S -> T (in dbSNP:rs11564148)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024953" FT VARIANT 1699 FT /note="Y -> C (in PARK8; shows no progressive reduction in FT neurite length and branching; no loss of interaction with FT SEC16A; shows an increase in activity in phosphorylation of FT RAB8A and RAB10; significantly suppresses lysosomal FT enlargement when overexpressed in LRRK2 knockout cells due FT to increased phosphorylation of Rab proteins; FT dbSNP:rs35801418)" FT /evidence="ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30209220" FT /id="VAR_024954" FT VARIANT 1723 FT /note="R -> P (in an ovarian serous carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040679" FT VARIANT 1728 FT /note="R -> H (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; dbSNP:rs145364431)" FT /evidence="ECO:0000269|PubMed:18213618, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:29212815" FT /id="VAR_054744" FT VARIANT 1728 FT /note="R -> L (in PARK8; dbSNP:rs145364431)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054745" FT VARIANT 1869 FT /note="M -> T (in PARK8; uncertain significance; FT dbSNP:rs35602796)" FT /evidence="ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858" FT /id="VAR_024955" FT VARIANT 1870 FT /note="L -> F (in dbSNP:rs281865053)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054746" FT VARIANT 1906 FT /note="K -> M (loss of kinase activity and ability to FT enhance NOD2 signaling; does not inhibit interaction with FT RAB29; shows a progressive increase in neurite length and FT branching; does not suppress lysosomal enlargement when FT overexpressed in LRRK2 knockout cells due to lack of FT phosphorylation activity)" FT /evidence="ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:27830463, FT ECO:0000269|PubMed:30209220" FT /id="VAR_071101" FT VARIANT 1941 FT /note="R -> H (in PARK8; dbSNP:rs77428810)" FT /evidence="ECO:0000269|PubMed:16272164" FT /id="VAR_024956" FT VARIANT 2012 FT /note="I -> T (in PARK8; uncertain significance; FT dbSNP:rs34015634)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024957" FT VARIANT 2019 FT /note="G -> S (in PARK8; shows an increase in activity in FT both autophosphorylation and phosphorylation of a generic FT substrate; results in increased PRDX3 phosphorylation FT promoting dysregulation of mitochondrial function and FT oxidative damage; results in increased APP phosphorylation FT on 'T-743' promoting neurotoxicity in dopaminergic neurons; FT shows increased kinase activity in the phosphorylation of FT RAB10; does not inhibit interaction with RAB29; shows a FT progressive reduction in neurite length and branching; FT shows distinctive spheroid-like inclusions within both FT neuronal processes and at intracellular membranous FT structures; shows lysosomal swelling and reduced retrograde FT transport of selective cargo between lysosomes and the FT Golgi apparatus; shows apoptotic mechanism of cell death; FT no loss of interaction with SEC16A; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs34637584)" FT /evidence="ECO:0000269|PubMed:15680455, FT ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, FT ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, FT ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, FT ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16001413, FT ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, FT ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, FT ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, FT ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, FT ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, FT ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18213618, FT ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, FT ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421" FT /id="VAR_024958" FT VARIANT 2020 FT /note="I -> T (in PARK8; significant increase in FT autophosphorylation of about 40% in comparison to wild-type FT protein in vitro; shows a progressive reduction in neurite FT length and branching; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs35870237)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16321986, FT ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220" FT /id="VAR_024959" FT VARIANT 2031 FT /note="T -> S (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; dbSNP:rs78029637)" FT /evidence="ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815" FT /id="VAR_082047" FT VARIANT 2081 FT /note="N -> D (in dbSNP:rs33995883)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024960" FT VARIANT 2119 FT /note="P -> L (in dbSNP:rs12423862)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024961" FT VARIANT 2141 FT /note="T -> M (in PARK8; dbSNP:rs111691891)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054747" FT VARIANT 2143 FT /note="R -> H (in PARK8; dbSNP:rs201271001)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054748" FT VARIANT 2175 FT /note="D -> H (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs72547981)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082048" FT VARIANT 2189 FT /note="Y -> C (in PARK8; no effect on WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs35658131)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082049" FT VARIANT 2261 FT /note="N -> I (in dbSNP:rs12581902)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024962" FT VARIANT 2356 FT /note="T -> I (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs113511708)" FT /evidence="ECO:0000269|PubMed:16272164, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024963" FT VARIANT 2385 FT /note="G -> R (in PARK8; under conditions of oxidative FT stress the variant protein is more toxic and is correlated FT with a higher rate of apoptosis; reduced binding to FT synaptic vesicles; no loss of interaction with SEC16A; FT shows an increase in activity in phosphorylation of RAB8A FT and RAB10; shows decreased WD domain homodimerization; FT reduced autophosphorylation at Ser-935; dbSNP:rs34778348)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17019612, ECO:0000269|PubMed:21641266, FT ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024964" FT VARIANT 2390 FT /note="V -> M (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs79546190)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082050" FT VARIANT 2395 FT /note="E -> K (in dbSNP:rs78964014)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054749" FT VARIANT 2397 FT /note="M -> T (in dbSNP:rs3761863)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:22415848" FT /id="VAR_024965" FT VARIANT 2439 FT /note="L -> I (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs72547983)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082051" FT VARIANT 2466 FT /note="L -> H (in PARK8; dbSNP:rs281865057)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054750" FT MUTAGEN 399 FT /note="R->E: Reduces membrane localization and abolishes FT interaction with RAB29/RAB7L1. Impairs RAB29-stimulated FT kinase activity on RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 403 FT /note="L->E: Reduces membrane localization and abolishes FT interaction with RAB29/RAB7L1. Impairs RAB29-stimulated FT kinase activity on RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 727 FT /note="C->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 728 FT /note="L->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 729 FT /note="L->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 760 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 761 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 762 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 789 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 790 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 791 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1343 FT /note="T->G: Decreased kinase activity; when associated FT with Q-1398." FT /evidence="ECO:0000269|PubMed:18230735" FT MUTAGEN 1347 FT /note="K->A: GTPase-dead mutant. Loss of interaction with FT SEC16A and impaired ability to recruit SEC16A to FT endoplasmic reticulum exit sites." FT /evidence="ECO:0000269|PubMed:25201882" FT MUTAGEN 1348 FT /note="T->N: Loss of GTP binding. Inhibits FT autophosphorylation and RAB10 phosphorylation; when FT associated with G-1441, C-1699, or S-2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1398 FT /note="R->Q: Decreased kinase activity; when associated FT with G-1343." FT /evidence="ECO:0000269|PubMed:18230735" FT MUTAGEN 1441 FT /note="R->G: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1588 FT /note="P->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1699 FT /note="Y->C: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1710 FT /note="N->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1791 FT /note="W->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1906 FT /note="K->A: Loss of kinase activity. Decreases proteasomal FT degradation of MAPT; when associated with N-1994 and A- FT 2017." FT /evidence="ECO:0000269|PubMed:26014385" FT MUTAGEN 1994 FT /note="D->A: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:28720718" FT MUTAGEN 1994 FT /note="D->N: Loss of kinase activity. No loss of FT interaction with SEC16A and no loss of ability to recruit FT SEC16A to endoplasmic reticulum exit sites. Decreases FT proteasomal degradation of MAPT; when associated with A- FT 1906 and A-2017." FT /evidence="ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26014385, ECO:0000269|PubMed:26824392" FT MUTAGEN 2017 FT /note="D->A: Loss of kinase activity. Decreases proteasomal FT degradation of MAPT; when associated with A-1906 and N- FT 1994. Loss of phosphorylation of RAB10; when associated FT with G-1441, C-1699, or S-2019." FT /evidence="ECO:0000269|PubMed:26014385, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736" FT MUTAGEN 2019 FT /note="G->S: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 2343 FT /note="L->D: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2344 FT /note="F->A: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2345 FT /note="S->D: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2346 FT /note="Y->A: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2391 FT /note="H->D: Increases kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2394 FT /note="R->E: Decreases WD domain homodimerization. FT Increases kinase activity and autophosphorylation at Ser- FT 1292." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2395 FT /note="E->R: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2408 FT /note="M->A,E: No effect on WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2409 FT /note="S->A: Decreases WD domain homodimerization." FT /evidence="ECO:0000269|PubMed:30635421" FT CONFLICT 212 FT /note="L -> S (in Ref. 1; AAV63975)" FT /evidence="ECO:0000305" FT HELIX 560..570 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 571..574 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 585..595 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 603..606 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 607..610 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 626..637 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 638..640 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 645..656 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 660..662 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 663..666 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 667..670 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 671..678 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 689..702 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 706..714 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 715..720 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 722..730 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 740..742 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 744..750 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 755..762 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 763..765 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 768..780 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 784..787 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 788..794 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 798..801 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 802..804 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 815..818 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 819..821 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 834..852 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 913..917 FT /evidence="ECO:0007829|PDB:5MYC" FT STRAND 986..988 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 998..1000 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1001..1003 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 1005..1009 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1010..1012 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1014..1017 FT /evidence="ECO:0007829|PDB:8TZF" FT HELIX 1030..1032 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1054..1056 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1057..1059 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1087..1089 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1102..1105 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1111..1113 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1133..1135 FT /evidence="ECO:0007829|PDB:8TZF" FT TURN 1146..1149 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1157..1159 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1177..1179 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1190..1193 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1200..1202 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1214..1216 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1224..1226 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1242..1244 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1249..1251 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1262..1266 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1272..1274 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1286..1290 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1310..1312 FT /evidence="ECO:0007829|PDB:8TZF" FT HELIX 1317..1327 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1329..1332 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1336..1341 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1347..1354 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1357..1359 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1365..1368 FT /evidence="ECO:0007829|PDB:6OJE" FT STRAND 1370..1378 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1382..1384 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1388..1395 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1398..1402 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1406..1410 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1411..1420 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1421..1423 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1426..1429 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1431..1441 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1447..1452 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1454..1456 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1459..1472 FT /evidence="ECO:0007829|PDB:6OJF" FT TURN 1473..1475 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1482..1487 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1490..1492 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1495..1513 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1518..1520 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1521..1524 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1531..1539 FT /evidence="ECO:0007829|PDB:8TZG" FT STRAND 1543..1549 FT /evidence="ECO:0007829|PDB:8TXZ" FT HELIX 1553..1557 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1564..1568 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1573..1579 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1581..1583 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1588..1590 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1591..1594 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1596..1599 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1600..1609 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1610..1612 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1628..1632 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1638..1640 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1643..1645 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1650..1655 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1661..1663 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1670..1672 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1687..1689 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1690..1699 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1701..1703 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1704..1715 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1716..1718 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1730..1733 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1735..1743 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1746..1753 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1761..1770 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1771..1791 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1793..1796 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1800..1802 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1809..1814 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1816..1819 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1823..1826 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1827..1835 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1838..1841 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1843..1845 FT /evidence="ECO:0007829|PDB:8TZB" FT STRAND 1849..1851 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1852..1854 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1857..1863 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1866..1868 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1872..1874 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1875..1877 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1881..1883 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1884..1887 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1889..1898 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1901..1908 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1910..1912 FT /evidence="ECO:0007829|PDB:8TZE" FT HELIX 1914..1924 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1935..1939 FT /evidence="ECO:0007829|PDB:8TZE" FT STRAND 1940..1942 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1946..1948 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1951..1954 FT /evidence="ECO:0007829|PDB:6VP6" FT HELIX 1955..1960 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1963..1965 FT /evidence="ECO:0007829|PDB:8TZE" FT HELIX 1968..1987 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1999..2003 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2013..2015 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2018..2025 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2036..2038 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 2041..2045 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2046..2048 FT /evidence="ECO:0007829|PDB:6VP6" FT HELIX 2054..2068 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2069..2072 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2080..2082 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 2085..2087 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2095..2099 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2105..2107 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2108..2114 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2119..2121 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2125..2132 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2135..2139 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2142..2145 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2152..2158 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2166..2171 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2173..2183 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2184..2186 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2189..2197 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2199..2207 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2208..2211 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2212..2219 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2224..2230 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2235..2237 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2245..2252 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2256..2258 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2262..2267 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2270..2276 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2278..2281 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2282..2284 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2288..2292 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2300..2304 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2315..2319 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2322..2330 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2335..2338 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2339..2343 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2347..2350 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2354..2367 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2371..2376 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2378..2380 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2382..2388 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2389..2393 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2397..2399 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 2403..2406 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2414..2419 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2421..2423 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2425..2432 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2434..2437 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2439..2441 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2444..2448 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2451..2462 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2468..2475 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2482..2484 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2491..2497 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2500..2521 FT /evidence="ECO:0007829|PDB:8TZC" SQ SEQUENCE 2527 AA; 286103 MW; 26142A0CECBBC3F4 CRC64; MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLIE VCPGTMQSLM GPQDVGNDWE VLGVHQLILK MLTVHNASVN LSVIGLKTLD LLLTSGKITL LILDEESDIF MLIFDAMHSF PANDEVQKLG CKALHVLFER VSEEQLTEFV ENKDYMILLS ALTNFKDEEE IVLHVLHCLH SLAIPCNNVE VLMSGNVRCY NIVVEAMKAF PMSERIQEVS CCLLHRLTLG NFFNILVLNE VHEFVVKAVQ QYPENAALQI SALSCLALLT ETIFLNQDLE EKNENQENDD EGEEDKLFWL EACYKALTWH RKNKHVQEAA CWALNNLLMY QNSLHEKIGD EDGHFPAHRE VMLSMLMHSS SKEVFQASAN ALSTLLEQNV NFRKILLSKG IHLNVLELMQ KHIHSPEVAE SGCKMLNHLF EGSNTSLDIM AAVVPKILTV MKRHETSLPV QLEALRAILH FIVPGMPEES REDTEFHHKL NMVKKQCFKN DIHKLVLAAL NRFIGNPGIQ KCGLKVISSI VHFPDALEML SLEGAMDSVL HTLQMYPDDQ EIQCLGLSLI GYLITKKNVF IGTGHLLAKI LVSSLYRFKD VAEIQTKGFQ TILAILKLSA SFSKLLVHHS FDLVIFHQMS SNIMEQKDQQ FLNLCCKCFA KVAMDDYLKN VMLERACDQN NSIMVECLLL LGADANQAKE GSSLICQVCE KESSPKLVEL LLNSGSREQD VRKALTISIG KGDSQIISLL LRRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQS DDLDSEGSEG SFLVKKKSNS ISVGEFYRDA VLQRCSPNLQ RHSNSLGPIF DHEDLLKRKR KILSSDDSLR SSKLQSHMRH SDSISSLASE REYITSLDLS ANELRDIDAL SQKCCISVHL EHLEKLELHQ NALTSFPQQL CETLKSLTHL DLHSNKFTSF PSYLLKMSCI ANLDVSRNDI GPSVVLDPTV KCPTLKQFNL SYNQLSFVPE NLTDVVEKLE QLILEGNKIS GICSPLRLKE LKILNLSKNH ISSLSENFLE ACPKVESFSA RMNFLAAMPF LPPSMTILKL SQNKFSCIPE AILNLPHLRS LDMSSNDIQY LPGPAHWKSL NLRELLFSHN QISILDLSEK AYLWSRVEKL HLSHNKLKEI PPEIGCLENL TSLDVSYNLE LRSFPNEMGK LSKIWDLPLD ELHLNFDFKH IGCKAKDIIR FLQQRLKKAV PYNRMKLMIV GNTGSGKTTL LQQLMKTKKS DLGMQSATVG IDVKDWPIQI RDKRKRDLVL NVWDFAGREE FYSTHPHFMT QRALYLAVYD LSKGQAEVDA MKPWLFNIKA RASSSPVILV GTHLDVSDEK QRKACMSKIT KELLNKRGFP AIRDYHFVNA TEESDALAKL RKTIINESLN FKIRDQLVVG QLIPDCYVEL EKIILSERKN VPIEFPVIDR KRLLQLVREN QLQLDENELP HAVHFLNESG VLLHFQDPAL QLSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMSQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSEI IIRLYEMPYF PMGFWSRLIN RLLEISPYML SGRERALRPN RMYWRQGIYL NWSPEAYCLV GSEVLDNHPE SFLKITVPSC RKGCILLGQV VDHIDSLMEE WFPGLLEIDI CGEGETLLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLGDGSF GSVYRAAYEG EEVAVKIFNK HTSLRLLRQE LVVLCHLHHP SLISLLAAGI RPRMLVMELA SKGSLDRLLQ QDKASLTRTL QHRIALHVAD GLRYLHSAMI IYRDLKPHNV LLFTLYPNAA IIAKIADYGI AQYCCRMGIK TSEGTPGFRA PEVARGNVIY NQQADVYSFG LLLYDILTTG GRIVEGLKFP NEFDELEIQG KLPDPVKEYG CAPWPMVEKL IKQCLKENPQ ERPTSAQVFD ILNSAELVCL TRRILLPKNV IVECMVATHH NSRNASIWLG CGHTDRGQLS FLDLNTEGYT SEEVADSRIL CLALVHLPVE KESWIVSGTQ SGTLLVINTE DGKKRHTLEK MTDSVTCLYC NSFSKQSKQK NFLLVGTADG KLAIFEDKTV KLKGAAPLKI LNIGNVSTPL MCLSESTNST ERNVMWGGCG TKIFSFSNDF TIQKLIETRT SQLFSYAAFS DSNIITVVVD TALYIAKQNS PVVEVWDKKT EKLCGLIDCV HFLREVMVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEIQ SCLTVWDINL PHEVQNLEKH IEVRKELAEK MRRTSVE // ID PACRG_HUMAN Reviewed; 296 AA. AC Q96M98; E1P5B5; Q6IMB8; Q8IZM1; Q8NHP5; Q9H1V9; DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2005, sequence version 2. DT 28-JAN-2026, entry version 171. DE RecName: Full=Parkin coregulated gene protein; DE AltName: Full=Molecular chaperone/chaperonin-binding protein; DE AltName: Full=PARK2 coregulated gene protein; GN Name=PACRG; Synonyms=GLUP; 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 2). RX PubMed=12547187; DOI=10.1016/s0022-2836(02)01376-1; RA West A.B., Lockhart P.J., O'Farell C., Farrer M.J.; RT "Identification of a novel gene linked to parkin via a bi-directional RT promoter."; RL J. Mol. Biol. 326:11-19(2003). RN [2] 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 [3] 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 [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 2). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP IDENTIFICATION, FUNCTION, AND INTERACTION WITH STIP1; PRKN; GPR37; HSPA8; RP TCP1; CCT2; CCT3; CCT4; CCT5; CCT6A; CCT7 AND CCT8. 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 [7] {ECO:0007744|PDB:7UNG} RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=36191189; DOI=10.1073/pnas.2207605119; RA Gui M., Croft J.T., Zabeo D., Acharya V., Kollman J.M., Burgoyne T., RA Hoog J.L., Brown A.; RT "SPACA9 is a lumenal protein of human ciliary singlet and doublet RT microtubules."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207605119-e2207605119(2022). RN [8] RP TISSUE SPECIFICITY, POLYMORPHISM, AND INVOLVEMENT IN LPRS2. RX PubMed=14737177; DOI=10.1038/nature02326; RA Mira M.T., Alcais A., Nguyen V.T., Moraes M.O., Di Flumeri C., Vu H.T., RA Mai C.P., Nguyen T.H., Nguyen N.B., Pham X.K., Sarno E.N., Alter A., RA Montpetit A., Moraes M.E., Moraes J.R., Dore C., Gallant C.J., Lepage P., RA Verner A., Van De Vosse E., Hudson T.J., Abel L., Schurr E.; RT "Susceptibility to leprosy is associated with PARK2 and PACRG."; RL Nature 427:636-640(2004). CC -!- FUNCTION: Microtubule inner protein (MIP) part of the dynein-decorated CC doublet microtubules (DMTs) in cilia axoneme, which is required for CC motile cilia beating (PubMed:36191189). Suppresses cell death induced CC by accumulation of unfolded Pael receptor (Pael-R, a substrate of CC Parkin) (PubMed:14532270). Facilitates the formation of inclusions CC consisting of Pael-R, molecular chaperones, protein degradation CC molecules and itself when proteasome is inhibited (PubMed:14532270). CC May play an important role in the formation of Lewy bodies and CC protection of dopaminergic neurons against Parkinson disease CC (PubMed:14532270). {ECO:0000269|PubMed:14532270, CC ECO:0000269|PubMed:36191189}. CC -!- SUBUNIT: Microtubule inner protein component of sperm flagellar doublet CC microtubules (By similarity). Forms a large molecular chaperone complex CC containing heat shock proteins 70 and 90 and chaperonin components CC (PubMed:14532270). Interacts with STIP1, PRKN, GPR37, HSPA8, TCP1/CCT1, CC CCT2, CCT3, CCT4, CCT5, CCT6A, CCT7 and CCT8 (PubMed:14532270). CC Interacts with MEIG1 (By similarity). {ECO:0000250|UniProtKB:Q9DAK2, CC ECO:0000269|PubMed:14532270}. CC -!- INTERACTION: CC Q96M98; Q8N4N3: KLHL36; NbExp=2; IntAct=EBI-11927350, EBI-6426427; CC Q96M98-2; Q5JSS6: MEIG1; NbExp=5; IntAct=EBI-11945452, EBI-18583441; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, cilium axoneme CC {ECO:0000269|PubMed:36191189}. Cytoplasm, cytoskeleton, flagellum CC axoneme {ECO:0000250|UniProtKB:Q9DAK2}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96M98-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96M98-2; Sequence=VSP_010033; CC -!- TISSUE SPECIFICITY: Expressed in all immune tissues, spleen, lymph CC nodes, thymus, tonsils, leukocyte and bone marrow. Expressed also in CC heart, brain, skeletal muscle, kidney, lung and pancreas. Expressed in CC primary Schwann cells and very weakly by monocyte-derived macrophages CC the primary host cells of Mycobacterium leprae, the causative agent of CC leprosy. Component of Lewy bodies, intraneuronal inclusions found in CC the brain of Parkinson disease patients. {ECO:0000269|PubMed:14737177, CC ECO:0000269|PubMed:36191189}. CC -!- POLYMORPHISM: Involved in susceptibility to leprosy (LPRS2) CC [MIM:607572]. LPRS2 is associated with polymorphisms in the 5'- CC regulatory region shared by the PRKN gene. CC {ECO:0000269|PubMed:14737177}. CC -!- MISCELLANEOUS: Linked to PRKN in a head-to-head arrangement on opposite CC DNA strands and share a common 5'-flanking promoter region. CC -!- MISCELLANEOUS: [Isoform 2]: May be due to exon skipping. {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; AF546872; AAN37911.1; -; mRNA. DR EMBL; AK057286; BAB71410.1; -; mRNA. DR EMBL; AL031121; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL137182; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL354942; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001576; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL078585; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590286; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL603788; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47565.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47566.1; -; Genomic_DNA. DR EMBL; BC030642; AAH30642.1; -; mRNA. DR EMBL; BC044227; AAH44227.1; -; mRNA. DR EMBL; BK001670; DAA02134.1; -; mRNA. DR CCDS; CCDS43524.1; -. [Q96M98-2] DR CCDS; CCDS5284.1; -. [Q96M98-1] DR RefSeq; NP_001073847.1; NM_001080378.2. [Q96M98-2] DR RefSeq; NP_001073848.1; NM_001080379.2. [Q96M98-2] DR RefSeq; NP_689623.2; NM_152410.3. [Q96M98-1] DR RefSeq; XP_047274164.1; XM_047418208.1. [Q96M98-2] DR RefSeq; XP_054210265.1; XM_054354290.1. [Q96M98-2] DR PDB; 6NDU; X-ray; 2.10 A; A=70-296. DR PDB; 6NEP; X-ray; 2.10 A; A=70-296. DR PDB; 6UCC; X-ray; 2.60 A; A=1-296. DR PDB; 7UNG; EM; 3.60 A; YB/YC/YD/YE/YF/YG=1-296. DR PDB; 8J07; EM; 4.10 A; YB/YC/YD/YF/YG/YH/YI/YJ/YK/YL/YM=1-296. DR PDBsum; 6NDU; -. DR PDBsum; 6NEP; -. DR PDBsum; 6UCC; -. DR PDBsum; 7UNG; -. DR PDBsum; 8J07; -. DR AlphaFoldDB; Q96M98; -. DR EMDB; EMD-26624; -. DR EMDB; EMD-35888; -. DR SMR; Q96M98; -. DR BioGRID; 126421; 28. DR CORUM; Q96M98; -. DR FunCoup; Q96M98; 189. DR IntAct; Q96M98; 4. DR STRING; 9606.ENSP00000337946; -. DR iPTMnet; Q96M98; -. DR PhosphoSitePlus; Q96M98; -. DR BioMuta; PACRG; -. DR DMDM; 77416872; -. DR MassIVE; Q96M98; -. DR PaxDb; 9606-ENSP00000337946; -. DR PeptideAtlas; Q96M98; -. DR ProteomicsDB; 77323; -. [Q96M98-1] DR ProteomicsDB; 77324; -. [Q96M98-2] DR Antibodypedia; 20047; 153 antibodies from 26 providers. DR DNASU; 135138; -. DR Ensembl; ENST00000337019.7; ENSP00000337946.3; ENSG00000112530.13. [Q96M98-1] DR Ensembl; ENST00000366888.7; ENSP00000355854.2; ENSG00000112530.13. [Q96M98-2] DR Ensembl; ENST00000366889.6; ENSP00000355855.2; ENSG00000112530.13. [Q96M98-2] DR GeneID; 135138; -. DR KEGG; hsa:135138; -. DR MANE-Select; ENST00000366888.7; ENSP00000355854.2; NM_001080379.2; NP_001073848.1. [Q96M98-2] DR UCSC; uc003qua.4; human. [Q96M98-1] DR AGR; HGNC:19152; -. DR ClinPGx; PA134909011; -. DR CTD; 135138; -. DR DisGeNET; 135138; -. DR GeneCards; PACRG; -. DR HGNC; HGNC:19152; PACRG. DR HPA; ENSG00000112530; Tissue enhanced (fallopian tube, testis). DR MalaCards; PACRG; -. DR MIM; 607572; phenotype. DR MIM; 608427; gene. DR OpenTargets; ENSG00000112530; -. DR VEuPathDB; HostDB:ENSG00000112530; -. DR eggNOG; KOG3961; Eukaryota. DR GeneTree; ENSGT00940000157330; -. DR HOGENOM; CLU_073223_1_0_1; -. DR InParanoid; Q96M98; -. DR OMA; INGPIHE; -. DR OrthoDB; 9479932at2759; -. DR PAN-GO; Q96M98; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q96M98; -. DR PathwayCommons; Q96M98; -. DR SignaLink; Q96M98; -. DR SIGNOR; Q96M98; -. DR Agora; ENSG00000112530; -. DR BioGRID-ORCS; 135138; 7 hits in 1141 CRISPR screens. DR ChiTaRS; PACRG; human. DR GeneWiki; PACRG; -. DR GenomeRNAi; 135138; -. DR Pharos; Q96M98; Tbio. DR PRO; PR:Q96M98; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q96M98; protein. DR Bgee; ENSG00000112530; Expressed in bronchial epithelial cell and 124 other cell types or tissues. DR ExpressionAtlas; Q96M98; baseline and differential. DR GO; GO:0160112; C:axonemal B tubule inner sheath; IEA:Ensembl. DR GO; GO:0005879; C:axonemal microtubule; IDA:UniProtKB. DR GO; GO:0044297; C:cell body; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0097386; C:glial cell projection; IEA:Ensembl. DR GO; GO:0002177; C:manchette; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0031982; C:vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0003779; F:actin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0048487; F:beta-tubulin binding; IDA: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:0030544; F:Hsp70 protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051879; F:Hsp90 protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL. DR GO; GO:0030317; P:flagellated sperm motility; IEA:Ensembl. DR GO; GO:0008104; P:intracellular protein localization; IEA:Ensembl. DR GO; GO:0007286; P:spermatid development; IEA:Ensembl. DR InterPro; IPR019399; Parkin_co-regulated_protein. DR PANTHER; PTHR21207:SF2; PARKIN COREGULATED GENE PROTEIN; 1. DR PANTHER; PTHR21207; PARKIN COREGULATED GENE PROTEIN PARK2 COREGULATED; 1. DR Pfam; PF10274; ParcG; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell projection; Cilium; Cytoplasm; KW Cytoskeleton; Flagellum; Proteomics identification; Reference proteome. FT CHAIN 1..296 FT /note="Parkin coregulated gene protein" FT /id="PRO_0000058169" FT VAR_SEQ 205..243 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12547187, FT ECO:0000303|PubMed:15489334" FT /id="VSP_010033" FT CONFLICT 93 FT /note="K -> R (in Ref. 2; BAB71410)" FT /evidence="ECO:0000305" FT CONFLICT 185 FT /note="A -> T (in Ref. 5; AAH30642)" FT /evidence="ECO:0000305" FT HELIX 70..77 FT /evidence="ECO:0007829|PDB:6NEP" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:6UCC" FT STRAND 96..98 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 100..102 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 105..114 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 115..117 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 123..138 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 139..141 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 143..145 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 146..157 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 162..178 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 182..186 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 187..189 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 190..193 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 197..200 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 260..274 FT /evidence="ECO:0007829|PDB:6NEP" FT HELIX 279..286 FT /evidence="ECO:0007829|PDB:6NEP" SQ SEQUENCE 296 AA; 33342 MW; 4A415741D430C7FB CRC64; MVAEKETLSL NKCPDKMPKR TKLLAQQPLP VHQPHSLVSE GFTVKAMMKN SVVRGPPAAG AFKERPTKPT AFRKFYERGD FPIALEHDSK GNKIAWKVEI EKLDYHHYLP LFFDGLCEMT FPYEFFARQG IHDMLEHGGN KILPVLPQLI IPIKNALNLR NRQVICVTLK VLQHLVVSAE MVGKALVPYY RQILPVLNIF KNMNGSYSLP RLECSGAIMA RCNLDHLGSS DPPTSASQVA EIIVNSGDGI DYSQQKRENI GDLIQETLEA FERYGGENAF INIKYVVPTY ESCLLN // 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 PTPA_HUMAN Reviewed; 358 AA. AC Q15257; A2A347; A9IZU4; B4DXM4; Q15258; Q53GZ3; Q5TZQ2; Q9BUK1; Q9NNZ7; AC Q9NNZ8; Q9NNZ9; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 3. DT 28-JAN-2026, entry version 211. DE RecName: Full=Serine/threonine-protein phosphatase 2A activator; DE EC=5.2.1.8 {ECO:0000250|UniProtKB:Q28717}; DE AltName: Full=PP2A, subunit B', PR53 isoform; DE AltName: Full=Phosphotyrosyl phosphatase activator; DE Short=PTPA; DE AltName: Full=Serine/threonine-protein phosphatase 2A regulatory subunit 4; DE AltName: Full=Serine/threonine-protein phosphatase 2A regulatory subunit B'; GN Name=PTPA {ECO:0000312|HGNC:HGNC:9308}; Synonyms=PPP2R4; 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 PARTIAL PROTEIN SEQUENCE. RC TISSUE=Heart; RX PubMed=8195217; DOI=10.1016/s0021-9258(17)40733-2; RA Cayla X., Van Hoof C., Bosch M., Waelkens E., Peeters B., Merlevede W., RA Goris J.; RT "Molecular cloning, expression, and characterization of PTPA, a protein RT that activates the tyrosyl phosphatase activity of protein phosphatase RT 2A."; RL J. Biol. Chem. 269:15668-15675(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RC TISSUE=Blood; RX PubMed=8530035; DOI=10.1006/geno.1995.1140; RA Van Hoof C., Aly M., Garcia A., Cayla X., Cassiman J.-J., Merlevede W., RA Goris J.; RT "Structure and chromosomal localization of the human gene of the RT phosphotyrosyl phosphatase activator (PTPA) of protein phosphatase 2A."; RL Genomics 28:261-272(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2; 3 AND 4). RX PubMed=10880964; DOI=10.1046/j.1432-1327.2000.01486.x; RA Janssens V., van Hoof C., Martens E., de Baere I., Merlevede W., Goris J.; RT "Identification and characterization of alternative splice products encoded RT by the human phosphotyrosyl phosphatase activator gene."; RL Eur. J. Biochem. 267:4406-4413(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT LEU-357. RC TISSUE=Liver; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 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 [10] RP FUNCTION IN APOPTOSIS, AND SUBCELLULAR LOCATION. RX PubMed=17333320; DOI=10.1007/s10495-006-0050-8; RA Azam S., Drobetsky E., Ramotar D.; RT "Overexpression of the cis/trans isomerase PTPA triggers caspase 3- RT dependent apoptosis."; RL Apoptosis 12:1243-1255(2007). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [14] {ECO:0007744|PDB:2G62} RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 22-358. RX PubMed=16782712; DOI=10.1074/jbc.c600100200; RA Magnusdottir A., Stenmark P., Flodin S., Nyman T., Hammarstroem M., Ehn M., RA Bakali H.M.A., Berglund H., Nordlund P.; RT "The crystal structure of a human PP2A phosphatase activator reveals a RT novel fold and highly conserved cleft implicated in protein-protein RT interactions."; RL J. Biol. Chem. 281:22434-22438(2006). RN [15] {ECO:0007744|PDB:2IXM} RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 20-357. RX PubMed=16885030; DOI=10.1016/j.molcel.2006.07.008; RA Leulliot N., Vicentini G., Jordens J., Quevillon-Cheruel S., Schiltz M., RA Barford D., van Tilbeurgh H., Goris J.; RT "Crystal structure of the PP2A phosphatase activator: implications for its RT PP2A-specific PPIase activity."; RL Mol. Cell 23:413-424(2006). RN [16] {ECO:0007744|PDB:2HV6, ECO:0007744|PDB:2HV7} RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH ATP AND MG(2+), RP FUNCTION IN MODULATION OF PP2A SUBSTRATE SPECIFICITY, ATP-BINDING, RP MUTAGENESIS OF ASP-185; ALA-239; GLY-240; VAL-244; GLU-305; VAL-316; RP GLY-325; MET-329 AND LYS-337, AND INTERACTION WITH THE PP2A(D) COMPLEX. RX PubMed=16916641; DOI=10.1016/j.molcel.2006.07.027; RA Chao Y., Xing Y., Chen Y., Xu Y., Lin Z., Li Z., Jeffrey P.D., Stock J.B., RA Shi Y.; RT "Structure and mechanism of the phosphotyrosyl phosphatase activator."; RL Mol. Cell 23:535-546(2006). RN [17] {ECO:0007744|PDB:4NY3} RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 22-358 IN COMPLEX WITH PPP2CA RP 304-309, AND INTERACTION WITH PPP2CA. RX PubMed=25003389; DOI=10.1515/hsz-2014-0106; RA Low C., Quistgaard E.M., Kovermann M., Anandapadamanaban M., Balbach J., RA Nordlund P.; RT "Structural basis for PTPA interaction with the invariant C-terminal tail RT of PP2A."; RL Biol. Chem. 395:881-889(2014). RN [18] RP INVOLVEMENT IN PARK25, VARIANTS PARK25 ASP-171 AND ARG-298, AND FUNCTION. RX PubMed=36073231; DOI=10.1093/brain/awac326; RG French and Mediterranean Parkinson disease Genetics Study Group; RG International Parkinsonism Genetics Network; RA Fevga C., Tesson C., Carreras Mascaro A., Courtin T., van Coller R., RA Sakka S., Ferraro F., Farhat N., Bardien S., Damak M., Carr J., Ferrien M., RA Boumeester V., Hundscheid J., Grillenzoni N., Kessissoglou I.A., RA Kuipers D.J.S., Quadri M., Corvol J.C., Mhiri C., Hassan B.A., RA Breedveld G.J., Lesage S., Mandemakers W., Brice A., Bonifati V.; RT "PTPA variants and impaired PP2A activity in early-onset parkinsonism with RT intellectual disability."; RL Brain 146:1496-1510(2023). CC -!- FUNCTION: PPIases accelerate the folding of proteins. It catalyzes the CC cis-trans isomerization of proline imidic peptide bonds in CC oligopeptides (By similarity). Acts as a regulatory subunit for CC serine/threonine-protein phosphatase 2A (PP2A) (PubMed:16916641, CC PubMed:36073231). Modulates PP2A activity or substrate specificity, CC probably by inducing a conformational change in the catalytic subunit, CC a proposed direct target of the PPIase (PubMed:16916641). Can CC reactivate inactive phosphatase PP2A-phosphatase methylesterase CC complexes (PP2A(i)) in presence of ATP and Mg(2+) (By similarity). CC Reversibly stimulates the variable phosphotyrosyl phosphatase activity CC of PP2A core heterodimer PP2A(D) in presence of ATP and Mg(2+) (in CC vitro) (PubMed:16916641). The phosphotyrosyl phosphatase activity is CC dependent of an ATPase activity of the PP2A(D):PPP2R4 complex CC (PubMed:16916641). Is involved in apoptosis; the function appears to be CC independent from PP2A (PubMed:17333320). {ECO:0000250|UniProtKB:Q28717, CC ECO:0000269|PubMed:16916641, ECO:0000269|PubMed:17333320, CC ECO:0000269|PubMed:36073231}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[protein]-peptidylproline (omega=180) = [protein]- CC peptidylproline (omega=0); Xref=Rhea:RHEA:16237, Rhea:RHEA- CC COMP:10747, Rhea:RHEA-COMP:10748, ChEBI:CHEBI:83833, CC ChEBI:CHEBI:83834; EC=5.2.1.8; CC Evidence={ECO:0000250|UniProtKB:Q28717}; CC -!- SUBUNIT: Associates with PP2A heterodimeric core enzyme PP2A(D), CC composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa CC constant regulatory subunit (PR65 or subunit A) (PubMed:16916641). CC Interacts with the catalytic subunit PPP2CA (via C-terminus) CC (PubMed:25003389). Interacts with PPP2CB (By similarity). CC {ECO:0000250|UniProtKB:P58389, ECO:0000269|PubMed:16916641, CC ECO:0000269|PubMed:25003389}. CC -!- INTERACTION: CC Q15257; Q4VCS5-2: AMOT; NbExp=3; IntAct=EBI-1774121, EBI-3891843; CC Q15257; P60510: PPP4C; NbExp=3; IntAct=EBI-1774121, EBI-1046072; CC Q15257; Q9NY27: PPP4R2; NbExp=2; IntAct=EBI-1774121, EBI-1048740; CC Q15257-2; Q5JTZ9: AARS2; NbExp=3; IntAct=EBI-12164121, EBI-308736; CC Q15257-2; A2BDD9: AMOT; NbExp=3; IntAct=EBI-12164121, EBI-17286414; CC Q15257-2; Q86Z20: CCDC125; NbExp=3; IntAct=EBI-12164121, EBI-11977221; CC Q15257-2; Q9GZT8: NIF3L1; NbExp=3; IntAct=EBI-12164121, EBI-740897; CC Q15257-2; P30153: PPP2R1A; NbExp=3; IntAct=EBI-12164121, EBI-302388; CC Q15257-2; Q9NZD8: SPG21; NbExp=5; IntAct=EBI-12164121, EBI-742688; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17333320}. Nucleus CC {ECO:0000269|PubMed:17333320}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=2; Synonyms=Beta; CC IsoId=Q15257-1; Sequence=Displayed; CC Name=1; Synonyms=Alpha; CC IsoId=Q15257-2; Sequence=VSP_005123; CC Name=3; Synonyms=Delta; CC IsoId=Q15257-3; Sequence=VSP_005122; CC Name=4; Synonyms=Epsilon; CC IsoId=Q15257-4; Sequence=VSP_005124; CC -!- TISSUE SPECIFICITY: Widely expressed. CC -!- DISEASE: Parkinson disease 25, autosomal recessive early-onset, with CC impaired intellectual development (PARK25) [MIM:620482]: An autosomal CC recessive, early-onset form of Parkinson disease, a complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. PARK25 is characterized by onset of parkinsonism in late CC childhood or adolescence, developmental delay and intellectual CC disability. Cognitive impairment is mild to moderate and non- CC progressive. {ECO:0000269|PubMed:36073231}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the PTPA-type PPIase family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41817/PPP2R4"; 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; X73478; CAA51873.1; -; mRNA. DR EMBL; X86428; CAA60163.1; -; Genomic_DNA. DR EMBL; X86429; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77601.1; -; Genomic_DNA. DR EMBL; X86429; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86431; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77602.1; -; Genomic_DNA. DR EMBL; X86429; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77603.1; -; Genomic_DNA. DR EMBL; X86429; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; AK302043; BAG63436.1; -; mRNA. DR EMBL; BT020119; AAV38922.1; -; mRNA. DR EMBL; AK222788; BAD96508.1; -; mRNA. DR EMBL; AL158151; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471090; EAW87876.1; -; Genomic_DNA. DR EMBL; CH471090; EAW87882.1; -; Genomic_DNA. DR EMBL; BC002545; AAH02545.1; -; mRNA. DR EMBL; BC011605; AAH11605.1; -; mRNA. DR CCDS; CCDS65156.1; -. [Q15257-3] DR CCDS; CCDS6920.1; -. [Q15257-2] DR PIR; A54021; A54021. DR RefSeq; NP_001180326.1; NM_001193397.1. DR RefSeq; NP_001258761.1; NM_001271832.2. [Q15257-3] DR RefSeq; NP_066954.2; NM_021131.4. [Q15257-2] DR RefSeq; NP_821067.1; NM_178000.3. [Q15257-2] DR RefSeq; NP_821068.1; NM_178001.3. [Q15257-1] DR RefSeq; NP_821070.1; NM_178003.3. [Q15257-4] DR PDB; 2G62; X-ray; 1.60 A; A=22-358. DR PDB; 2HV6; X-ray; 1.90 A; A/B=1-358. DR PDB; 2HV7; X-ray; 2.50 A; A/B/C/D/E/F/G/H=1-358. DR PDB; 2IXM; X-ray; 1.50 A; A=20-357. DR PDB; 4LAC; X-ray; 2.82 A; B=19-358. DR PDB; 4NY3; X-ray; 1.80 A; A/B=22-358. DR PDBsum; 2G62; -. DR PDBsum; 2HV6; -. DR PDBsum; 2HV7; -. DR PDBsum; 2IXM; -. DR PDBsum; 4LAC; -. DR PDBsum; 4NY3; -. DR AlphaFoldDB; Q15257; -. DR SMR; Q15257; -. DR BioGRID; 111516; 114. DR FunCoup; Q15257; 1883. DR IntAct; Q15257; 28. DR MINT; Q15257; -. DR STRING; 9606.ENSP00000377036; -. DR BindingDB; Q15257; -. DR ChEMBL; CHEMBL2505; -. DR GlyCosmos; Q15257; 1 site, 1 glycan. DR GlyGen; Q15257; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q15257; -. DR MetOSite; Q15257; -. DR PhosphoSitePlus; Q15257; -. DR SwissPalm; Q15257; -. DR BioMuta; PTPA; -. DR DMDM; 116242737; -. DR OGP; Q15257; -. DR CPTAC; CPTAC-259; -. DR CPTAC; CPTAC-260; -. DR jPOST; Q15257; -. DR MassIVE; Q15257; -. DR PaxDb; 9606-ENSP00000377036; -. DR PeptideAtlas; Q15257; -. DR ProteomicsDB; 60499; -. [Q15257-1] DR ProteomicsDB; 60500; -. [Q15257-2] DR ProteomicsDB; 60501; -. [Q15257-3] DR ProteomicsDB; 60502; -. [Q15257-4] DR Pumba; Q15257; -. DR Antibodypedia; 1074; 372 antibodies from 39 providers. DR CPTC; Q15257; 4 antibodies. DR DNASU; 5524; -. DR Ensembl; ENST00000337738.6; ENSP00000337448.1; ENSG00000119383.22. [Q15257-1] DR Ensembl; ENST00000355007.7; ENSP00000347109.3; ENSG00000119383.22. [Q15257-4] DR Ensembl; ENST00000357197.8; ENSP00000349726.4; ENSG00000119383.22. [Q15257-3] DR Ensembl; ENST00000393370.7; ENSP00000377036.2; ENSG00000119383.22. [Q15257-2] DR GeneID; 5524; -. DR KEGG; hsa:5524; -. DR MANE-Select; ENST00000393370.7; ENSP00000377036.2; NM_178000.3; NP_821067.1. [Q15257-2] DR UCSC; uc004bxl.3; human. [Q15257-1] DR AGR; HGNC:9308; -. DR ClinPGx; PA33671; -. DR CTD; 5524; -. DR DisGeNET; 5524; -. DR GeneCards; PTPA; -. DR HGNC; HGNC:9308; PTPA. DR HPA; ENSG00000119383; Low tissue specificity. DR MalaCards; PTPA; -. DR MIM; 600756; gene. DR MIM; 620482; phenotype. DR OpenTargets; ENSG00000119383; -. DR VEuPathDB; HostDB:ENSG00000119383; -. DR eggNOG; KOG2867; Eukaryota. DR GeneTree; ENSGT00390000011500; -. DR InParanoid; Q15257; -. DR OMA; SWIKINA; -. DR OrthoDB; 16120at2759; -. DR PAN-GO; Q15257; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q15257; -. DR PathwayCommons; Q15257; -. DR SignaLink; Q15257; -. DR SIGNOR; Q15257; -. DR Agora; ENSG00000119383; -. DR BioGRID-ORCS; 5524; 570 hits in 1181 CRISPR screens. DR ChiTaRS; PTPA; human. DR EvolutionaryTrace; Q15257; -. DR GeneWiki; PPP2R4; -. DR GenomeRNAi; 5524; -. DR Pharos; Q15257; Tchem. DR PRO; PR:Q15257; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; Q15257; protein. DR Bgee; ENSG00000119383; Expressed in endometrium epithelium and 210 other cell types or tissues. DR ExpressionAtlas; Q15257; baseline and differential. DR GO; GO:1904949; C:ATPase complex; IDA:HGNC-UCL. DR GO; GO:0034704; C:calcium channel complex; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000159; C:protein phosphatase type 2A complex; IDA:HGNC-UCL. DR GO; GO:0005524; F:ATP binding; IDA:HGNC-UCL. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; IBA:GO_Central. DR GO; GO:0019902; F:phosphatase binding; IDA:HGNC-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IDA:HGNC-UCL. DR GO; GO:0051721; F:protein phosphatase 2A binding; IDA:HGNC-UCL. DR GO; GO:0019888; F:protein phosphatase regulator activity; IDA:HGNC-UCL. DR GO; GO:0008160; F:protein tyrosine phosphatase activator activity; IDA:HGNC-UCL. DR GO; GO:0005102; F:signaling receptor binding; IPI:BHF-UCL. DR GO; GO:0007052; P:mitotic spindle organization; IBA:GO_Central. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR CDD; cd04087; PTPA; 1. DR FunFam; 1.20.120.1150:FF:000001; Serine/threonine-protein phosphatase 2A activator; 1. DR Gene3D; 1.20.120.1150; -; 1. DR InterPro; IPR004327; Phstyr_phstse_ac. DR InterPro; IPR043170; PTPA_C_lid. DR InterPro; IPR037218; PTPA_sf. DR PANTHER; PTHR10012; SERINE/THREONINE-PROTEIN PHOSPHATASE 2A REGULATORY SUBUNIT B; 1. DR PANTHER; PTHR10012:SF0; SERINE_THREONINE-PROTEIN PHOSPHATASE 2A ACTIVATOR; 1. DR Pfam; PF03095; PTPA; 1. DR PIRSF; PIRSF016325; Phstyr_phstse_ac; 1. DR SUPFAM; SSF140984; PTPA-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cytoplasm; KW Direct protein sequencing; Disease variant; Intellectual disability; KW Isomerase; Magnesium; Metal-binding; Neurodegeneration; Nucleotide-binding; KW Nucleus; Parkinson disease; Parkinsonism; Proteomics identification; KW Reference proteome; Rotamase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..358 FT /note="Serine/threonine-protein phosphatase 2A activator" FT /id="PRO_0000071524" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 183 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 188 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 189 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 243 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV6" FT BINDING 249 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV6" FT BINDING 339 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 342 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 343 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:19413330" FT VAR_SEQ 45..108 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_005122" FT VAR_SEQ 73..149 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_005124" FT VAR_SEQ 73..107 FT /note="Missing (in isoform 1)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:8195217, ECO:0000303|Ref.5, FT ECO:0000303|Ref.6" FT /id="VSP_005123" FT VARIANT 28 FT /note="K -> R (in dbSNP:rs17481693)" FT /id="VAR_028101" FT VARIANT 171 FT /note="A -> D (in PARK25; likely pathogenic; decreases PP2A FT complex levels; impairs PP2A phosphatase activation)" FT /evidence="ECO:0000269|PubMed:36073231" FT /id="VAR_089150" FT VARIANT 208 FT /note="R -> Q (in dbSNP:rs4836639)" FT /id="VAR_028102" FT VARIANT 298 FT /note="M -> R (in PARK25; likely pathogenic; decreases PP2A FT complex levels; impairs PP2A phosphatase activation)" FT /evidence="ECO:0000269|PubMed:36073231" FT /id="VAR_089151" FT VARIANT 357 FT /note="S -> L (in dbSNP:rs2480452)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_028103" FT MUTAGEN 185 FT /note="D->A: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 239 FT /note="A->D: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 240 FT /note="G->D: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 244 FT /note="V->D: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 305 FT /note="E->A: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 316 FT /note="V->D: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 325 FT /note="G->D: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 329 FT /note="M->D: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 337 FT /note="K->G: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT CONFLICT 113 FT /note="V -> L (in Ref. 1; CAA51873, 2; CAA60163 and 3; FT CAB77601/CAB77602)" FT /evidence="ECO:0000305" FT CONFLICT 297 FT /note="Missing (in Ref. 2; CAA60163 and 3; CAB77601/ FT CAB77602/CAB77603)" FT /evidence="ECO:0000305" FT CONFLICT 357 FT /note="S -> V (in Ref. 1; AA sequence)" FT /evidence="ECO:0000305" FT HELIX 34..40 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 43..58 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 59..61 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 108..124 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 139..156 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 161..166 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 167..175 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 181..184 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 188..203 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 209..211 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 212..217 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 219..233 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 237..240 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 243..245 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 247..250 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 253..261 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 262..264 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 270..274 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 276..282 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 283..285 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 287..298 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 303..306 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 308..313 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 319..333 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 334..336 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 348..350 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:2IXM" SQ SEQUENCE 358 AA; 40668 MW; 2A962521AF5B4CF7 CRC64; MAEGERQPPP DSSEEAPPAT QNFIIPKKEI HTVPDMGKWK RSQAYADYIG FILTLNEGVK GKKLTFEYRV SEMWNEVHEE KEQAAKQSVS CDECIPLPRA GHCAPSEAIE KLVALLNTLD RWIDETPPVD QPSRFGNKAY RTWYAKLDEE AENLVATVVP THLAAAVPEV AVYLKESVGN STRIDYGTGH EAAFAAFLCC LCKIGVLRVD DQIAIVFKVF NRYLEVMRKL QKTYRMEPAG SQGVWGLDDF QFLPFIWGSS QLIDHPYLEP RHFVDEKAVN ENHKDYMFLE CILFITEMKT GPFAEHSNQL WNISAVPSWS KVNQGLIRMY KAECLEKFPV IQHFKFGSLL PIHPVTSG // ID RAB32_HUMAN Reviewed; 225 AA. AC Q13637; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=Ras-related protein Rab-32; DE EC=3.6.5.2 {ECO:0000269|PubMed:11784320, ECO:0000269|PubMed:21808068}; GN Name=RAB32 {ECO:0000312|HGNC:HGNC:9772}; 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]. RA Burke S., Seabra M.C.; RT "Cloning of novel Rab proteins with the yeast two-hybrid system."; RL Submitted (OCT-1996) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 16-225, TISSUE SPECIFICITY, MUTAGENESIS OF RP GLN-85, FUNCTION, AND CATALYTIC ACTIVITY. RC TISSUE=Platelet; RX PubMed=11784320; DOI=10.1046/j.0014-2956.2001.02645.x; RA Bao X., Faris A.E., Jang E.K., Haslam R.J.; RT "Molecular cloning, bacterial expression and properties of Rab31 and RT Rab32."; RL Eur. J. Biochem. 269:259-271(2002). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP PROTEIN SEQUENCE OF 2-22; 28-38; 66-72; 77-87; 111-119; 128-144; 164-186 RP AND 211-217, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Platelet; RA Bienvenut W.V., Claeys D.; RL Submitted (NOV-2005) to UniProtKB. RN [8] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF RP THR-39; ALA-185 AND LEU-188. RX PubMed=12186851; DOI=10.1083/jcb.200204081; RA Alto N.M., Soderling J., Scott J.D.; RT "Rab32 is an A-kinase anchoring protein and participates in mitochondrial RT dynamics."; RL J. Cell Biol. 158:659-668(2002). RN [9] 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 [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP INTERACTION WITH ANKRD27, FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY RP REGULATION. RX PubMed=21808068; DOI=10.1074/jbc.m111.261115; RA Nottingham R.M., Ganley I.G., Barr F.A., Lambright D.G., Pfeffer S.R.; RT "RUTBC1 protein, a Rab9A effector that activates GTP hydrolysis by Rab32 RT and Rab33B proteins."; RL J. Biol. Chem. 286:33213-33222(2011). RN [13] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=21255211; DOI=10.1111/j.1600-0854.2011.01165.x; RA Seto S., Tsujimura K., Koide Y.; RT "Rab GTPases regulating phagosome maturation are differentially recruited RT to mycobacterial phagosomes."; RL Traffic 12:407-420(2011). RN [14] RP FUNCTION, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION. RX PubMed=23084991; DOI=10.1016/j.cub.2012.09.020; RA Gerondopoulos A., Langemeyer L., Liang J.R., Linford A., Barr F.A.; RT "BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine RT nucleotide exchange factor."; RL Curr. Biol. 22:2135-2139(2012). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71, 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 [18] RP ACETYLATION AT ALA-2, AND CLEAVAGE OF INITIATOR METHIONINE. RX PubMed=25489052; DOI=10.1093/hmg/ddu611; RA Myklebust L.M., Van Damme P., Stoeve S.I., Doerfel M.J., Abboud A., RA Kalvik T.V., Grauffel C., Jonckheere V., Wu Y., Swensen J., Kaasa H., RA Liszczak G., Marmorstein R., Reuter N., Lyon G.J., Gevaert K., Arnesen T.; RT "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt- RT acetylation defects."; RL Hum. Mol. Genet. 24:1956-1976(2015). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [20] RP FUNCTION, AND INTERACTION WITH LRRK2. RX PubMed=38127736; DOI=10.1126/science.adi9926; RA Zhu H., Tonelli F., Turk M., Prescott A., Alessi D.R., Sun J.; RT "Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2."; RL Science 382:1404-1411(2023). RN [21] {ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2} RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-225 IN COMPLEX WITH MG(2+); GTP RP ANALOG AND ANKRD27, MUTAGENESIS OF GLY-89; ASN-90; MET-91; ARG-93 AND RP VAL-94, COFACTOR, AND DOMAIN. RX PubMed=24856514; DOI=10.1016/j.devcel.2014.04.010; RA Hesketh G.G., Perez-Dorado I., Jackson L.P., Wartosch L., Schafer I.B., RA Gray S.R., McCoy A.J., Zeldin O.B., Garman E.F., Harbour M.E., Evans P.R., RA Seaman M.N., Luzio J.P., Owen D.J.; RT "VARP is recruited on to endosomes by direct interaction with retromer, RT where together they function in export to the cell surface."; RL Dev. Cell 29:591-606(2014). RN [22] RP VARIANT ARG-71, AND INVOLVEMENT IN PARK26. RX PubMed=38614108; DOI=10.1016/s1474-4422(24)00121-2; RG Global Parkinson's Genetics Program (GP2); RA Gustavsson E.K., Follett J., Trinh J., Barodia S.K., Real R., Liu Z., RA Grant-Peters M., Fox J.D., Appel-Cresswell S., Stoessl A.J., Rajput A., RA Rajput A.H., Auer R., Tilney R., Sturm M., Haack T.B., Lesage S., RA Tesson C., Brice A., Vilarino-Gueell C., Ryten M., Goldberg M.S., RA West A.B., Hu M.T., Morris H.R., Sharma M., Gan-Or Z., Samanci B., Lis P., RA Perinan M.T., Amouri R., Ben Sassi S., Hentati F., Tonelli F., Alessi D.R., RA Farrer M.J.; RT "RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, RT association, and functional analyses."; RL Lancet Neurol. 23:603-614(2024). RN [23] RP VARIANT ARG-71, INVOLVEMENT IN PARK26, INTERACTION WITH LRRK2, AND RP CHARACTERIZATION OF VARIANT ARG-71. RX PubMed=38858457; DOI=10.1038/s41588-024-01787-7; RG Project MinE ALS Sequencing Consortium; RA Hop P.J., Lai D., Keagle P.J., Baron D.M., Kenna B.J., Kooyman M., RA Halter C., Straniero L., Asselta R., Bonvegna S., Soto-Beasley A.I., RA Wszolek Z.K., Uitti R.J., Isaias I.U., Pezzoli G., Ticozzi N., Ross O.A., RA Veldink J.H., Foroud T.M., Kenna K.P., Landers J.E.; RT "Systematic rare variant analyses identify RAB32 as a susceptibility gene RT for familial Parkinson's disease."; RL Nat. Genet. 56:1371-1376(2024). CC -!- FUNCTION: The small GTPases Rab are key regulators of intracellular CC membrane trafficking, from the formation of transport vesicles to their CC fusion with membranes (PubMed:11784320, PubMed:21808068). Rabs cycle CC between an inactive GDP-bound form and an active GTP-bound form that is CC able to recruit to membranes different set of downstream effectors CC directly responsible for vesicle formation, movement, tethering and CC fusion (PubMed:11784320). Also acts as an A-kinase anchoring protein by CC binding to the type II regulatory subunit of protein kinase A and CC anchoring it to the mitochondrion. Also involved in synchronization of CC mitochondrial fission (PubMed:12186851). Plays a role in the maturation CC of phagosomes that engulf pathogens, such as S.aureus and CC M.tuberculosis (PubMed:21255211). Plays an important role in the CC control of melanin production and melanosome biogenesis CC (PubMed:23084991). In concert with RAB38, regulates the proper CC trafficking of melanogenic enzymes TYR, TYRP1 and DCT/TYRP2 to CC melanosomes in melanocytes (By similarity). Stimulates phosphorylation CC of RAB10 'Thr-73' by LRRK2 (PubMed:38127736). CC {ECO:0000250|UniProtKB:Q9CZE3, ECO:0000269|PubMed:11784320, CC ECO:0000269|PubMed:12186851, ECO:0000269|PubMed:21255211, CC ECO:0000269|PubMed:21808068, ECO:0000269|PubMed:23084991, CC ECO:0000269|PubMed:38127736}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.2; CC Evidence={ECO:0000269|PubMed:11784320, ECO:0000269|PubMed:21808068}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670; CC Evidence={ECO:0000305|PubMed:11784320, ECO:0000305|PubMed:21808068}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:24856514}; CC -!- ACTIVITY REGULATION: Regulated by guanine the nucleotide exchange CC factor (GEF) BLOC-3 complex composed of HPS1 and HPS4 which promote the CC exchange of bound GDP for free GTP (PubMed:23084991). Regulated by the CC GTPase activating protein (GAP) SGSM2/RUTBC1 which increases the GTP CC hydrolysis activity (PubMed:21808068). Inhibited by GDP dissociation CC inhibitors (GDIs) which prevent Rab-GDP dissociation (Probable). CC {ECO:0000269|PubMed:21808068, ECO:0000269|PubMed:23084991, CC ECO:0000305}. CC -!- SUBUNIT: Interacts with ANKRD27 (PubMed:21269460, PubMed:24856514). A CC decreased interaction with ANKRD27 seen in the presence of SGSM2 CC (PubMed:21269460). Interacts with LRRK2 (via N-terminus); this CC interaction results in stimulation of RAB10 phosphorylation by LRRK2 CC (PubMed:38127736, PubMed:38858457). {ECO:0000269|PubMed:24856514, CC ECO:0000269|PubMed:38127736, ECO:0000269|PubMed:38858457}. CC -!- INTERACTION: CC Q13637; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-9837586, EBI-742054; CC Q13637; A0A087WWI0: LRMDA; NbExp=3; IntAct=EBI-9837586, EBI-18393842; CC Q13637; Q5S007: LRRK2; NbExp=12; IntAct=EBI-9837586, EBI-5323863; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:12186851}. CC Mitochondrion outer membrane {ECO:0000269|PubMed:23084991, CC ECO:0000305|PubMed:12186851}; Lipid-anchor CC {ECO:0000305|PubMed:12186851}. Cytoplasmic vesicle, phagosome CC {ECO:0000269|PubMed:21255211}. Cytoplasmic vesicle, phagosome membrane CC {ECO:0000305}; Lipid-anchor {ECO:0000305}; Cytoplasmic side CC {ECO:0000305}. Melanosome {ECO:0000250|UniProtKB:Q9CZE3}. Melanosome CC membrane {ECO:0000269|PubMed:23084991}. Note=Recruited to phagosomes CC containing S.aureus or M.tuberculosis (PubMed:21255211). The BLOC-3 CC complex, a heterodimer of HPS1 and HPS4 promotes its membrane CC localization (PubMed:23084991). {ECO:0000269|PubMed:21255211, CC ECO:0000269|PubMed:23084991}. CC -!- TISSUE SPECIFICITY: Widely expressed with high levels in heart, liver, CC kidney, bone marrow, testis, colon and fetal lung. CC {ECO:0000269|PubMed:11784320, ECO:0000269|PubMed:12186851}. CC -!- DOMAIN: Switch I, switch II and the interswitch regions are CC characteristic of Rab GTPases and mediate the interactions with Rab CC downstream effectors. The switch regions undergo conformational changes CC upon nucleotide binding which drive interaction with specific sets of CC effector proteins, with most effectors only binding to GTP-bound Rab. CC {ECO:0000269|PubMed:24856514}. CC -!- DISEASE: Parkinson disease 26, autosomal dominant (PARK26) CC [MIM:620923]: An autosomal dominant form of Parkinson disease, a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. PARK26 shows incomplete penetrance. CC {ECO:0000269|PubMed:38614108, ECO:0000269|PubMed:38858457}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U71127; AAB09599.1; -; mRNA. DR EMBL; AF498958; AAM21106.1; -; mRNA. DR EMBL; BT020016; AAV38819.1; -; mRNA. DR EMBL; AL133539; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC015061; AAH15061.1; -; mRNA. DR EMBL; U59878; AAB02833.1; -; mRNA. DR CCDS; CCDS5210.1; -. DR RefSeq; NP_006825.1; NM_006834.5. DR PDB; 4CYM; X-ray; 2.80 A; A/B/C=1-225. DR PDB; 4CZ2; X-ray; 2.97 A; A/B/C=1-225. DR PDB; 5OEC; X-ray; 2.30 A; B=20-201. DR PDB; 5OED; X-ray; 2.90 A; B=20-201. DR PDB; 6FF8; X-ray; 2.13 A; A/B=20-198. DR PDBsum; 4CYM; -. DR PDBsum; 4CZ2; -. DR PDBsum; 5OEC; -. DR PDBsum; 5OED; -. DR PDBsum; 6FF8; -. DR AlphaFoldDB; Q13637; -. DR SMR; Q13637; -. DR BioGRID; 116177; 80. DR DIP; DIP-61889N; -. DR FunCoup; Q13637; 968. DR IntAct; Q13637; 64. DR MINT; Q13637; -. DR STRING; 9606.ENSP00000356465; -. DR TCDB; 8.A.248.1.5; the ras-related rab gtpase (rrrg) family. DR GlyGen; Q13637; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q13637; -. DR PhosphoSitePlus; Q13637; -. DR BioMuta; RAB32; -. DR DMDM; 2833245; -. DR jPOST; Q13637; -. DR MassIVE; Q13637; -. DR PaxDb; 9606-ENSP00000356465; -. DR PeptideAtlas; Q13637; -. DR ProteomicsDB; 59632; -. DR Pumba; Q13637; -. DR Antibodypedia; 19849; 176 antibodies from 29 providers. DR DNASU; 10981; -. DR Ensembl; ENST00000367495.4; ENSP00000356465.3; ENSG00000118508.6. DR GeneID; 10981; -. DR KEGG; hsa:10981; -. DR MANE-Select; ENST00000367495.4; ENSP00000356465.3; NM_006834.5; NP_006825.1. DR UCSC; uc003qln.2; human. DR AGR; HGNC:9772; -. DR ClinPGx; PA34123; -. DR CTD; 10981; -. DR DisGeNET; 10981; -. DR GeneCards; RAB32; -. DR HGNC; HGNC:9772; RAB32. DR HPA; ENSG00000118508; Tissue enhanced (bone). DR MalaCards; RAB32; -. DR MIM; 612906; gene. DR MIM; 620923; phenotype. DR OpenTargets; ENSG00000118508; -. DR VEuPathDB; HostDB:ENSG00000118508; -. DR eggNOG; KOG4423; Eukaryota. DR GeneTree; ENSGT00940000162477; -. DR HOGENOM; CLU_041217_10_6_1; -. DR InParanoid; Q13637; -. DR OMA; ARRKLCC; -. DR OrthoDB; 245989at2759; -. DR PAN-GO; Q13637; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13637; -. DR PathwayCommons; Q13637; -. DR Reactome; R-HSA-8873719; RAB geranylgeranylation. DR Reactome; R-HSA-8876198; RAB GEFs exchange GTP for GDP on RABs. DR SignaLink; Q13637; -. DR SIGNOR; Q13637; -. DR Agora; ENSG00000118508; -. DR BioGRID-ORCS; 10981; 10 hits in 1158 CRISPR screens. DR EvolutionaryTrace; Q13637; -. DR GenomeRNAi; 10981; -. DR Pharos; Q13637; Tbio. DR PRO; PR:Q13637; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q13637; protein. DR Bgee; ENSG00000118508; Expressed in monocyte and 159 other cell types or tissues. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005769; C:early endosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0012505; C:endomembrane system; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0042470; C:melanosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0044233; C:mitochondria-associated endoplasmic reticulum membrane contact site; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0045335; C:phagocytic vesicle; IDA:UniProtKB. DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005802; C:trans-Golgi network; IBA:GO_Central. DR GO; GO:0035650; F:AP-1 adaptor complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0035651; F:AP-3 adaptor complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0036461; F:BLOC-2 complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0003925; F:G protein activity; IMP:UniProtKB. DR GO; GO:0005525; F:GTP binding; NAS:ParkinsonsUK-UCL. DR GO; GO:0030742; F:GTP-dependent protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB. DR GO; GO:0019882; P:antigen processing and presentation; IMP:UniProtKB. DR GO; GO:0035646; P:endosome to melanosome transport; IMP:ParkinsonsUK-UCL. DR GO; GO:0006886; P:intracellular protein transport; IBA:GO_Central. DR GO; GO:1903232; P:melanosome assembly; IDA:UniProtKB. DR GO; GO:0032438; P:melanosome organization; IBA:GO_Central. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0090382; P:phagosome maturation; IMP:UniProtKB. DR GO; GO:0072657; P:protein localization to membrane; IMP:ParkinsonsUK-UCL. DR GO; GO:0016192; P:vesicle-mediated transport; IEA:InterPro. DR CDD; cd04107; Rab32_Rab38; 1. DR FunFam; 3.40.50.300:FF:000222; RAB32, member RAS oncogene family; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR030697; Rab29/Rab38/Rab32. DR InterPro; IPR005225; Small_GTP-bd. DR InterPro; IPR001806; Small_GTPase. DR NCBIfam; TIGR00231; small_GTP; 1. DR PANTHER; PTHR47981; RAB FAMILY; 1. DR PANTHER; PTHR47981:SF41; RAS-RELATED PROTEIN RAB-32 ISOFORM X1; 1. DR Pfam; PF00071; Ras; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00175; RAB; 1. DR SMART; SM00176; RAN; 1. DR SMART; SM00173; RAS; 1. DR SMART; SM00174; RHO; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51419; RAB; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasmic vesicle; Direct protein sequencing; KW Disease variant; GTP-binding; Hydrolase; Lipoprotein; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding; KW Parkinson disease; Parkinsonism; Phosphoprotein; Prenylation; KW Proteomics identification; Reference proteome. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:25489052, ECO:0000269|Ref.7, FT ECO:0007744|PubMed:22223895" FT CHAIN 2..225 FT /note="Ras-related protein Rab-32" FT /id="PRO_0000121235" FT REGION 52..60 FT /note="Switch-I" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00753, FT ECO:0000269|PubMed:24856514, ECO:0007744|PDB:4CYM, FT ECO:0007744|PDB:4CZ2" FT REGION 84..100 FT /note="Switch-II" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00753, FT ECO:0000269|PubMed:24856514, ECO:0007744|PDB:4CYM, FT ECO:0007744|PDB:4CZ2" FT REGION 178..197 FT /note="PKA-RII subunit binding domain" FT BINDING 36 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 37 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 38 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 39 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 39 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 40 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 51 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 52 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 54 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 57 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 57 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 81 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:24856514, FT ECO:0007744|PDB:4CZ2" FT BINDING 84 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 143 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 144 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 146 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 175 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT BINDING 176 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000305|PubMed:24856514, FT ECO:0007744|PDB:4CYM, ECO:0007744|PDB:4CZ2" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|PubMed:25489052, ECO:0000269|Ref.7, FT ECO:0007744|PubMed:22223895" FT MOD_RES 71 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT LIPID 224 FT /note="S-geranylgeranyl cysteine" FT /evidence="ECO:0000250" FT LIPID 225 FT /note="S-geranylgeranyl cysteine" FT /evidence="ECO:0000250" FT VARIANT 71 FT /note="S -> R (risk factor for PARK26; increased FT interaction with LRRK2; dbSNP:rs200251693)" FT /evidence="ECO:0000269|PubMed:38614108, FT ECO:0000269|PubMed:38858457" FT /id="VAR_089968" FT MUTAGEN 39 FT /note="T->N: Decreased GTP-binding activity." FT /evidence="ECO:0000269|PubMed:12186851" FT MUTAGEN 85 FT /note="Q->L: No change in GTPase activity." FT /evidence="ECO:0000269|PubMed:11784320" FT MUTAGEN 89 FT /note="G->T: Impairs interaction with ANKRD27; when FT associated with S-90 and L-94." FT /evidence="ECO:0000269|PubMed:24856514" FT MUTAGEN 90 FT /note="N->S: Impairs interaction with ANKRD27; when FT associated with T-89 and L-94." FT /evidence="ECO:0000269|PubMed:24856514" FT MUTAGEN 91 FT /note="M->S: Impairs interaction with ANKRD27; when FT associated with S-93." FT /evidence="ECO:0000269|PubMed:24856514" FT MUTAGEN 93 FT /note="R->S: Impairs interaction with ANKRD27; when FT associated with M-91." FT /evidence="ECO:0000269|PubMed:24856514" FT MUTAGEN 94 FT /note="V->L: Impairs interaction with ANKRD27; when FT associated with T-89 and S-90." FT /evidence="ECO:0000269|PubMed:24856514" FT MUTAGEN 185 FT /note="A->F: Abolishes binding to protein kinase A type II FT regulatory subunit." FT /evidence="ECO:0000269|PubMed:12186851" FT MUTAGEN 188 FT /note="L->P: Abolishes binding to protein kinase A type II FT regulatory subunit." FT /evidence="ECO:0000269|PubMed:12186851" FT STRAND 22..33 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 38..47 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 59..70 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 73..82 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 84..88 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 92..96 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 101..107 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 111..127 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 138..143 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 155..165 FT /evidence="ECO:0007829|PDB:6FF8" FT STRAND 168..174 FT /evidence="ECO:0007829|PDB:6FF8" FT TURN 175..178 FT /evidence="ECO:0007829|PDB:6FF8" FT HELIX 181..197 FT /evidence="ECO:0007829|PDB:6FF8" SQ SEQUENCE 225 AA; 24997 MW; 91D41BAC1E3434CA CRC64; MAGGGAGDPG LGAAAAPAPE TREHLFKVLV IGELGVGKTS IIKRYVHQLF SQHYRATIGV DFALKVLNWD SRTLVRLQLW DIAGQERFGN MTRVYYKEAV GAFVVFDISR SSTFEAVLKW KSDLDSKVHL PNGSPIPAVL LANKCDQNKD SSQSPSQVDQ FCKEHGFAGW FETSAKDNIN IEEAARFLVE KILVNHQSFP NEENDVDKIK LDQETLRAEN KSQCC // 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 RN19A_HUMAN Reviewed; 838 AA. AC Q9NV58; A3KCU9; Q52LG1; Q9H5H9; Q9H8M8; Q9UFG0; Q9UFX6; Q9Y4Y1; DT 11-JUL-2001, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 3. DT 28-JAN-2026, entry version 205. DE RecName: Full=E3 ubiquitin-protein ligase RNF19A; DE EC=2.3.2.31 {ECO:0000250|UniProtKB:O60260}; DE AltName: Full=Double ring-finger protein; DE Short=Dorfin; DE AltName: Full=RING finger protein 19A; DE AltName: Full=p38; GN Name=RNF19A; Synonyms=RNF19; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH UBE2L3 RP AND UBE2L6, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RC TISSUE=Spinal cord; RX PubMed=11237715; DOI=10.1006/bbrc.2001.4414; RA Niwa J., Ishigaki S., Doyu M., Suzuki T., Tanaka K., Sobue G.; RT "A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase RT activity."; RL Biochem. Biophys. Res. Commun. 281:706-713(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-89 (ISOFORM 3). RA Kim T., Huh J., Kim H.; RT "Expression and promoter activity of MaLR element of Dorfin gene related to RT Parkinson disease."; RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 426-838 (ISOFORM 1), AND RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 142-838 (ISOFORM 2). RC TISSUE=Hepatoma, Ovarian carcinoma, 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 [MRNA] OF 422-824 (ISOFORM 1), AND INTERACTION WITH RP SP1. RC TISSUE=Colon; RX PubMed=10976766; DOI=10.1023/a:1007177623283; RA Gunther M., Laithier M., Brison O.; RT "A set of proteins interacting with transcription factor Sp1 identified in RT a two-hybrid screening."; RL Mol. Cell. Biochem. 210:131-142(2000). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 524-838 (ISOFORM 1). RC TISSUE=Fetal kidney, and Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SOD1. RX PubMed=12145308; DOI=10.1074/jbc.m206559200; RA Niwa J., Ishigaki S., Hishikawa N., Yamamoto M., Doyu M., Murata S., RA Tanaka K., Taniguchi N., Sobue G.; RT "Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated RT neurotoxicity."; RL J. Biol. Chem. 277:36793-36798(2002). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SNCAIP. RX PubMed=12750386; DOI=10.1074/jbc.m302763200; RA Ito T., Niwa J., Hishikawa N., Ishigaki S., Doyu M., Sobue G.; RT "Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1."; RL J. Biol. Chem. 278:29106-29114(2003). RN [9] RP FUNCTION, INTERACTION WITH VCP, MUTAGENESIS OF CYS-132 AND CYS-135, AND RP SUBCELLULAR LOCATION. RX PubMed=15456787; DOI=10.1074/jbc.m406683200; RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S., RA Kakizuka A., Tanaka K., Sobue G.; RT "Physical and functional interaction between dorfin and valosin-containing RT protein that are colocalized in ubiquitylated inclusions in RT neurodegenerative disorders."; RL J. Biol. Chem. 279:51376-51385(2004). RN [10] RP FUNCTION, AND INTERACTION WITH CASR AND VCP. RX PubMed=16513638; DOI=10.1074/jbc.m513552200; RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.; RT "Calcium-sensing receptor ubiquitination and degradation mediated by the E3 RT ubiquitin ligase dorfin."; RL J. Biol. Chem. 281:11610-11617(2006). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-631, 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 [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-631, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from E2 CC ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a CC thioester and then directly transfers the ubiquitin to targeted CC substrates, such as SNCAIP or CASR. Specifically ubiquitinates CC pathogenic SOD1 variants, which leads to their proteasomal degradation CC and to neuronal protection. {ECO:0000269|PubMed:11237715, CC ECO:0000269|PubMed:12145308, ECO:0000269|PubMed:12750386, CC ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16513638}. 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:0000250|UniProtKB:O60260}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Interacts with UBE2L3 and UBE2L6. Interacts with transcription CC factor Sp1. Interacts with VCP, CASR, SNCAIP and with some SOD1 CC variants which cause amyotrophic lateral sclerosis, but not with wild- CC type SOD1. {ECO:0000269|PubMed:10976766, ECO:0000269|PubMed:11237715, CC ECO:0000269|PubMed:12145308, ECO:0000269|PubMed:12750386, CC ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16513638}. CC -!- INTERACTION: CC Q9NV58; P00441: SOD1; NbExp=3; IntAct=EBI-1390270, EBI-990792; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane CC protein {ECO:0000305}. Cytoplasm, cytoskeleton, microtubule organizing CC center, centrosome {ECO:0000269|PubMed:11237715, CC ECO:0000269|PubMed:12145308, ECO:0000269|PubMed:12750386, CC ECO:0000269|PubMed:15456787}. Note=Present in the hyaline inclusion CC bodies specifically found in motor neurons from amyotrophic lateral CC sclerosis patients. Present in the Lewy bodies specifically found in CC neurons from Parkinson disease patients. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9NV58-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NV58-2; Sequence=VSP_021010, VSP_021011; CC Name=3; CC IsoId=Q9NV58-3; Sequence=VSP_028631; CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in heart. CC Ubiquitously expressed in the central nervous system. CC {ECO:0000269|PubMed:11237715}. 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:0000250|UniProtKB:O60260}. CC -!- SIMILARITY: Belongs to the RBR family. RNF19 subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAB14581.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=BAB15647.1; 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; AB029316; BAB39353.1; -; mRNA. DR EMBL; BC093938; AAH93938.1; -; mRNA. DR EMBL; BC093940; AAH93940.1; -; mRNA. DR EMBL; AB271914; BAF48117.1; -; mRNA. DR EMBL; AK001774; BAA91900.1; -; mRNA. DR EMBL; AK023455; BAB14581.1; ALT_INIT; mRNA. DR EMBL; AK027070; BAB15647.1; ALT_INIT; mRNA. DR EMBL; AJ242975; CAB45132.1; -; mRNA. DR EMBL; AL110253; CAB53700.1; -; mRNA. DR EMBL; AL122096; CAB59264.1; -; mRNA. DR CCDS; CCDS6286.1; -. [Q9NV58-1] DR PIR; T34528; T34528. DR RefSeq; NP_001267468.1; NM_001280539.2. [Q9NV58-1] DR RefSeq; NP_001340766.1; NM_001353837.2. [Q9NV58-1] DR RefSeq; NP_001340767.1; NM_001353838.2. [Q9NV58-1] DR RefSeq; NP_056250.3; NM_015435.4. [Q9NV58-1] DR RefSeq; NP_904355.1; NM_183419.4. [Q9NV58-1] DR RefSeq; XP_047277620.1; XM_047421664.1. [Q9NV58-1] DR RefSeq; XP_047277621.1; XM_047421665.1. [Q9NV58-1] DR RefSeq; XP_047277622.1; XM_047421666.1. [Q9NV58-1] DR RefSeq; XP_047277623.1; XM_047421667.1. [Q9NV58-1] DR RefSeq; XP_047277624.1; XM_047421668.1. [Q9NV58-1] DR RefSeq; XP_047277625.1; XM_047421669.1. [Q9NV58-1] DR RefSeq; XP_047277626.1; XM_047421670.1. [Q9NV58-1] DR RefSeq; XP_047277627.1; XM_047421671.1. [Q9NV58-1] DR RefSeq; XP_047277628.1; XM_047421672.1. [Q9NV58-1] DR RefSeq; XP_047277629.1; XM_047421673.1. [Q9NV58-1] DR RefSeq; XP_054216220.1; XM_054360245.1. [Q9NV58-1] DR RefSeq; XP_054216221.1; XM_054360246.1. [Q9NV58-1] DR RefSeq; XP_054216222.1; XM_054360247.1. [Q9NV58-1] DR RefSeq; XP_054216223.1; XM_054360248.1. [Q9NV58-1] DR RefSeq; XP_054216224.1; XM_054360249.1. [Q9NV58-1] DR RefSeq; XP_054216225.1; XM_054360250.1. [Q9NV58-1] DR RefSeq; XP_054216226.1; XM_054360251.1. [Q9NV58-1] DR RefSeq; XP_054216227.1; XM_054360252.1. [Q9NV58-1] DR RefSeq; XP_054216228.1; XM_054360253.1. [Q9NV58-1] DR RefSeq; XP_054216229.1; XM_054360254.1. [Q9NV58-1] DR AlphaFoldDB; Q9NV58; -. DR BioGRID; 117405; 27. DR CORUM; Q9NV58; -. DR FunCoup; Q9NV58; 1316. DR IntAct; Q9NV58; 17. DR MINT; Q9NV58; -. DR STRING; 9606.ENSP00000428968; -. DR GlyGen; Q9NV58; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q9NV58; -. DR PhosphoSitePlus; Q9NV58; -. DR BioMuta; RNF19A; -. DR DMDM; 116242764; -. DR jPOST; Q9NV58; -. DR MassIVE; Q9NV58; -. DR PaxDb; 9606-ENSP00000428968; -. DR PeptideAtlas; Q9NV58; -. DR ProteomicsDB; 82747; -. [Q9NV58-1] DR ProteomicsDB; 82748; -. [Q9NV58-2] DR ProteomicsDB; 82749; -. [Q9NV58-3] DR Pumba; Q9NV58; -. DR Antibodypedia; 3140; 215 antibodies from 29 providers. DR DNASU; 25897; -. DR Ensembl; ENST00000341084.7; ENSP00000342667.2; ENSG00000034677.14. [Q9NV58-1] DR Ensembl; ENST00000519449.5; ENSP00000428968.1; ENSG00000034677.14. [Q9NV58-1] DR GeneID; 25897; -. DR KEGG; hsa:25897; -. DR MANE-Select; ENST00000341084.7; ENSP00000342667.2; NM_183419.4; NP_904355.1. DR UCSC; uc003yjj.3; human. [Q9NV58-1] DR AGR; HGNC:13432; -. DR ClinPGx; PA162401601; -. DR CTD; 25897; -. DR DisGeNET; 25897; -. DR GeneCards; RNF19A; -. DR HGNC; HGNC:13432; RNF19A. DR HPA; ENSG00000034677; Low tissue specificity. DR MIM; 607119; gene. DR OpenTargets; ENSG00000034677; -. DR VEuPathDB; HostDB:ENSG00000034677; -. DR eggNOG; KOG1815; Eukaryota. DR GeneTree; ENSGT00940000158703; -. DR HOGENOM; CLU_016793_1_0_1; -. DR InParanoid; Q9NV58; -. DR OMA; HQCSISL; -. DR OrthoDB; 1431934at2759; -. DR PAN-GO; Q9NV58; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q9NV58; -. DR PathwayCommons; Q9NV58; -. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9NV58; -. DR SIGNOR; Q9NV58; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000034677; -. DR BioGRID-ORCS; 25897; 64 hits in 1187 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; RNF19A; human. DR GeneWiki; RNF19A; -. DR GenomeRNAi; 25897; -. DR Pharos; Q9NV58; Tbio. DR PRO; PR:Q9NV58; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q9NV58; protein. DR Bgee; ENSG00000034677; Expressed in calcaneal tendon and 187 other cell types or tissues. DR ExpressionAtlas; Q9NV58; baseline and differential. DR GO; GO:0005813; C:centrosome; TAS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000151; C:ubiquitin ligase complex; IBA:GO_Central. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IBA:GO_Central. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0000226; P:microtubule cytoskeleton organization; TAS:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR CDD; cd20362; BRcat_RBR_RNF19A; 1. DR CDD; cd20355; Rcat_RBR_RNF19; 1. DR CDD; cd16775; RING-HC_RBR_RNF19A; 1. DR FunFam; 1.20.120.1750:FF:000001; RBR-type E3 ubiquitin transferase; 1. DR FunFam; 2.20.25.20:FF:000004; RBR-type E3 ubiquitin transferase; 1. DR FunFam; 3.30.40.10:FF:000052; RBR-type E3 ubiquitin transferase; 1. DR Gene3D; 1.20.120.1750; -; 1. DR Gene3D; 2.20.25.20; -; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR031127; E3_UB_ligase_RBR. DR InterPro; IPR002867; IBR_dom. DR InterPro; IPR044066; TRIAD_supradom. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR11685; RBR FAMILY RING FINGER AND IBR DOMAIN-CONTAINING; 1. DR Pfam; PF01485; IBR; 1. DR Pfam; PF22191; IBR_1; 1. DR SMART; SM00647; IBR; 2. DR SMART; SM00184; RING; 1. DR SUPFAM; SSF57850; RING/U-box; 3. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Cytoskeleton; Membrane; Metal-binding; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW Transferase; Transmembrane; Transmembrane helix; Ubl conjugation pathway; KW Zinc; Zinc-finger. FT CHAIN 1..838 FT /note="E3 ubiquitin-protein ligase RNF19A" FT /id="PRO_0000056061" FT TRANSMEM 368..388 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 424..444 FT /note="Helical" FT /evidence="ECO:0000255" FT ZN_FING 132..179 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 199..264 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 301..332 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 41..61 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 128..351 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 622..685 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 660..838 FT /note="Interaction with CASR" FT /evidence="ECO:0000269|PubMed:16513638" FT REGION 700..721 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 46..57 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 630..662 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 671..683 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 700..717 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 316 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 132 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 135 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 150 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 152 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 155 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 158 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 176 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 179 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 219 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 224 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 241 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 246 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 251 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 254 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 259 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 264 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 301 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 304 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 321 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 324 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 329 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 332 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 340 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 347 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT MOD_RES 631 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:24275569" FT VAR_SEQ 1..31 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_028631" FT VAR_SEQ 572..604 FT /note="RYSLSGESGTVSLGTVSDNASTKAMAGSILNSY -> AAVAAAGRWAYSPAT FT LRCRRSEELKNIHDSS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_021010" FT VAR_SEQ 605..838 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_021011" FT VARIANT 835 FT /note="Q -> H (in dbSNP:rs9642785)" FT /id="VAR_028045" FT MUTAGEN 132 FT /note="C->S: Abolishes interaction with VCP and E3 ligase FT activity toward mutant SOD1; when associated with S-135." FT /evidence="ECO:0000269|PubMed:15456787" FT MUTAGEN 135 FT /note="C->S: Abolishes interaction with VCP and E3 ligase FT activity toward mutant SOD1; when associated with S-132." FT /evidence="ECO:0000269|PubMed:15456787" FT CONFLICT 645 FT /note="H -> Y (in Ref. 1; BAB39353)" FT /evidence="ECO:0000305" FT CONFLICT 744 FT /note="S -> R (in Ref. 6; CAB53700)" FT /evidence="ECO:0000305" SQ SEQUENCE 838 AA; 90696 MW; 00A7DED5023FDC06 CRC64; MQEQEIGFIS KYNEGLCVNT DPVSILTSIL DMSLHRQMGS DRDLQSSASS VSLPSVKKAP KKRRISIGSL FRRKKDNKRK SRELNGGVDG IASIESIHSE MCTDKNSIFS TNTSSDNGLT SISKQIGDFI ECPLCLLRHS KDRFPDIMTC HHRSCVDCLR QYLRIEISES RVNISCPECT ERFNPHDIRL ILSDDVLMEK YEEFMLRRWL VADPDCRWCP APDCGYAVIA FGCASCPKLT CGREGCGTEF CYHCKQIWHP NQTCDAARQE RAQSLRLRTI RSSSISYSQE SGAAADDIKP CPRCAAYIIK MNDGSCNHMT CAVCGCEFCW LCMKEISDLH YLSPSGCTFW GKKPWSRKKK ILWQLGTLVG APVGIALIAG IAIPAMIIGI PVYVGRKIHN RYEGKDVSKH KRNLAIAGGV TLSVIVSPVV AAVTVGIGVP IMLAYVYGVV PISLCRSGGC GVSAGNGKGV RIEFDDENDI NVGGTNTAVD TTSVAEARHN PSIGEGSVGG LTGSLSASGS HMDRIGAIRD NLSETASTMA LAGASITGSL SGSAMVNCFN RLEVQADVQK ERYSLSGESG TVSLGTVSDN ASTKAMAGSI LNSYIPLDKE GNSMEVQVDI ESKPSKFRHN SGSSSVDDGS ATRSHAGGSS SGLPEGKSSA TKWSKEATAG KKSKSGKLRK KGNMKINETR EDMDAQLLEQ QSTNSSEFEA PSLSDSMPSV ADSHSSHFSE FSCSDLESMK TSCSHGSSDY HTRFATVNIL PEVENDRLEN SPHQCSISVV TQTASCSEVS QLNHIAEEHG NNGIKPNVDL YFGDALKETN NNHSHQTMEL KVAIQTEI // ID RNF11_HUMAN Reviewed; 154 AA. AC Q9Y3C5; A8KAI2; Q5T7R8; DT 06-JUN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 28-JAN-2026, entry version 186. DE RecName: Full=RING finger protein 11; GN Name=RNF11; ORFNames=CGI-123; 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=10673045; DOI=10.1016/s0167-4781(99)00190-6; RA Seki N., Hattori A., Hayashi A., Kozuma S., Sasaki M., Suzuki Y., RA Sugano S., Muramatsu M., Saito T.; RT "Cloning and expression profile of mouse and human genes, Rnf11/RNF11, RT encoding a novel RING-H2 finger protein."; RL Biochim. Biophys. Acta 1489:421-427(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=10810093; DOI=10.1101/gr.10.5.703; RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.; RT "Identification of novel human genes evolutionarily conserved in RT Caenorhabditis elegans by comparative proteomics."; RL Genome Res. 10:703-713(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP PROTEIN SEQUENCE OF 70-113 AND 132-154, PHOSPHORYLATION AT THR-135, RP SUBCELLULAR LOCATION, INTERACTION WITH 14-3-3, AND MUTAGENESIS OF THR-135. RX PubMed=16123141; DOI=10.1158/1541-7786.mcr-04-0166; RA Connor M.K., Azmi P.B., Subramaniam V., Li H., Seth A.K.; RT "Molecular characterization of ring finger protein 11."; RL Mol. Cancer Res. 3:453-461(2005). RN [8] RP INTERACTION WITH ITCH, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND RP MUTAGENESIS OF TYR-40. RX PubMed=14559117; DOI=10.1016/j.bbadis.2003.07.001; RA Kitching R., Wong M.J., Koehler D., Burger A.M., Landberg G., Gish G., RA Seth A.K.; RT "The RING-H2 protein RNF11 is differentially expressed in breast tumours RT and interacts with HECT-type E3 ligases."; RL Biochim. Biophys. Acta 1639:104-112(2003). RN [9] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INTERACTION WITH SMURF2 AND RP UBE2D1, UBIQUITINATION, AND MUTAGENESIS OF TYR-40; CYS-99 AND CYS-102. RX PubMed=14562029; DOI=10.1038/sj.bjc.6601301; RA Subramaniam V., Li H., Wong M.J., Kitching R., Attisano L., Wrana J., RA Zubovits J., Burger A.M., Seth A.K.; RT "The RING-H2 protein RNF11 is overexpressed in breast cancer and is a RT target of Smurf2 E3 ligase."; RL Br. J. Cancer 89:1538-1544(2003). RN [10] RP FUNCTION, INTERACTION WITH ZNF350; EPS15 AND STAMBP, AND MUTAGENESIS OF RP TYR-40; CYS-99 AND CYS-102. RX PubMed=14755250; DOI=10.1038/sj.onc.1207319; RA Li H., Seth A.K.; RT "An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein."; RL Oncogene 23:1801-1808(2004). RN [11] RP TISSUE SPECIFICITY. RX PubMed=17917589; DOI=10.1097/nen.0b013e3181567f17; RA Anderson L.R., Betarbet R., Gearing M., Gulcher J., Hicks A.A., RA Stefansson K., Lah J.J., Levey A.I.; RT "PARK10 candidate RNF11 is expressed by vulnerable neurons and localizes to RT Lewy bodies in Parkinson disease brain."; RL J. Neuropathol. Exp. Neurol. 66:955-964(2007). RN [12] RP INTERACTION WITH WWP1, AND MUTAGENESIS OF TYR-40. RX PubMed=18724389; DOI=10.1038/onc.2008.288; RA Chen C., Zhou Z., Liu R., Li Y., Azmi P.B., Seth A.K.; RT "The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 RT and EGFR through RING finger protein 11."; RL Oncogene 27:6845-6855(2008). RN [13] RP INTERACTION WITH TAX1BP1; TNFAIP3 AND RIPK1, AND MUTAGENESIS OF TYR-40 AND RP CYS-99. RX PubMed=19131965; DOI=10.1038/emboj.2008.285; RA Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.; RT "The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB RT signalling."; RL EMBO J. 28:513-522(2009). RN [14] RP INTERACTION WITH UBE2N, AND MUTAGENESIS OF MET-103; ASP-127 AND ASP-128. RX PubMed=18615712; DOI=10.1002/prot.22120; RA Scheper J., Oliva B., Villa-Freixa J., Thomson T.M.; RT "Analysis of electrostatic contributions to the selectivity of interactions RT between RING-finger domains and ubiquitin-conjugating enzymes."; RL Proteins 74:92-103(2009). RN [15] RP INTERACTION WITH GGA1, MYRISTOYLATION AT GLY-2, PALMITOYLATION AT CYS-4, RP UBIQUITINATION BY ITCH, AND MUTAGENESIS OF GLY-2; CYS-4; ASP-12; LEU-15; RP LEU-16; CYS-99 AND CYS-102. RX PubMed=20676133; DOI=10.1038/onc.2010.294; RA Santonico E., Belleudi F., Panni S., Torrisi M.R., Cesareni G., RA Castagnoli L.; RT "Multiple modification and protein interaction signals drive the Ring RT finger protein 11 (RNF11) E3 ligase to the endosomal compartment."; RL Oncogene 29:5604-5618(2010). RN [16] RP MYRISTOYLATION AT GLY-2. RX PubMed=20213681; DOI=10.1002/pmic.200900783; RA Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E., RA Tsunasawa S., Utsumi T.; RT "Strategy for comprehensive identification of human N-myristoylated RT proteins using an insect cell-free protein synthesis system."; RL Proteomics 10:1780-1793(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, 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 [18] 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). CC -!- FUNCTION: Essential component of a ubiquitin-editing protein complex, CC comprising also TNFAIP3, ITCH and TAX1BP1, that ensures the transient CC nature of inflammatory signaling pathways. Promotes the association of CC TNFAIP3 to RIPK1 after TNF stimulation. TNFAIP3 deubiquitinates 'Lys- CC 63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys- CC 48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation CC and consequently termination of the TNF- or LPS-mediated activation of CC NF-kappa-B. Recruits STAMBP to the E3 ubiquitin-ligase SMURF2 for CC ubiquitination, leading to its degradation by the 26S proteasome. CC {ECO:0000269|PubMed:14755250}. CC -!- SUBUNIT: Interacts (when phosphorylated) with 14-3-3. Interacts with CC the E3 ubiquitin-ligases NEDD4, ITCH, SMURF2 and WWP1 (By similarity). CC Also interacts with the E2 ubiquitin-conjugating enzymes UBE2D1 and CC UBE2N, but neither with CDC34, nor with UBE2L3. Interacts with ZNF350, CC EPS15 and STAMBP. After TNF stimulation, interacts with TAX1BP1, CC TNFAIP3 and RIPK1; these interactions are transient and they are lost CC after 1 hour of stimulation with TNF (By similarity). Interacts with CC GGA1. {ECO:0000250, ECO:0000269|PubMed:14559117, CC ECO:0000269|PubMed:14562029, ECO:0000269|PubMed:14755250, CC ECO:0000269|PubMed:16123141, ECO:0000269|PubMed:18615712, CC ECO:0000269|PubMed:18724389, ECO:0000269|PubMed:19131965, CC ECO:0000269|PubMed:20676133}. CC -!- SUBCELLULAR LOCATION: Early endosome. Recycling endosome. Cytoplasm. CC Nucleus. Note=Predominantly cytoplasmic, when unphosphorylated, and CC nuclear, when phosphorylated by PKB/AKT1. CC {ECO:0000269|PubMed:16123141}. CC -!- TISSUE SPECIFICITY: Expressed at low levels in the lung, liver, kidney, CC pancreas, spleen, prostate, thymus, ovary, small intestine, colon, and CC peripheral blood lymphocytes, and, at intermediate levels, in the CC testis, heart, brain and placenta. Highest expression in the skeletal CC muscle. In the brain, expressed at different levels in several regions: CC high levels in the amygdala, moderate in the hippocampus and thalamus, CC low in the caudate and extremely low levels in the corpus callosum (at CC protein level). Restricted to neurons, enriched in somatodendritic CC compartments and excluded from white matter (at protein level). In CC substantia nigra, present in cell bodies and processes of dopaminergic CC and nondopaminergic cells (at protein level). In Parkinson disease, CC sequestered in Lewy bodies and neurites. Overexpressed in breast cancer CC cells, but not detected in the surrounding stroma and weakly, if at CC all, in normal breast epithelial cells (at protein level). Also CC expressed in several tumor cell lines. {ECO:0000269|PubMed:14559117, CC ECO:0000269|PubMed:14562029, ECO:0000269|PubMed:17917589}. CC -!- DOMAIN: The PPxY motif mediates interaction with NEDD4. {ECO:0000250}. CC -!- PTM: Ubiquitinated in the presence of ITCH, or SMURF2, and UBE2D1, as CC well as WWP1. {ECO:0000269|PubMed:14562029, CC ECO:0000269|PubMed:20676133}. CC -!- PTM: Phosphorylation by PKB/AKT1 may accelerate degradation by the CC proteasome. {ECO:0000269|PubMed:16123141}. CC -!- PTM: Acylation at both Gly-2 and Cys-4 is required for proper CC localization to the endosomes. {ECO:0000269|PubMed:20676133}. 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; AB024703; BAA84683.1; -; mRNA. DR EMBL; AF151881; AAD34118.1; -; mRNA. DR EMBL; AK293047; BAF85736.1; -; mRNA. DR EMBL; AK313140; BAG35959.1; -; mRNA. DR EMBL; AL162430; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471059; EAX06831.1; -; Genomic_DNA. DR EMBL; BC020964; AAH20964.1; -; mRNA. DR EMBL; BC047654; AAH47654.1; -; mRNA. DR CCDS; CCDS556.1; -. DR RefSeq; NP_055187.1; NM_014372.5. DR AlphaFoldDB; Q9Y3C5; -. DR SMR; Q9Y3C5; -. DR BioGRID; 117941; 163. DR CORUM; Q9Y3C5; -. DR FunCoup; Q9Y3C5; 348. DR MINT; Q9Y3C5; -. DR STRING; 9606.ENSP00000242719; -. DR GlyGen; Q9Y3C5; 1 site. DR iPTMnet; Q9Y3C5; -. DR PhosphoSitePlus; Q9Y3C5; -. DR SwissPalm; Q9Y3C5; -. DR BioMuta; RNF11; -. DR DMDM; 21362884; -. DR jPOST; Q9Y3C5; -. DR MassIVE; Q9Y3C5; -. DR PaxDb; 9606-ENSP00000242719; -. DR PeptideAtlas; Q9Y3C5; -. DR ProteomicsDB; 86014; -. DR Pumba; Q9Y3C5; -. DR Antibodypedia; 32937; 178 antibodies from 23 providers. DR DNASU; 26994; -. DR Ensembl; ENST00000242719.4; ENSP00000242719.3; ENSG00000123091.6. DR GeneID; 26994; -. DR KEGG; hsa:26994; -. DR MANE-Select; ENST00000242719.4; ENSP00000242719.3; NM_014372.5; NP_055187.1. DR UCSC; uc001csi.5; human. DR AGR; HGNC:10056; -. DR ClinPGx; PA34420; -. DR CTD; 26994; -. DR DisGeNET; 26994; -. DR GeneCards; RNF11; -. DR HGNC; HGNC:10056; RNF11. DR HPA; ENSG00000123091; Low tissue specificity. DR MIM; 612598; gene. DR OpenTargets; ENSG00000123091; -. DR VEuPathDB; HostDB:ENSG00000123091; -. DR eggNOG; KOG0800; Eukaryota. DR GeneTree; ENSGT00730000110988; -. DR HOGENOM; CLU_123539_1_0_1; -. DR InParanoid; Q9Y3C5; -. DR OMA; HLDCIDN; -. DR OrthoDB; 9984778at2759; -. DR PAN-GO; Q9Y3C5; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9Y3C5; -. DR PathwayCommons; Q9Y3C5; -. DR SignaLink; Q9Y3C5; -. DR SIGNOR; Q9Y3C5; -. DR Agora; ENSG00000123091; -. DR BioGRID-ORCS; 26994; 45 hits in 1199 CRISPR screens. DR ChiTaRS; RNF11; human. DR GeneWiki; RNF11; -. DR GenomeRNAi; 26994; -. DR Pharos; Q9Y3C5; Tbio. DR PRO; PR:Q9Y3C5; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9Y3C5; protein. DR Bgee; ENSG00000123091; Expressed in lateral nuclear group of thalamus and 213 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell. DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; TAS:ProtInc. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:FlyBase. DR GO; GO:0008270; F:zinc ion binding; TAS:ProtInc. DR GO; GO:0051865; P:protein autoubiquitination; IDA:FlyBase. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd16468; RING-H2_RNF11; 1. DR FunFam; 3.30.40.10:FF:000134; Ring finger protein 11; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR042981; RNF11_RING-H2. DR InterPro; IPR052804; UEC_component. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR46359; GEO07743P1; 1. DR PANTHER; PTHR46359:SF1; RING FINGER PROTEIN 11; 1. DR Pfam; PF13639; zf-RING_2; 1. DR SMART; SM00184; RING; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW Cytoplasm; Direct protein sequencing; Endosome; Lipoprotein; Metal-binding; KW Myristate; Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Ubl conjugation pathway; Zinc; KW Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT CHAIN 2..154 FT /note="RING finger protein 11" FT /id="PRO_0000056050" FT ZN_FING 99..140 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 1..53 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 37..40 FT /note="PPxY motif" FT COMPBIAS 1..12 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 41..51 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 14 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 25 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QYK7" FT MOD_RES 135 FT /note="Phosphothreonine; by PKB/AKT1" FT /evidence="ECO:0000269|PubMed:16123141" FT LIPID 2 FT /note="N-myristoyl glycine" FT /evidence="ECO:0000269|PubMed:20213681, FT ECO:0000269|PubMed:20676133" FT LIPID 4 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:20676133" FT VARIANT 11 FT /note="D -> E (in dbSNP:rs12077069)" FT /id="VAR_058272" FT MUTAGEN 2 FT /note="G->A: Loss of myristoylation. Change in subcellular FT location: Becomes diffused throughout the cytosol. Strong FT reduction of ubiquitination. Reduced efficiency of ITCH- FT binding." FT /evidence="ECO:0000269|PubMed:20676133" FT MUTAGEN 4 FT /note="C->S: Change in subcellular location: Becomes FT partially cytosolic and retained in association with the FT Golgi apparatus. Partial reduction of ubiquitination." FT /evidence="ECO:0000269|PubMed:20676133" FT MUTAGEN 12 FT /note="D->A: Loss of GGA1-binding." FT /evidence="ECO:0000269|PubMed:20676133" FT MUTAGEN 15 FT /note="L->A: Loss of GGA1-binding." FT /evidence="ECO:0000269|PubMed:20676133" FT MUTAGEN 16 FT /note="L->A: Loss of GGA1-binding." FT /evidence="ECO:0000269|PubMed:20676133" FT MUTAGEN 40 FT /note="Y->A: Loss of ITCH-, SMURF2- and WWP1-binding. FT Partial loss of ubiquitination by ITCH. No effect on FT STAMBP-binding; when associated with S-99 and S-102. FT Persistent TNF-mediated NFKBIA phosphorylation. Loss of FT stimulus-dependent complex formation with TAX1BP1, TNFAIP3 FT and RIPK1." FT /evidence="ECO:0000269|PubMed:14559117, FT ECO:0000269|PubMed:14562029, ECO:0000269|PubMed:14755250, FT ECO:0000269|PubMed:18724389, ECO:0000269|PubMed:19131965" FT MUTAGEN 99 FT /note="C->S: No effect on STAMBP- and SMURF2-binding; when FT associated with S-102. Persistent TNF-mediated NFKBIA FT phosphorylation. No effect on STAMBP-binding; when FT associated with A-40 and S-102. No effect on ubiquitination FT by ITCH; when associated with S-102. Loss of stimulus- FT dependent complex formation with TAX1BP1, TNFAIP3 and FT RIPK1." FT /evidence="ECO:0000269|PubMed:14562029, FT ECO:0000269|PubMed:14755250, ECO:0000269|PubMed:19131965, FT ECO:0000269|PubMed:20676133" FT MUTAGEN 102 FT /note="C->S: No effect on STAMBP- and SMURF2-binding; when FT associated with S-99. No effect on ubiquitination by ITCH; FT when associated with S-102. No effect on STAMBP-binding; FT when associated with A-40 and S-99." FT /evidence="ECO:0000269|PubMed:14562029, FT ECO:0000269|PubMed:14755250, ECO:0000269|PubMed:20676133" FT MUTAGEN 103 FT /note="M->A,G: Loss of UBE2N-binding. No gain of UBE2L3- FT binding." FT /evidence="ECO:0000269|PubMed:18615712" FT MUTAGEN 103 FT /note="M->L: No effect on UBE2N-binding. No gain of UBE2L3- FT binding; when associated with L-127 and L-128." FT /evidence="ECO:0000269|PubMed:18615712" FT MUTAGEN 103 FT /note="M->V: No effect on UBE2N-binding. Gain of UBE2L3- FT binding." FT /evidence="ECO:0000269|PubMed:18615712" FT MUTAGEN 127 FT /note="D->L: No effect on UBE2N-binding. No gain of UBE2L3- FT binding; when associated with L-128." FT /evidence="ECO:0000269|PubMed:18615712" FT MUTAGEN 128 FT /note="D->L: No effect on UBE2N-binding. No gain of UBE2L3- FT binding." FT /evidence="ECO:0000269|PubMed:18615712" FT MUTAGEN 135 FT /note="T->E: Loss of phosphorylation and of 14-3-3- FT binding." FT /evidence="ECO:0000269|PubMed:16123141" FT CONFLICT 124 FT /note="D -> G (in Ref. 3; BAF85736)" FT /evidence="ECO:0000305" SQ SEQUENCE 154 AA; 17444 MW; C368E38148FC1D0D CRC64; MGNCLKSPTS DDISLLHESQ SDRASFGEGT EPDQEPPPPY QEQVPVPVYH PTPSQTRLAT QLTEEEQIRI AQRIGLIQHL PKGVYDPGRD GSEKKIRECV ICMMDFVYGD PIRFLPCMHI YHLDCIDDWL MRSFTCPSCM EPVDAALLSS YETN // ID SAP_HUMAN Reviewed; 524 AA. AC P07602; P07292; P15793; P78538; P78541; P78546; P78547; P78558; Q53Y86; AC Q6IBQ6; Q92739; Q92740; Q92741; Q92742; DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 2. DT 28-JAN-2026, entry version 268. DE RecName: Full=Prosaposin; DE AltName: Full=Proactivator polypeptide; DE Contains: DE RecName: Full=Saposin-A; DE AltName: Full=Protein A; DE Contains: DE RecName: Full=Saposin-B-Val; DE Contains: DE RecName: Full=Saposin-B; DE AltName: Full=Cerebroside sulfate activator; DE Short=CSAct; DE AltName: Full=Dispersin; DE AltName: Full=Sphingolipid activator protein 1; DE Short=SAP-1; DE AltName: Full=Sulfatide/GM1 activator; DE Contains: DE RecName: Full=Saposin-C; DE AltName: Full=A1 activator; DE AltName: Full=Co-beta-glucosidase; DE AltName: Full=Glucosylceramidase activator; DE AltName: Full=Sphingolipid activator protein 2; DE Short=SAP-2; DE Contains: DE RecName: Full=Saposin-D; DE AltName: Full=Component C; DE AltName: Full=Protein C; DE Flags: Precursor; GN Name=PSAP; Synonyms=GLBA, SAP1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Liver; RX PubMed=2515150; DOI=10.1016/0888-7543(89)90014-1; RA Rorman E.G., Grabowski G.A.; RT "Molecular cloning of a human co-beta-glucosidase cDNA: evidence that four RT sphingolipid hydrolase activator proteins are encoded by single genes in RT humans and rats."; RL Genomics 5:486-492(1989). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2498298; DOI=10.1093/oxfordjournals.jbchem.a122629; RA Nakano T., Sandhoff K., Stuemper J., Christomanou H., Suzuki K.; RT "Structure of full-length cDNA coding for sulfatide activator, a Co-beta- RT glucosidase and two other homologous proteins: two alternate forms of the RT sulfatide activator."; RL J. Biochem. 105:152-154(1989). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SAP-MU-0). RC TISSUE=Brain, Eye, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-524. RX PubMed=2842863; DOI=10.1126/science.2842863; RA O'Brien J.S., Kretz K.A., Dewji N., Wenger D.A., Esch F., Fluharty A.L.; RT "Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same RT genetic locus."; RL Science 241:1098-1101(1988). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 14-524. RX PubMed=1612590; DOI=10.1016/0888-7543(92)90247-p; RA Rorman E.G., Scheinker V., Grabowski G.A.; RT "Structure and evolution of the human prosaposin chromosomal gene."; RL Genomics 13:312-318(1992). RN [10] RP PROTEIN SEQUENCE OF 17-24 AND 165-172. RX PubMed=8323276; DOI=10.1006/abbi.1993.1328; RA Hiraiwa M., O'Brien J.S., Kishimoto Y., Galdzicka M., Fluharty A.L., RA Ginns E.I., Martin B.M.; RT "Isolation, characterization, and proteolysis of human prosaposin, the RT precursor of saposins (sphingolipid activator proteins)."; RL Arch. Biochem. Biophys. 304:110-116(1993). RN [11] RP PROTEIN SEQUENCE OF 17-26. RC TISSUE=Milk; RX PubMed=1958198; DOI=10.1016/s0006-291x(05)81415-9; RA Kondoh K., Hineno T., Sano A., Kakimoto Y.; RT "Isolation and characterization of prosaposin from human milk."; RL Biochem. Biophys. Res. Commun. 181:286-292(1991). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 59-125 AND 304-513. RC TISSUE=Brain; RX PubMed=2013321; DOI=10.1016/0014-5793(91)80308-p; RA Holtschmidt H., Sandhoff K., Fuerst W., Kwon H.Y., Schnabel D., Suzuki K.; RT "The organization of the gene for the human cerebroside sulfate activator RT protein."; RL FEBS Lett. 280:267-270(1991). RN [13] RP PROTEIN SEQUENCE OF 60-142. RX PubMed=2717620; DOI=10.1073/pnas.86.9.3389; RA Morimoto S., Martin B.M., Yamamoto Y., Kretz K.A., O'Brien J.S., RA Kishimoto Y.; RT "Saposin A: second cerebrosidase activator protein."; RL Proc. Natl. Acad. Sci. U.S.A. 86:3389-3393(1989). RN [14] RP PROTEIN SEQUENCE OF 62-84 AND 410-431. RX PubMed=8370464; DOI=10.1016/0014-5793(93)80908-d; RA Tyynela J., Palmer D.N., Baumann M., Haltia M.; RT "Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis."; RL FEBS Lett. 330:8-12(1993). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 164-524. RX PubMed=2825202; DOI=10.1073/pnas.84.23.8652; RA Dewji N.N., Wenger D.A., O'Brien J.S.; RT "Nucleotide sequence of cloned cDNA for human sphingolipid activator RT protein 1 precursor."; RL Proc. Natl. Acad. Sci. U.S.A. 84:8652-8656(1987). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 195-263. RX PubMed=2868718; DOI=10.1016/s0006-291x(86)80518-6; RA Dewji N.N., Wenger D.A., Fujibayashi S., Donoviel M., Esch F., Hill F., RA O'Brien J.S.; RT "Molecular cloning of the sphingolipid activator protein-1 (SAP-1), the RT sulfatide sulfatase activator."; RL Biochem. Biophys. Res. Commun. 134:989-994(1986). RN [17] RP PROTEIN SEQUENCE OF 195-274. RX PubMed=3242555; DOI=10.1515/bchm3.1988.369.2.1361; RA Kleinschmidt T., Christomanou H., Braunitzer G.; RT "Complete amino-acid sequence of the naturally occurring A2 activator RT protein for enzymic sphingomyelin degradation: identity to the sulfatide RT activator protein (SAP-1)."; RL Biol. Chem. Hoppe-Seyler 369:1361-1365(1988). RN [18] RP PROTEIN SEQUENCE OF 195-274. RC TISSUE=Kidney; RX PubMed=2209618; DOI=10.1111/j.1432-1033.1990.tb19280.x; RA Furst W., Schubert J., Machleidt W., Meyer H.E., Sandhoff K.; RT "The complete amino-acid sequences of human ganglioside GM2 activator RT protein and cerebroside sulfate activator protein."; RL Eur. J. Biochem. 192:709-714(1990). RN [19] RP PROTEIN SEQUENCE OF 311-390. RX PubMed=3442600; DOI=10.1515/bchm3.1987.368.2.1571; RA Kleinschmidt T., Christomanou H., Braunitzer G.; RT "Complete amino-acid sequence and carbohydrate content of the naturally RT occurring glucosylceramide activator protein (A1 activator) absent from a RT new human Gaucher disease variant."; RL Biol. Chem. Hoppe-Seyler 368:1571-1578(1987). RN [20] RP PROTEIN SEQUENCE OF 405-484. RX PubMed=2845979; DOI=10.1016/s0006-291x(88)80855-6; RA Morimoto S., Martin B.M., Kishimoto Y., O'Brien J.S.; RT "Saposin D: a sphingomyelinase activator."; RL Biochem. Biophys. Res. Commun. 156:403-410(1988). RN [21] RP PROTEIN SEQUENCE OF 407-484. RX PubMed=3048308; DOI=10.1515/bchm3.1988.369.1.317; RA Furst W., Machleidt W., Sandhoff K.; RT "The precursor of sulfatide activator protein is processed to three RT different proteins."; RL Biol. Chem. Hoppe-Seyler 369:317-328(1988). RN [22] RP PARTIAL PROTEIN SEQUENCE (SAPOSIN-B), AND STRUCTURE OF CARBOHYDRATES. RC TISSUE=Urine; RX PubMed=10562467; DOI=10.1006/mgme.1999.2900; RA Fluharty A.L., Lombardo C., Louis A., Stevens R.L., Whitelegge J.P., RA Waring A.J., To T., Fluharty C.B., Faull K.F.; RT "Preparation of the cerebroside sulfate activator (CSAct or saposin B) from RT human urine."; RL Mol. Genet. Metab. 68:391-403(1999). RN [23] RP DISULFIDE BONDS IN SAPOSINS-B AND C, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=7730378; DOI=10.1074/jbc.270.17.9953; RA Vaccaro A.M., Salvioli R., Barca A., Tatti M., Ciaffoni F., Maras B., RA Siciliano R., Zappacosta F., Amoresano A., Pucci P.; RT "Structural analysis of saposin C and B. Complete localization of disulfide RT bridges."; RL J. Biol. Chem. 270:9953-9960(1995). RN [24] RP FUNCTION. RX PubMed=10383054; RX DOI=10.1002/(sici)1098-1136(199906)26:4<353::aid-glia9>3.3.co;2-7; RA Hiraiwa M., Campana W.M., Mizisin A.P., Mohiuddin L., O'Brien J.S.; RT "Prosaposin: a myelinotrophic protein that promotes expression of myelin RT constituents and is secreted after nerve injury."; RL Glia 26:353-360(1999). RN [25] RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Urine; RX PubMed=10510427; RX DOI=10.1002/(sici)1096-9888(199910)34:10<1040::aid-jms863>3.0.co;2-x; RA Faull K.F., Whitelegge J.P., Higginson J., To T., Johnson J., RA Krutchinsky A.N., Standing K.G., Waring A.J., Stevens R.L., Fluharty C.B., RA Fluharty A.L.; RT "Cerebroside sulfate activator protein (Saposin B): chromatographic and RT electrospray mass spectrometric properties."; RL J. Mass Spectrom. 34:1040-1054(1999). RN [26] RP GLYCOSYLATION AT ASN-215, AND STRUCTURE OF CARBOHYDRATE ON ASN-215. RX PubMed=11180632; RX DOI=10.1002/1096-9888(200012)35:12<1416::aid-jms75>3.0.co;2-k; RA Faull K.F., Johnson J., Kim M.J., To T., Whitelegge J.P., Stevens R.L., RA Fluharty C.B., Fluharty A.L.; RT "Structure of the asparagine-linked sugar chains of porcine kidney and RT human urine cerebroside sulfate activator protein."; RL J. Mass Spectrom. 35:1416-1424(2000). RN [27] RP DISULFIDE BONDS IN SAPOSIN-D. RX PubMed=10406958; DOI=10.1046/j.1432-1327.1999.00521.x; RA Tatti M., Salvioli R., Ciaffoni F., Pucci P., Andolfo A., Amoresano A., RA Vaccaro A.M.; RT "Structural and membrane-binding properties of saposin D."; RL Eur. J. Biochem. 263:486-494(1999). RN [28] RP SUBCELLULAR LOCATION, AND INTERACTION WITH SORT1. RX PubMed=14657016; DOI=10.1093/emboj/cdg629; RA Lefrancois S., Zeng J., Hassan A.J., Canuel M., Morales C.R.; RT "The lysosomal trafficking of sphingolipid activator proteins (SAPs) is RT mediated by sortilin."; RL EMBO J. 22:6430-6437(2003). RN [29] RP DISULFIDE BONDS IN SAPOSIN-B. RX PubMed=12510003; DOI=10.1016/s1046-5928(02)00597-1; RA Ahn V.E., Faull K.F., Whitelegge J.P., Higginson J., Fluharty A.L., RA Prive G.G.; RT "Expression, purification, crystallization, and preliminary X-ray analysis RT of recombinant human saposin B."; RL Protein Expr. Purif. 27:186-193(2003). RN [30] RP GLYCOSYLATION AT ASN-80; ASN-101; ASN-215; ASN-332 AND ASN-426. RX PubMed=19167329; DOI=10.1016/j.cell.2008.11.047; RA Ruiz-Canada C., Kelleher D.J., Gilmore R.; RT "Cotranslational and posttranslational N-glycosylation of polypeptides by RT distinct mammalian OST isoforms."; RL Cell 136:272-283(2009). RN [31] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-80; ASN-101; ASN-332 AND RP ASN-426. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [33] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=21835174; DOI=10.1016/j.yexcr.2011.07.017; RA Yuan L., Morales C.R.; RT "Prosaposin sorting is mediated by oligomerization."; RL Exp. Cell Res. 317:2456-2467(2011). RN [34] RP INTERACTION WITH SORT1, AND SUBCELLULAR LOCATION. RX PubMed=22431521; DOI=10.1128/mcb.06726-11; RA Mamo A., Jules F., Dumaresq-Doiron K., Costantino S., Lefrancois S.; RT "The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal RT sorting."; RL Mol. Cell. Biol. 32:1855-1866(2012). RN [35] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [36] RP INTERACTION WITH GRN. RX PubMed=26370502; DOI=10.1083/jcb.201502029; RA Zhou X., Sun L., Bastos de Oliveira F., Qi X., Brown W.J., Smolka M.B., RA Sun Y., Hu F.; RT "Prosaposin facilitates sortilin-independent lysosomal trafficking of RT progranulin."; RL J. Cell Biol. 210:991-1002(2015). RN [37] RP CLEAVAGE OF SIGNAL PEPTIDE [LARGE SCALE ANALYSIS] AFTER ALA-16, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 195-273, AND MUTAGENESIS OF RP ILE-240. RX PubMed=12518053; DOI=10.1073/pnas.0136947100; RA Ahn V.E., Faull K.F., Whitelegge J.P., Fluharty A.L., Prive G.G.; RT "Crystal structure of saposin B reveals a dimeric shell for lipid RT binding."; RL Proc. Natl. Acad. Sci. U.S.A. 100:38-43(2003). RN [39] RP REVIEW ON MLDSAPB VARIANTS. RX PubMed=7866401; DOI=10.1002/humu.1380040402; RA Gieselmann V., Zlotogora J., Harris A., Wenger D.A., Morris C.P.; RT "Molecular genetics of metachromatic leukodystrophy."; RL Hum. Mutat. 4:233-242(1994). RN [40] RP VARIANT MLDSAPB ILE-217. RX PubMed=2302219; DOI=10.1016/0006-291x(90)90912-7; RA Rafi M.A., Zhang X.-L., Degala G., Wenger D.A.; RT "Detection of a point mutation in sphingolipid activator protein-1 mRNA in RT patients with a variant form of metachromatic leukodystrophy."; RL Biochem. Biophys. Res. Commun. 166:1017-1023(1990). RN [41] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT MLDSAPB ILE-217. RX PubMed=2320574; DOI=10.1073/pnas.87.7.2541; RA Kretz K.A., Carson G.S., Morimoto S., Kishimoto Y., Fluharty A.L., RA O'Brien J.S.; RT "Characterization of a mutation in a family with saposin B deficiency: a RT glycosylation site defect."; RL Proc. Natl. Acad. Sci. U.S.A. 87:2541-2544(1990). RN [42] RP VARIANT MLDSAPB SER-241, NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE RP SPLICING. RX PubMed=2019586; DOI=10.1016/s0021-9258(20)89483-6; RA Holtschmidt H., Sandhoff K., Kwon H.Y., Harzer K., Nakano T., Suzuki K.; RT "Sulfatide activator protein. Alternative splicing that generates three RT mRNAs and a newly found mutation responsible for a clinical disease."; RL J. Biol. Chem. 266:7556-7560(1991). RN [43] RP INVOLVEMENT IN PSAPD. RX PubMed=1371116; DOI=10.1016/s0021-9258(19)50733-5; RA Schnabel D., Schroder M., Furst W., Klein A., Hurwitz R., Zenk T., RA Weber J., Harzer K., Paton B.C., Poulos A., Suzuki K., Sandhoff K.; RT "Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is RT caused by a mutation in the initiation codon of their common gene."; RL J. Biol. Chem. 267:3312-3315(1992). RN [44] RP VARIANT GDSAPC PHE-388. RX PubMed=2060627; DOI=10.1016/0014-5793(91)80760-z; RA Schnabel D., Schroeder M., Sandhoff K.; RT "Mutation in the sphingolipid activator protein 2 in a patient with a RT variant of Gaucher disease."; RL FEBS Lett. 284:57-59(1991). RN [45] RP VARIANT MLDSAPB LYS-215. RX PubMed=10196694; DOI=10.1038/sj.ejhg.5200266; RA Regis S., Filocamo M., Corsolini F., Caroli F., Keulemans J.L.M., RA van Diggelen O.P., Gatti R.; RT "An Asn > Lys substitution in saposin B involving a conserved amino acidic RT residue and leading to the loss of the single N-glycosylation site in a RT patient with metachromatic leukodystrophy and normal arylsulphatase A RT activity."; RL Eur. J. Hum. Genet. 7:125-130(1999). RN [46] RP VARIANT MLDSAPB HIS-215, AND CHARACTERIZATION OF VARIANT MLDSAPB HIS-215. RX PubMed=10682309; DOI=10.1023/a:1005603014401; RA Wrobe D., Henseler M., Huettler S., Pascual Pascual S.I., Chabas A., RA Sandhoff K.; RT "A non-glycosylated and functionally deficient mutant (N215H) of the RT sphingolipid activator protein B (SAP-B) in a novel case of metachromatic RT leukodystrophy (MLD)."; RL J. Inherit. Metab. Dis. 23:63-76(2000). RN [47] RP INVOLVEMENT IN PSAPD. RX PubMed=11309366; DOI=10.1093/hmg/10.9.927; RA Hulkova H., Cervenkova M., Ledvinova J., Tochackova M., Hrebicek M., RA Poupetova H., Befekadu A., Berna L., Paton B.C., Harzer K., Boor A., RA Smid F., Elleder M.; RT "A novel mutation in the coding region of the prosaposin gene leads to a RT complete deficiency of prosaposin and saposins, and is associated with a RT complex sphingolipidosis dominated by lactosylceramide accumulation."; RL Hum. Mol. Genet. 10:927-940(2001). RN [48] RP VARIANT KRBSAPA VAL-70 DEL. RX PubMed=15773042; DOI=10.1016/j.ymgme.2004.10.004; RA Spiegel R., Bach G., Sury V., Mengistu G., Meidan B., Shalev S., Shneor Y., RA Mandel H., Zeigler M.; RT "A mutation in the saposin A coding region of the prosaposin gene in an RT infant presenting as Krabbe disease: first report of saposin A deficiency RT in humans."; RL Mol. Genet. Metab. 84:160-166(2005). RN [49] RP VARIANT GDSAPC PRO-349. RX PubMed=17919309; DOI=10.1111/j.1399-0004.2007.00899.x; RA Tylki-Szymanska A., Czartoryska B., Vanier M.T., Poorthuis B.J., RA Groener J.A., Lugowska A., Millat G., Vaccaro A.M., Jurkiewicz E.; RT "Non-neuronopathic Gaucher disease due to saposin C deficiency."; RL Clin. Genet. 72:538-542(2007). RN [50] RP INVOLVEMENT IN PARK24, VARIANTS PARK24 TYR-412 AND PRO-453, AND RP CHARACTERIZATION OF VARIANTS PARK24 TYR-412 AND PRO-453. RX PubMed=32201884; DOI=10.1093/brain/awaa064; RA Oji Y., Hatano T., Ueno S.I., Funayama M., Ishikawa K.I., Okuzumi A., RA Noda S., Sato S., Satake W., Toda T., Li Y., Hino-Takai T., Kakuta S., RA Tsunemi T., Yoshino H., Nishioka K., Hattori T., Mizutani Y., Mutoh T., RA Yokochi F., Ichinose Y., Koh K., Shindo K., Takiyama Y., Hamaguchi T., RA Yamada M., Farrer M.J., Uchiyama Y., Akamatsu W., Wu Y.R., Matsuda J., RA Hattori N.; RT "Variants in saposin D domain of prosaposin gene linked to Parkinson's RT disease."; RL Brain 143:1190-1205(2020). CC -!- FUNCTION: Saposin-A and saposin-C stimulate the hydrolysis of CC glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and CC galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin- CC C apparently acts by combining with the enzyme and acidic lipid to form CC an activated complex, rather than by solubilizing the substrate. CC -!- FUNCTION: Saposin-B stimulates the hydrolysis of galacto-cerebroside CC sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta- CC galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha- CC galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex CC with the substrates of the sphingolipid hydrolases. CC -!- FUNCTION: Saposin-D is a specific sphingomyelin phosphodiesterase CC activator (EC 3.1.4.12). CC -!- FUNCTION: [Prosaposin]: Behaves as a myelinotrophic and neurotrophic CC factor, these effects are mediated by its G-protein-coupled receptors, CC GPR37 and GPR37L1, undergoing ligand-mediated internalization followed CC by ERK phosphorylation signaling. {ECO:0000250|UniProtKB:Q61207, CC ECO:0000269|PubMed:10383054}. CC -!- FUNCTION: Saposins are specific low-molecular mass non-enzymic CC proteins, they participate in the lysosomal degradation of CC sphingolipids, which takes place by the sequential action of specific CC hydrolases. CC -!- SUBUNIT: Saposin-B is a homodimer. Prosaposin exists as a roughly half- CC half mixture of monomers and disulfide-linked dimers (PubMed:10406958, CC PubMed:12510003, PubMed:21835174, PubMed:7730378). Monomeric prosaposin CC interacts (via C-terminus) with sortilin/SORT1, the interaction is CC required for targeting to lysosomes (PubMed:14657016, PubMed:22431521). CC Interacts with GRN; facilitates lysosomal delivery of progranulin from CC the extracellular space and the biosynthetic pathway (PubMed:26370502). CC {ECO:0000269|PubMed:10406958, ECO:0000269|PubMed:12510003, CC ECO:0000269|PubMed:14657016, ECO:0000269|PubMed:21835174, CC ECO:0000269|PubMed:22431521, ECO:0000269|PubMed:26370502, CC ECO:0000269|PubMed:7730378}. CC -!- INTERACTION: CC P07602; P05067: APP; NbExp=3; IntAct=EBI-716699, EBI-77613; CC P07602; Q92624: APPBP2; NbExp=3; IntAct=EBI-716699, EBI-743771; CC P07602; P31944: CASP14; NbExp=3; IntAct=EBI-716699, EBI-2510738; CC P07602; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-716699, EBI-9087876; CC P07602; P28799: GRN; NbExp=6; IntAct=EBI-716699, EBI-747754; CC P07602; P07948: LYN; NbExp=3; IntAct=EBI-716699, EBI-79452; CC P07602; P50542-3: PEX5; NbExp=3; IntAct=EBI-716699, EBI-12181987; CC P07602; O96006: ZBED1; NbExp=4; IntAct=EBI-716699, EBI-740037; CC P07602-1; P07602-1: PSAP; NbExp=5; IntAct=EBI-10635648, EBI-10635648; CC P07602-1; P55072: VCP; NbExp=3; IntAct=EBI-10635648, EBI-355164; CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:14657016, CC ECO:0000269|PubMed:21835174, ECO:0000269|PubMed:22431521}. CC -!- SUBCELLULAR LOCATION: [Prosaposin]: Secreted CC {ECO:0000250|UniProtKB:Q61207}. Note=Secreted as a fully glycosylated CC 70 kDa protein composed of complex glycans. CC {ECO:0000250|UniProtKB:Q61207}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=Sap-mu-0; CC IsoId=P07602-1; Sequence=Displayed; CC Name=Sap-mu-6; CC IsoId=P07602-2; Sequence=VSP_006014; CC Name=Sap-mu-9; CC IsoId=P07602-3; Sequence=VSP_006015; CC -!- PTM: The lysosomal precursor is proteolytically processed to 4 small CC peptides, which are similar to each other and are sphingolipid CC hydrolase activator proteins. CC -!- PTM: N-linked glycans show a high degree of microheterogeneity. CC {ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329}. CC -!- PTM: The one residue extended Saposin-B-Val is only found in 5% of the CC chains. CC -!- DISEASE: Combined saposin deficiency (PSAPD) [MIM:611721]: An autosomal CC recessive storage disorder characterized by hepatosplenomegaly and CC severe neurologic disease, due to absence of all saposins. PSAPD has a CC fatal outcome in infancy. {ECO:0000269|PubMed:11309366, CC ECO:0000269|PubMed:1371116}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Metachromatic leukodystrophy due to saposin B deficiency CC (MLDSAPB) [MIM:249900]: A form of metachromatic leukodystrophy CC biochemically characterized by tissue accumulation of cerebroside-3- CC sulfate, saposin B deficiency, and normal arylsulfatase A activity. CC Clinical manifestations include periventricular white matter CC abnormalities, demyelination, and peripheral neuropathy. Additional CC neurological features include dysarthria, ataxic gait, psychomotor CC regression, seizures, cognitive decline and spastic quadriparesis. CC {ECO:0000269|PubMed:10196694, ECO:0000269|PubMed:10682309, CC ECO:0000269|PubMed:2019586, ECO:0000269|PubMed:2302219, CC ECO:0000269|PubMed:2320574}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gaucher disease, atypical, due to saposin C deficiency CC (GDSAPC) [MIM:610539]: A disease characterized by marked CC glucosylceramide accumulation in the spleen without having a deficiency CC of glucosylceramide-beta glucosidase characteristic of classic Gaucher CC disease. Gaucher disease is a lysosomal storage disorder characterized CC by skeletal deterioration, hepatosplenomegaly, and organ dysfunction. CC There are several subtypes based on the presence and severity of CC neurological involvement. {ECO:0000269|PubMed:17919309, CC ECO:0000269|PubMed:2060627}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Krabbe disease, atypical, due to saposin A deficiency CC (KRBSAPA) [MIM:611722]: An autosomal recessive disorder of CC galactosylceramide metabolism. Clinical features include neurologic CC regression around age 3 months, loss of spontaneous movements, CC hyporeflexia, generalized brain atrophy, and diffuse white matter CC dysmyelination. {ECO:0000269|PubMed:15773042}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PSAP saposin-D region are found in a variant CC of Tay-Sachs disease (GM2-gangliosidosis). CC -!- DISEASE: Parkinson disease 24, autosomal dominant (PARK24) CC [MIM:619491]: An autosomal dominant form of Parkinson disease, a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. PARK24 shows incomplete penetrance. CC {ECO:0000269|PubMed:32201884}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Saposin-B co-purifies with 1 molecule of CC phosphatidylethanolamine. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42980/PSAP"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J03077; AAA52560.1; -; mRNA. DR EMBL; D00422; BAA00321.1; -; mRNA. DR EMBL; BT006849; AAP35495.1; -; mRNA. DR EMBL; CR456746; CAG33027.1; -; mRNA. DR EMBL; AC073370; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL731541; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471083; EAW54437.1; -; Genomic_DNA. DR EMBL; BC001503; AAH01503.1; -; mRNA. DR EMBL; BC004275; AAH04275.1; -; mRNA. DR EMBL; BC007612; AAH07612.1; -; mRNA. DR EMBL; M86181; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; X57107; CAA40391.1; -; Genomic_DNA. DR EMBL; X57108; CAA40392.1; -; Genomic_DNA. DR EMBL; M12710; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; J03015; AAB59494.1; -; mRNA. DR EMBL; M32221; AAA60303.1; -; mRNA. DR EMBL; M60257; AAA36595.1; -; mRNA. DR EMBL; M60258; AAA36596.1; -; mRNA. DR EMBL; M60255; AAA36594.1; -; mRNA. DR CCDS; CCDS7311.1; -. [P07602-1] DR PIR; JX0061; SAHUP. DR RefSeq; NP_001035930.1; NM_001042465.3. [P07602-3] DR RefSeq; NP_001035931.1; NM_001042466.3. [P07602-2] DR RefSeq; NP_002769.1; NM_002778.4. [P07602-1] DR PDB; 1M12; NMR; -; A=311-390. DR PDB; 1N69; X-ray; 2.20 A; A/B/C=195-273. DR PDB; 1SN6; NMR; -; A=311-390. DR PDB; 2DOB; X-ray; 2.00 A; A=60-140. DR PDB; 2GTG; X-ray; 2.40 A; A=311-391. DR PDB; 2QYP; X-ray; 2.45 A; A/B=311-392. DR PDB; 2R0R; X-ray; 2.50 A; A/B=407-484. DR PDB; 2R1Q; X-ray; 2.50 A; A=407-484. DR PDB; 2RB3; X-ray; 2.10 A; A/B/C/D=407-484. DR PDB; 2Z9A; X-ray; 2.50 A; A/B=311-389. DR PDB; 3BQP; X-ray; 1.30 A; A/B=405-484. DR PDB; 3BQQ; X-ray; 2.00 A; A/B/C/D=405-484. DR PDB; 4DDJ; X-ray; 1.90 A; A=60-140. DR PDB; 4UEX; X-ray; 1.80 A; A/B=60-142. DR PDB; 4V2O; X-ray; 2.13 A; A/B/C=195-273. DR PDB; 6SLR; X-ray; 2.38 A; A/B/C=195-272. DR PDB; 8EQU; EM; 2.80 A; C/F=60-140. DR PDB; 9AVS; X-ray; 3.53 A; C=195-273. DR PDB; 9AXG; X-ray; 2.68 A; A/B=195-273. DR PDB; 9I63; X-ray; 1.65 A; A/B=405-486. DR PDBsum; 1M12; -. DR PDBsum; 1N69; -. DR PDBsum; 1SN6; -. DR PDBsum; 2DOB; -. DR PDBsum; 2GTG; -. DR PDBsum; 2QYP; -. DR PDBsum; 2R0R; -. DR PDBsum; 2R1Q; -. DR PDBsum; 2RB3; -. DR PDBsum; 2Z9A; -. DR PDBsum; 3BQP; -. DR PDBsum; 3BQQ; -. DR PDBsum; 4DDJ; -. DR PDBsum; 4UEX; -. DR PDBsum; 4V2O; -. DR PDBsum; 6SLR; -. DR PDBsum; 8EQU; -. DR PDBsum; 9AVS; -. DR PDBsum; 9AXG; -. DR PDBsum; 9I63; -. DR AlphaFoldDB; P07602; -. DR EMDB; EMD-28546; -. DR SASBDB; P07602; -. DR SMR; P07602; -. DR BioGRID; 111639; 131. DR CORUM; P07602; -. DR DIP; DIP-29803N; -. DR FunCoup; P07602; 964. DR IntAct; P07602; 134. DR MINT; P07602; -. DR STRING; 9606.ENSP00000378394; -. DR BindingDB; P07602; -. DR ChEMBL; CHEMBL3580523; -. DR DrugBank; DB01966; Di-Stearoyl-3-Sn-Phosphatidylethanolamine. DR TCDB; 1.C.35.2.1; the amoebapore (amoebapore) family. DR GlyConnect; 1645; 140 N-Linked glycans (6 sites), 2 O-Linked glycans (3 sites). DR GlyCosmos; P07602; 14 sites, 167 glycans. DR GlyGen; P07602; 23 sites, 291 N-linked glycans (7 sites), 1 N-linked;o-linked glycan (2 sites), 4 O-linked glycans (16 sites). DR iPTMnet; P07602; -. DR MetOSite; P07602; -. DR PhosphoSitePlus; P07602; -. DR BioMuta; PSAP; -. DR DMDM; 134218; -. DR jPOST; P07602; -. DR MassIVE; P07602; -. DR PaxDb; 9606-ENSP00000378394; -. DR PeptideAtlas; P07602; -. DR PRIDE; P07602; -. DR ProteomicsDB; 52019; -. [P07602-1] DR ProteomicsDB; 52020; -. [P07602-2] DR ProteomicsDB; 52021; -. [P07602-3] DR Pumba; P07602; -. DR TopDownProteomics; P07602-1; -. [P07602-1] DR Antibodypedia; 1388; 513 antibodies from 37 providers. DR DNASU; 5660; -. DR Ensembl; ENST00000394936.8; ENSP00000378394.3; ENSG00000197746.16. [P07602-1] DR GeneID; 5660; -. DR KEGG; hsa:5660; -. DR MANE-Select; ENST00000394936.8; ENSP00000378394.3; NM_002778.4; NP_002769.1. DR UCSC; uc001jsm.4; human. [P07602-1] DR AGR; HGNC:9498; -. DR ClinPGx; PA33845; -. DR CTD; 5660; -. DR DisGeNET; 5660; -. DR GeneCards; PSAP; -. DR HGNC; HGNC:9498; PSAP. DR HPA; ENSG00000197746; Low tissue specificity. DR MalaCards; PSAP; -. DR MIM; 176801; gene. DR MIM; 249900; phenotype. DR MIM; 610539; phenotype. DR MIM; 611721; phenotype. DR MIM; 611722; phenotype. DR MIM; 619491; phenotype. DR OpenTargets; ENSG00000197746; -. DR Orphanet; 309252; Atypical Gaucher disease due to saposin C deficiency. DR Orphanet; 139406; Encephalopathy due to prosaposin deficiency. DR Orphanet; 206436; Infantile Krabbe disease. DR Orphanet; 309271; Metachromatic leukodystrophy, adult form. DR Orphanet; 309263; Metachromatic leukodystrophy, juvenile form. DR Orphanet; 309256; Metachromatic leukodystrophy, late infantile form. DR VEuPathDB; HostDB:ENSG00000197746; -. DR eggNOG; KOG1340; Eukaryota. DR GeneTree; ENSGT00940000156695; -. DR HOGENOM; CLU_033757_0_0_1; -. DR InParanoid; P07602; -. DR OrthoDB; 69496at2759; -. DR PAN-GO; P07602; 6 GO annotations based on evolutionary models. DR PhylomeDB; P07602; -. DR PathwayCommons; P07602; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SignaLink; P07602; -. DR SIGNOR; P07602; -. DR Agora; ENSG00000197746; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5660; 21 hits in 1170 CRISPR screens. DR ChiTaRS; PSAP; human. DR EvolutionaryTrace; P07602; -. DR GeneWiki; Prosaposin; -. DR GenomeRNAi; 5660; -. DR Pharos; P07602; Tbio. DR PRO; PR:P07602; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P07602; protein. DR Bgee; ENSG00000197746; Expressed in monocyte and 211 other cell types or tissues. DR ExpressionAtlas; P07602; baseline and differential. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; IDA:CAFA. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0008047; F:enzyme activator activity; TAS:ProtInc. DR GO; GO:1905573; F:ganglioside GM1 binding; IDA:CAFA. DR GO; GO:1905574; F:ganglioside GM2 binding; IDA:CAFA. DR GO; GO:1905575; F:ganglioside GM3 binding; IDA:CAFA. DR GO; GO:1905577; F:ganglioside GP1c binding; IDA:CAFA. DR GO; GO:1905576; F:ganglioside GT1b binding; IDA:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005543; F:phospholipid binding; IDA:CAFA. DR GO; GO:0002020; F:protease binding; IPI:MGI. DR GO; GO:0042803; F:protein homodimerization activity; IDA:CAFA. DR GO; GO:0097110; F:scaffold protein binding; IPI:ARUK-UCL. DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0060742; P:epithelial cell differentiation involved in prostate gland development; IBA:GO_Central. DR GO; GO:1905572; P:ganglioside GM1 transport to membrane; IDA:CAFA. DR GO; GO:0010467; P:gene expression; IDA:MGI. DR GO; GO:0007041; P:lysosomal transport; IDA:UniProtKB. DR GO; GO:0060736; P:prostate gland growth; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IBA:GO_Central. DR GO; GO:0006665; P:sphingolipid metabolic process; IEA:UniProtKB-KW. DR FunFam; 1.10.225.10:FF:000002; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000004; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000005; prosaposin isoform X2; 1. DR FunFam; 1.10.225.10:FF:000006; prosaposin isoform X2; 1. DR Gene3D; 1.10.225.10; Saposin-like; 4. DR InterPro; IPR003119; SAP_A. DR InterPro; IPR007856; SapB_1. DR InterPro; IPR008138; SapB_2. DR InterPro; IPR008373; Saposin. DR InterPro; IPR011001; Saposin-like. DR InterPro; IPR021165; Saposin_chordata. DR InterPro; IPR008139; SaposinB_dom. DR InterPro; IPR051428; Sphingo_Act-Surfact_Prot. DR PANTHER; PTHR11480:SF36; PROSAPOSIN; 1. DR PANTHER; PTHR11480; SAPOSIN-RELATED; 1. DR Pfam; PF02199; SapA; 2. DR Pfam; PF05184; SapB_1; 3. DR Pfam; PF03489; SapB_2; 4. DR PIRSF; PIRSF002431; Saposin; 1. DR PRINTS; PR01797; SAPOSIN. DR SMART; SM00162; SAPA; 2. DR SMART; SM00741; SapB; 4. DR SUPFAM; SSF47862; Saposin; 4. DR PROSITE; PS51110; SAP_A; 2. DR PROSITE; PS50015; SAP_B; 4. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Direct protein sequencing; KW Disease variant; Disulfide bond; Gangliosidosis; Gaucher disease; KW Glycoprotein; Leukodystrophy; Lipid metabolism; Lysosome; KW Metachromatic leukodystrophy; Neurodegeneration; Parkinson disease; KW Parkinsonism; Proteomics identification; Reference proteome; Repeat; KW Secreted; Signal; Sphingolipid metabolism. FT SIGNAL 1..16 FT /evidence="ECO:0000269|PubMed:1958198, FT ECO:0000269|PubMed:8323276, ECO:0007744|PubMed:25944712" FT CHAIN 17..524 FT /note="Prosaposin" FT /evidence="ECO:0000269|PubMed:8323276" FT /id="PRO_0000424774" FT PROPEP 17..59 FT /evidence="ECO:0000305" FT /id="PRO_0000031616" FT CHAIN 60..142 FT /note="Saposin-A" FT /evidence="ECO:0000269|PubMed:2717620" FT /id="PRO_0000031617" FT PROPEP 143..194 FT /evidence="ECO:0000305" FT /id="PRO_0000031618" FT CHAIN 195..274 FT /note="Saposin-B-Val" FT /evidence="ECO:0000269|PubMed:2209618, FT ECO:0000269|PubMed:3242555" FT /id="PRO_0000031619" FT CHAIN 195..273 FT /note="Saposin-B" FT /evidence="ECO:0000269|PubMed:2209618" FT /id="PRO_0000031620" FT PROPEP 275..310 FT /evidence="ECO:0000305" FT /id="PRO_0000031621" FT CHAIN 311..390 FT /note="Saposin-C" FT /evidence="ECO:0000269|PubMed:3442600" FT /id="PRO_0000031622" FT PROPEP 393..404 FT /evidence="ECO:0000305" FT /id="PRO_0000031623" FT CHAIN 405..486 FT /note="Saposin-D" FT /evidence="ECO:0000269|PubMed:2845979" FT /id="PRO_0000031624" FT PROPEP 487..524 FT /evidence="ECO:0000305" FT /id="PRO_0000031625" FT DOMAIN 18..58 FT /note="Saposin A-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00414" FT DOMAIN 59..142 FT /note="Saposin B-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 194..275 FT /note="Saposin B-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 311..392 FT /note="Saposin B-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 405..486 FT /note="Saposin B-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415" FT DOMAIN 488..524 FT /note="Saposin A-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00414" FT SITE 215 FT /note="Not glycosylated; in variant MLDSAPB Ile-217" FT CARBOHYD 80 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329, FT ECO:0000269|PubMed:2842863" FT CARBOHYD 101 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329, FT ECO:0000269|PubMed:2842863" FT CARBOHYD 215 FT /note="N-linked (GlcNAc...) (complex) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:11180632, ECO:0000269|PubMed:19167329" FT /id="CAR_000176" FT CARBOHYD 332 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329" FT CARBOHYD 426 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19167329" FT DISULFID 63..138 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 66..132 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 94..106 FT /evidence="ECO:0000305|PubMed:2717620" FT DISULFID 198..271 FT /evidence="ECO:0000269|PubMed:12510003" FT DISULFID 201..265 FT /evidence="ECO:0000269|PubMed:12510003" FT DISULFID 230..241 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 315..388 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 318..382 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 346..357 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415, FT ECO:0000269|PubMed:7730378" FT DISULFID 409..482 FT /evidence="ECO:0000269|PubMed:10406958" FT DISULFID 412..476 FT /evidence="ECO:0000269|PubMed:10406958" FT DISULFID 440..451 FT /evidence="ECO:0000269|PubMed:10406958" FT VAR_SEQ 259 FT /note="M -> MDQ (in isoform Sap-mu-6)" FT /evidence="ECO:0000305" FT /id="VSP_006014" FT VAR_SEQ 260 FT /note="Q -> QDQQ (in isoform Sap-mu-9)" FT /evidence="ECO:0000305" FT /id="VSP_006015" FT VARIANT 70 FT /note="Missing (in KRBSAPA)" FT /evidence="ECO:0000269|PubMed:15773042" FT /id="VAR_042440" FT VARIANT 215 FT /note="N -> H (in MLDSAPB; reduces the intracellular FT activity of the protein significantly; dbSNP:rs121918107)" FT /evidence="ECO:0000269|PubMed:10682309" FT /id="VAR_031823" FT VARIANT 215 FT /note="N -> K (in MLDSAPB; dbSNP:rs770171865)" FT /evidence="ECO:0000269|PubMed:10196694" FT /id="VAR_031899" FT VARIANT 217 FT /note="T -> I (in MLDSAPB; juvenile; affects glycosylation FT at N-215; dbSNP:rs121918103)" FT /evidence="ECO:0000269|PubMed:2302219, FT ECO:0000269|PubMed:2320574" FT /id="VAR_006943" FT VARIANT 241 FT /note="C -> S (in MLDSAPB; severe; dbSNP:rs121918104)" FT /evidence="ECO:0000269|PubMed:2019586" FT /id="VAR_006944" FT VARIANT 349 FT /note="L -> P (in GDSAPC; dbSNP:rs121918110)" FT /evidence="ECO:0000269|PubMed:17919309" FT /id="VAR_042441" FT VARIANT 388 FT /note="C -> F (in GDSAPC)" FT /evidence="ECO:0000269|PubMed:2060627" FT /id="VAR_006945" FT VARIANT 412 FT /note="C -> Y (in PARK24; associated with disease FT susceptibility; affects the intracellular trafficking, FT resulting in endoplasmic reticulum retention; affects the FT intracellular trafficking, resulting in endoplasmic FT reticulum retention; cells carrying this variant show FT accumulation of autophagic vacuoles, impaired autophagic FT flux and alpha-synuclein/SNCA aggregation; FT dbSNP:rs1842252448)" FT /evidence="ECO:0000269|PubMed:32201884" FT /id="VAR_086130" FT VARIANT 453 FT /note="Q -> P (in PARK24; associated with disease FT susceptibility; affects the intracellular trafficking, FT resulting in endoplasmic reticulum retention; cells FT carrying this variant show accumulation of autophagic FT vacuoles, impaired autophagic flux and alpha-synuclein/SNCA FT aggregation; dbSNP:rs2133029712)" FT /evidence="ECO:0000269|PubMed:32201884" FT /id="VAR_086131" FT MUTAGEN 240 FT /note="I->C: Strongly decreases stimulation of cerebroside FT sulfate hydrolysis." FT /evidence="ECO:0000269|PubMed:12518053" FT CONFLICT 369 FT /note="L -> P (in Ref. 4; CAG33027)" FT /evidence="ECO:0000305" FT HELIX 61..78 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 83..96 FT /evidence="ECO:0007829|PDB:4UEX" FT STRAND 97..99 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 100..122 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 128..134 FT /evidence="ECO:0007829|PDB:4UEX" FT HELIX 196..214 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 218..229 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 230..233 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 237..257 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 261..267 FT /evidence="ECO:0007829|PDB:4V2O" FT HELIX 314..330 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 335..345 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 346..348 FT /evidence="ECO:0007829|PDB:1M12" FT HELIX 351..373 FT /evidence="ECO:0007829|PDB:2GTG" FT HELIX 378..384 FT /evidence="ECO:0007829|PDB:2GTG" FT TURN 386..388 FT /evidence="ECO:0007829|PDB:1SN6" FT HELIX 409..422 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 429..439 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 440..442 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 445..447 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 448..466 FT /evidence="ECO:0007829|PDB:3BQP" FT HELIX 472..478 FT /evidence="ECO:0007829|PDB:3BQP" SQ SEQUENCE 524 AA; 58113 MW; 71977F7A8C9E1533 CRC64; MYALFLLASL LGAALAGPVL GLKECTRGSA VWCQNVKTAS DCGAVKHCLQ TVWNKPTVKS LPCDICKDVV TAAGDMLKDN ATEEEILVYL EKTCDWLPKP NMSASCKEIV DSYLPVILDI IKGEMSRPGE VCSALNLCES LQKHLAELNH QKQLESNKIP ELDMTEVVAP FMANIPLLLY PQDGPRSKPQ PKDNGDVCQD CIQMVTDIQT AVRTNSTFVQ ALVEHVKEEC DRLGPGMADI CKNYISQYSE IAIQMMMHMQ PKEICALVGF CDEVKEMPMQ TLVPAKVASK NVIPALELVE PIKKHEVPAK SDVYCEVCEF LVKEVTKLID NNKTEKEILD AFDKMCSKLP KSLSEECQEV VDTYGSSILS ILLEEVSPEL VCSMLHLCSG TRLPALTVHV TQPKDGGFCE VCKKLVGYLD RNLEKNSTKQ EILAALEKGC SFLPDPYQKQ CDQFVAEYEP VLIEILVEVM DPSFVCLKIG ACPSAHKPLL GTEKCIWGPS YWCQNTETAA QCNAVEHCKR HVWN // ID SEPT4_HUMAN Reviewed; 996 AA. AC O43236; A0A5F9ZHH3; B2RD42; B3KSX9; B4DXC6; B4DXV5; Q6IAP3; Q8N821; Q8NEP4; AC Q9H315; Q9UM58; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 28-JAN-2026, sequence version 2. DT 28-JAN-2026, entry version 207. DE RecName: Full=Septin-4 {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Bradeion beta {ECO:0000303|PubMed:11511094}; DE AltName: Full=Brain protein H5 {ECO:0000250|UniProtKB:P28661}; DE AltName: Full=CE5B3 beta {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Cell division control-related protein 2 {ECO:0000312|HGNC:HGNC:9165}; DE Short=hCDCREL-2 {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Peanut-like protein 2 {ECO:0000303|PubMed:9889007}; GN Name=SEPTIN4 {ECO:0000312|HGNC:HGNC:9165}; GN Synonyms=C17orf47 {ECO:0000312|HGNC:HGNC:9165}, GN PNUTL2 {ECO:0000303|PubMed:9889007}, SEP4 {ECO:0000312|HGNC:HGNC:9165}, GN SEPT4 {ECO:0000312|HGNC:HGNC:9165}; ORFNames=hucep-7; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=9889007; DOI=10.1006/geno.1998.5612; RA Paavola P., Horelli-Kuitunen N., Palotie A., Peltonen L.; RT "Characterization of a novel gene, PNUTL2, on human chromosome 17q22-q23 RT and its exclusion as the Meckel syndrome gene."; RL Genomics 55:122-125(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY. RC TISSUE=Brain, and Fetal brain; RX PubMed=11167005; DOI=10.1016/s0378-1119(00)00527-8; RA Zieger B., Tran H., Hainmann I., Wunderle D., Zgaga-Griesz A., Blaeser S., RA Ware J.; RT "Characterization and expression analysis of two human septin genes, PNUTL1 RT and PNUTL2."; RL Gene 261:197-203(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ARTS), FUNCTION (ISOFORM ARTS), TISSUE RP SPECIFICITY (ISOFORM ARTS), SUBCELLULAR LOCATION (ISOFORM ARTS), AND RP MUTAGENESIS OF 137-GLY--SER-139 (ISOFORM ARTS). RC TISSUE=Fetal brain; RX PubMed=11146656; DOI=10.1038/35046566; RA Larisch S., Yi Y., Lotan R., Kerner H., Eimerl S., Parks W.T., Yossi G., RA Reffey S.B., de Caestecker M.P., Danielpour D., Book-Melamed N., RA Timberg R., Duckett C., Lechleider R.J., Steller H., Orly J., Kim S.-J., RA Roberts A.B.; RT "A novel mitochondrial septin-like protein, ARTS, mediates apoptosis RT dependent on its P-loop motif."; RL Nat. Cell Biol. 2:915-921(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11511094; DOI=10.1006/bbrc.2001.5413; RA Tanaka M., Tanaka T., Kijima H., Itoh J., Matsuda T., Hori S., Yamamoto M.; RT "Characterization of tissue- and cell-type-specific expression of a novel RT human septin family gene, Bradeion."; RL Biochem. Biophys. Res. Commun. 286:547-553(2001). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Yoshimoto M., Yazaki M., Matsumoto K., Takayama K.; RT "Molecular cloning of a new GTP binding protein from human brain."; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Zha D., Hu G.; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4; 5 AND 8). RC TISSUE=Amygdala, Brain cortex, Subthalamic nucleus, 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 8). RC TISSUE=Hippocampus, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP INTERACTION WITH SEPTIN8, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=15116257; DOI=10.1160/th03-09-0578; RA Blaeser S., Horn J., Wuermell P., Bauer H., Struempell S., Nurden P., RA Pagenstecher A., Busse A., Wunderle D., Hainmann I., Zieger B.; RT "The novel human platelet septin SEPT8 is an interaction partner of RT SEPT4."; RL Thromb. Haemost. 91:959-966(2004). RN [13] RP PROTEIN SEQUENCE OF 659-675 AND 800-808, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RC TISSUE=Fetal brain; RA Lubec G., Chen W.-Q.; RL Submitted (JAN-2009) to UniProtKB. RN [14] RP FUNCTION (ISOFORM ARTS). RX PubMed=15837787; DOI=10.1074/jbc.m501955200; RA Lotan R., Rotem A., Gonen H., Finberg J.P.M., Kemeny S., Steller H., RA Ciechanover A., Larisch S.; RT "Regulation of the proapoptotic ARTS protein by ubiquitin-mediated RT degradation."; RL J. Biol. Chem. 280:25802-25810(2005). RN [15] RP TISSUE SPECIFICITY. RX PubMed=15915442; DOI=10.1002/path.1789; RA Hall P.A., Jung K., Hillan K.J., Russell S.E.H.; RT "Expression profiling the human septin gene family."; RL J. Pathol. 206:269-278(2005). RN [16] 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 [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-843, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=18318008; DOI=10.1002/pmic.200700884; RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., RA Zou H., Gu J.; RT "Large-scale phosphoproteome analysis of human liver tissue by enrichment RT and fractionation of phosphopeptides with strong anion exchange RT chromatography."; RL Proteomics 8:1346-1361(2008). RN [18] RP INTERACTION WITH XIAP, AND SUBCELLULAR LOCATION. RX PubMed=21695558; DOI=10.1007/s10495-011-0622-0; RA Bornstein B., Gottfried Y., Edison N., Shekhtman A., Lev T., Glaser F., RA Larisch S.; RT "ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a RT mechanism that is different from other IAP-antagonists."; RL Apoptosis 16:869-881(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635; SER-636 AND SER-843, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] RP INTERACTION WITH SEPTIN9 HNA VARIANTS. RX PubMed=17546647; DOI=10.1002/humu.20554; RA Sudo K., Ito H., Iwamoto I., Morishita R., Asano T., Nagata K.; RT "SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are RT associated with altered interactions with SEPT4/SEPT11 and resistance to RT Rho/Rhotekin-signaling."; RL Hum. Mutat. 28:1005-1013(2007). RN [21] RP FUNCTION (ISOFORM ARTS), SUBCELLULAR LOCATION (ISOFORM ARTS), INTERACTION RP WITH XIAP (ISOFORM ARTS), AND MUTAGENESIS OF 137-GLY--SER-139 (ISOFORM RP ARTS). RX PubMed=15029247; DOI=10.1038/sj.emboj.7600155; RA Gottfried Y., Rotem A., Lotan R., Steller H., Larisch S.; RT "The mitochondrial ARTS protein promotes apoptosis through targeting RT XIAP."; RL EMBO J. 23:1627-1635(2004). RN [22] RP INTERACTION WITH AREL1, AND UBIQUITINATION. RX PubMed=23479728; DOI=10.1074/jbc.m112.436113; RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y., RA Chae H.D., Shin D.Y.; RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, RT and ARTS."; RL J. Biol. Chem. 288:12014-12021(2013). RN [23] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=25588830; DOI=10.1242/jcs.158998; RA Kuo Y.C., Shen Y.R., Chen H.I., Lin Y.H., Wang Y.Y., Chen Y.R., Wang C.Y., RA Kuo P.L.; RT "SEPT12 orchestrates the formation of mammalian sperm annulus by organizing RT core octameric complexes with other SEPT proteins."; RL J. Cell Sci. 128:923-934(2015). RN [24] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH BCL2 AND XIAP, AND INTERACTION RP WITH BCL2 AND XIAP. RX PubMed=29020630; DOI=10.1016/j.celrep.2017.09.052; RA Edison N., Curtz Y., Paland N., Mamriev D., Chorubczyk N., RA Haviv-Reingewertz T., Kfir N., Morgenstern D., Kupervaser M., Kagan J., RA Kim H.T., Larisch S.; RT "Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis."; RL Cell Rep. 21:442-454(2017). RN [25] RP TISSUE SPECIFICITY. RX PubMed=30389919; DOI=10.1038/s41467-018-06941-4; RA Koren E., Yosefzon Y., Ankawa R., Soteriou D., Jacob A., Nevelsky A., RA Ben-Yosef R., Bar-Sela G., Fuchs Y.; RT "ARTS mediates apoptosis and regeneration of the intestinal stem cell RT niche."; RL Nat. Commun. 9:4582-4582(2018). RN [26] RP INVOLVEMENT IN SPGF99, VARIANTS SPGF99 69-ARG--TYR-996 DEL AND RP 241-ARG--TYR-996 DEL, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=36135717; DOI=10.1002/humu.24475; RA Wang G., Zhu X., Gao Y., Lv M., Li K., Tang D., Wu H., Xu C., Geng H., RA Shen Q., Zha X., Duan Z., Zhang J., Hua R., Tao F., Zhou P., Wei Z., RA Cao Y., Guo R., He X.; RT "Biallelic loss-of-function mutations in SEPTIN4 (C17ORF47), encoding a RT conserved annulus protein, cause thin midpiece spermatozoa and male RT infertility in humans."; RL Hum. Mutat. 43:2079-2090(2022). CC -!- FUNCTION: Filament-forming cytoskeletal GTPase (Probable). Pro- CC apoptotic protein involved in LGR5-positive intestinal stem cell and CC Paneth cell expansion in the intestines, via its interaction with XIAP CC (By similarity). May also play a role in the regulation of cell fate in CC the intestine (By similarity). Positive regulator of apoptosis involved CC in hematopoietic stem cell homeostasis; via its interaction with XIAP CC (By similarity). Negative regulator of repair and hair follicle CC regeneration in response to injury, due to inhibition of hair follicle CC stem cell proliferation, potentially via its interaction with XIAP (By CC similarity). Plays an important role in male fertility and sperm CC motility (PubMed:36135717). During spermiogenesis, essential for the CC establishment of the annulus (a fibrous ring structure connecting the CC midpiece and the principal piece of the sperm flagellum) which is a CC requisite for the structural and mechanical integrity of the sperm CC (PubMed:36135717). Involved in the migration of cortical neurons and CC the formation of neuron leading processes during embryonic development CC (By similarity). Required for dopaminergic metabolism in presynaptic CC autoreceptors; potentially via activity as a presynaptic scaffold CC protein (By similarity). {ECO:0000250|UniProtKB:P28661, CC ECO:0000269|PubMed:36135717, ECO:0000305}. CC -!- FUNCTION: [Isoform ARTS]: Required for the induction of cell death CC mediated by TGF-beta and possibly by other apoptotic stimuli CC (PubMed:11146656, PubMed:15837787). Induces apoptosis through binding CC and inhibition of XIAP resulting in significant reduction in XIAP CC levels, leading to caspase activation and cell death (PubMed:15029247). CC Mediates the interaction between BCL2 and XIAP, thereby positively CC regulating the ubiquitination and degradation of BCL2 and promoting CC apoptosis (PubMed:29020630). {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:15029247, ECO:0000269|PubMed:15837787, CC ECO:0000269|PubMed:29020630}. CC -!- SUBUNIT: Septins polymerize into heterooligomeric protein complexes CC that form filaments, and can associate with cellular membranes, actin CC filaments and microtubules. GTPase activity is required for filament CC formation. Interacts with SEPTIN8 (PubMed:15116257). In a mesenchymal CC cell line, interacts with SEPTIN9 isoform 2 variants HNA Trp-106 and CC Phe-111, but not the wild type SEPTIN9 (PubMed:17546647). Component of CC a septin core octameric complex consisting of SEPTIN12, SEPTIN7, CC SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7- CC 6-4-4-6-7-12 (PubMed:25588830). Interacts with SEPTIN14 (via C- CC terminus) (By similarity). Interacts with DYRK1A (By similarity). CC Interacts with SLC6A3/DAT and SNCA/alpha-synuclein (By similarity). CC Interacts with STX1A; in the striatum (By similarity). Interacts with CC XIAP (via BIR3 domain) following the induction of apoptosis (By CC similarity). Interacts with AREL1 (via HECT domain); in the cytoplasm CC following induction of apoptosis (PubMed:23479728). CC {ECO:0000250|UniProtKB:P28661, ECO:0000269|PubMed:15116257, CC ECO:0000269|PubMed:17546647, ECO:0000269|PubMed:23479728, CC ECO:0000269|PubMed:25588830}. CC -!- SUBUNIT: [Isoform ARTS]: Part of a complex composed of SEPTIN4 isoform CC ARTS, XIAP and BCL2, within the complex interacts with both BCL2 (via CC BH3 domain) and XIAP, ARTS acts as a scaffold protein and stabilizes CC the complex (PubMed:29020630). Interacts with XIAP (via BIR3 domain) CC following the induction of apoptosis (PubMed:15029247, CC PubMed:21695558). {ECO:0000269|PubMed:15029247, CC ECO:0000269|PubMed:21695558, ECO:0000269|PubMed:29020630}. CC -!- INTERACTION: CC O43236; P05067: APP; NbExp=3; IntAct=EBI-1047513, EBI-77613; CC O43236; P63167: DYNLL1; NbExp=5; IntAct=EBI-1047513, EBI-349105; CC O43236; Q96FJ2: DYNLL2; NbExp=3; IntAct=EBI-1047513, EBI-742371; CC O43236; P42858: HTT; NbExp=3; IntAct=EBI-1047513, EBI-466029; CC O43236; Q8IYM1: SEPTIN12; NbExp=6; IntAct=EBI-1047513, EBI-2585067; CC O43236; P37840: SNCA; NbExp=3; IntAct=EBI-1047513, EBI-985879; CC O43236-6; Q8IUQ4: SIAH1; NbExp=2; IntAct=EBI-4372019, EBI-747107; CC O43236-6; P98170: XIAP; NbExp=4; IntAct=EBI-4372019, EBI-517127; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P28661}. Cell CC projection, cilium, flagellum {ECO:0000269|PubMed:25588830, CC ECO:0000269|PubMed:36135717}. Cytoplasmic vesicle, secretory vesicle CC {ECO:0000269|PubMed:15116257}. Cell projection, axon CC {ECO:0000250|UniProtKB:P28661}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:P28661}. Perikaryon CC {ECO:0000250|UniProtKB:P28661}. Synapse {ECO:0000269|PubMed:17296554}. CC Note=In platelets, found in areas surrounding alpha-granules CC (PubMed:15116257). Found in the sperm annulus, a fibrous ring structure CC connecting the midpiece and the principal piece of the sperm flagellum CC (PubMed:25588830, PubMed:36135717). Expressed and colocalized with CC SLC6A3 and SNCA in axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:P28661, CC ECO:0000269|PubMed:15116257, ECO:0000269|PubMed:25588830, CC ECO:0000269|PubMed:36135717}. CC -!- SUBCELLULAR LOCATION: [Isoform ARTS]: Mitochondrion CC {ECO:0000269|PubMed:11146656, ECO:0000269|PubMed:15029247, CC ECO:0000269|PubMed:21695558}. Nucleus {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:15029247}. Note=While predominantly localized in the CC mitochondria under resting conditions, translocates into the nucleus CC after TGF-beta treatment and apoptosis induction. CC {ECO:0000269|PubMed:11146656}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=7; CC IsoId=O43236-7; Sequence=Displayed; CC Name=1; Synonyms=PNUTL2, PNUTL2a, H5/CDCrel-2 CC {ECO:0000303|PubMed:11167005}, SEPT4_i1; CC IsoId=O43236-1; Sequence=VSP_062618; CC Name=2; Synonyms=PNUTL2b, CDCrel-1 {ECO:0000303|PubMed:11167005}; CC IsoId=O43236-2; Sequence=VSP_062619; CC Name=3; CC IsoId=O43236-3; Sequence=VSP_062621; CC Name=4; CC IsoId=O43236-4; Sequence=VSP_062620; CC Name=5; CC IsoId=O43236-5; Sequence=VSP_062617; CC Name=ARTS {ECO:0000303|PubMed:11146656}; Synonyms=SEPT4_i2; CC IsoId=O43236-6; Sequence=VSP_062619, VSP_062624, VSP_062625; CC Name=8; CC IsoId=O43236-8; Sequence=VSP_062622, VSP_062623; CC -!- TISSUE SPECIFICITY: Widely expressed in adult and fetal tissues with CC highest expression in adult brain (at protein level), heart, liver and CC adrenal gland and fetal heart, kidney, liver and lung. Expressed in CC presynaptic terminals of dopaminergic neurons projecting from the CC substantia nigra pars compacta to the striatum (at protein level) CC (PubMed:17296554). Expressed in axonal varicosities in dopaminergic CC nerve terminals (at protein level) (PubMed:17296554). Expressed in the CC putamen and in the adjacent cerebral cortex (at protein level) CC (PubMed:17296554). Expressed in colonic crypts (at protein level) CC (PubMed:30389919). Expressed in platelets. Expressed in spermatozoa (at CC protein level) (PubMed:36135717). {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:11167005, ECO:0000269|PubMed:11511094, CC ECO:0000269|PubMed:15116257, ECO:0000269|PubMed:15915442, CC ECO:0000269|PubMed:17296554, ECO:0000269|PubMed:30389919, CC ECO:0000269|PubMed:36135717, ECO:0000269|PubMed:9889007}. CC -!- TISSUE SPECIFICITY: [Isoform ARTS]: Highly expressed in the brain and CC heart. {ECO:0000269|PubMed:11146656}. CC -!- PTM: Phosphorylated by DYRK1A. {ECO:0000250|UniProtKB:P28661}. CC -!- PTM: Ubiquitinated by AREL1. {ECO:0000269|PubMed:23479728}. CC -!- DISEASE: Spermatogenic failure 99 (SPGF99) [MIM:621194]: An autosomal CC recessive, male infertility disorder characterized by CC asthenoteratozoospermia with markedly reduced sperm progressive CC motility, and abnormal sperm morphology. Patient sperm exhibit a thin CC midpiece, absence of the annulus, and disorganization of the CC mitochondrial sheath. {ECO:0000269|PubMed:36135717}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Colocalizes with alpha-synuclein in Lewy bodies in the CC substantia nigra pars compacta of Parkinson disease patients CC (PubMed:17296554). Shows reduced expression in dopaminergic nerve CC terminals of the striatum in sporadic Parkinson disease CC (PubMed:17296554). {ECO:0000269|PubMed:17296554}. CC -!- MISCELLANEOUS: [Isoform ARTS]: May be defective in GTP-binding. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like CC GTPase superfamily. Septin GTPase family. {ECO:0000255|PROSITE- CC ProRule:PRU01056}. 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; AF073312; AAC25673.1; -; mRNA. DR EMBL; U88829; AAD00653.1; -; mRNA. DR EMBL; U88870; AAD00657.1; -; mRNA. DR EMBL; AF176379; AAG45673.1; -; mRNA. DR EMBL; AB008753; BAB70695.1; -; mRNA. DR EMBL; D89278; BAB46922.1; -; mRNA. DR EMBL; AF035811; AAB88512.1; -; mRNA. DR EMBL; CR457111; CAG33392.1; -; mRNA. DR EMBL; AK315396; BAG37789.1; -; mRNA. DR EMBL; AK094579; BAG52891.1; -; mRNA. DR EMBL; AK294094; BAG57432.1; -; mRNA. DR EMBL; AK301914; BAG63338.1; -; mRNA. DR EMBL; AK302146; BAG63517.1; -; mRNA. DR EMBL; AK097440; BAC05054.1; -; mRNA. DR EMBL; AC005666; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471109; EAW94440.1; -; Genomic_DNA. DR EMBL; CH471109; EAW94442.1; -; Genomic_DNA. DR EMBL; BC018056; AAH18056.3; -; mRNA. DR EMBL; BC022189; AAH22189.2; -; mRNA. DR CCDS; CCDS11609.1; -. [O43236-2] DR CCDS; CCDS11610.1; -. [O43236-1] DR CCDS; CCDS32691.1; -. [O43236-8] DR CCDS; CCDS45743.1; -. [O43236-6] DR CCDS; CCDS56041.1; -. [O43236-3] DR CCDS; CCDS58581.1; -. [O43236-5] DR CCDS; CCDS58582.1; -. [O43236-4] DR CCDS; CCDS92368.1; -. [O43236-7] DR RefSeq; NP_001033793.3; NM_001038704.4. [O43236-8] DR RefSeq; NP_001185642.1; NM_001198713.2. [O43236-3] DR RefSeq; NP_001243711.1; NM_001256782.2. [O43236-4] DR RefSeq; NP_001243751.1; NM_001256822.2. [O43236-5] DR RefSeq; NP_001355700.1; NM_001368771.2. [O43236-7] DR RefSeq; NP_004565.1; NM_004574.5. [O43236-1] DR RefSeq; NP_536340.1; NM_080415.4. [O43236-6] DR RefSeq; NP_536341.1; NM_080416.4. [O43236-2] DR RefSeq; XP_006722018.1; XM_006721955.4. [O43236-5] DR RefSeq; XP_011523214.1; XM_011524912.3. [O43236-5] DR RefSeq; XP_024306576.1; XM_024450808.2. [O43236-5] DR RefSeq; XP_047292265.1; XM_047436309.1. [O43236-4] DR RefSeq; XP_054172497.1; XM_054316522.1. [O43236-4] DR RefSeq; XP_054172501.1; XM_054316526.1. [O43236-5] DR RefSeq; XP_054172502.1; XM_054316527.1. [O43236-5] DR RefSeq; XP_054172503.1; XM_054316528.1. [O43236-5] DR PDB; 6WB3; X-ray; 1.35 A; A/B=966-995. DR PDBsum; 6WB3; -. DR AlphaFoldDB; O43236; -. DR SMR; O43236; -. DR BioGRID; 111415; 28. DR BioGRID; 129753; 3. DR FunCoup; O43236; 359. DR IntAct; O43236; 27. DR MINT; O43236; -. DR STRING; 9606.ENSP00000354874; -. DR iPTMnet; O43236; -. DR PhosphoSitePlus; O43236; -. DR SwissPalm; O43236; -. DR BioMuta; C17orf47; -. DR BioMuta; SEPT4; -. DR DMDM; 300669697; -. DR jPOST; O43236; -. DR MassIVE; O43236; -. DR PaxDb; 9606-ENSP00000402000; -. DR PeptideAtlas; O43236; -. DR ProteomicsDB; 48814; -. [O43236-1] DR ProteomicsDB; 48815; -. [O43236-2] DR ProteomicsDB; 48816; -. [O43236-3] DR ProteomicsDB; 48817; -. [O43236-4] DR ProteomicsDB; 48818; -. [O43236-5] DR ProteomicsDB; 48819; -. [O43236-6] DR ProteomicsDB; 73193; -. DR Antibodypedia; 3484; 276 antibodies from 37 providers. DR DNASU; 284083; -. DR DNASU; 5414; -. DR Ensembl; ENST00000317256.10; ENSP00000321071.6; ENSG00000108387.16. [O43236-2] DR Ensembl; ENST00000317268.7; ENSP00000321674.3; ENSG00000108387.16. [O43236-1] DR Ensembl; ENST00000321691.3; ENSP00000354874.2; ENSG00000108387.16. [O43236-8] DR Ensembl; ENST00000393086.5; ENSP00000376801.1; ENSG00000108387.16. [O43236-2] DR Ensembl; ENST00000412945.7; ENSP00000414779.3; ENSG00000108387.16. [O43236-3] DR Ensembl; ENST00000426861.5; ENSP00000402348.1; ENSG00000108387.16. [O43236-6] DR Ensembl; ENST00000457347.6; ENSP00000402000.2; ENSG00000108387.16. [O43236-4] DR Ensembl; ENST00000583114.5; ENSP00000463768.1; ENSG00000108387.16. [O43236-5] DR Ensembl; ENST00000672673.2; ENSP00000500383.1; ENSG00000108387.16. [O43236-7] DR Ensembl; ENST00000672699.1; ENSP00000500355.1; ENSG00000108387.16. [O43236-4] DR GeneID; 5414; -. DR KEGG; hsa:5414; -. DR MANE-Select; ENST00000672673.2; ENSP00000500383.1; NM_001368771.2; NP_001355700.1. [O43236-7] DR UCSC; uc002iwm.4; human. [O43236-1] DR AGR; HGNC:9165; -. DR ClinPGx; PA33487; -. DR CTD; 5414; -. DR DisGeNET; 5414; -. DR GeneCards; SEPTIN4; -. DR HGNC; HGNC:9165; SEPTIN4. DR HPA; ENSG00000108387; Group enriched (brain, retina). DR MalaCards; SEPTIN4; -. DR MIM; 603696; gene. DR MIM; 621194; phenotype. DR OpenTargets; ENSG00000108387; -. DR Orphanet; 171709; Male infertility due to globozoospermia. DR VEuPathDB; HostDB:ENSG00000108387; -. DR eggNOG; ENOG502SETZ; Eukaryota. DR eggNOG; KOG2655; Eukaryota. DR GeneTree; ENSGT00390000018146; -. DR HOGENOM; CLU_575631_0_0_1; -. DR InParanoid; O43236; -. DR OMA; SSICTEP; -. DR OrthoDB; 416553at2759; -. DR PAN-GO; O43236; 11 GO annotations based on evolutionary models. DR PhylomeDB; O43236; -. DR PathwayCommons; O43236; -. DR Reactome; R-HSA-111457; Release of apoptotic factors from the mitochondria. [O43236-6] DR Reactome; R-HSA-111469; SMAC, XIAP-regulated apoptotic response. [O43236-6] DR SignaLink; O43236; -. DR SIGNOR; O43236; -. DR Agora; ENSG00000108387; -. DR BioGRID-ORCS; 284083; 14 hits in 1105 CRISPR screens. DR BioGRID-ORCS; 5414; 9 hits in 1084 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SEPT4; human. DR GeneWiki; SEPT4; -. DR GenomeRNAi; 5414; -. DR Pharos; O43236; Tbio. DR PRO; PR:Q8NEP4; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; O43236; protein. DR Bgee; ENSG00000108387; Expressed in C1 segment of cervical spinal cord and 149 other cell types or tissues. DR ExpressionAtlas; O43236; baseline and differential. DR GO; GO:0030424; C:axon; ISS:UniProtKB. DR GO; GO:0032153; C:cell division site; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; ISS:UniProtKB. DR GO; GO:0098691; C:dopaminergic synapse; IDA:SynGO. DR GO; GO:0015630; C:microtubule cytoskeleton; IBA:GO_Central. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; NAS:UniProtKB. DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; IDA:SynGO. DR GO; GO:0031105; C:septin complex; IDA:UniProtKB. DR GO; GO:0005940; C:septin ring; IBA:GO_Central. DR GO; GO:0097227; C:sperm annulus; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central. DR GO; GO:0005525; F:GTP binding; IMP:CAFA. DR GO; GO:0003924; F:GTPase activity; IMP:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:CAFA. DR GO; GO:0000287; F:magnesium ion binding; IMP:CAFA. DR GO; GO:0060090; F:molecular adaptor activity; IBA:GO_Central. DR GO; GO:0005198; F:structural molecule activity; TAS:ProtInc. DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB. DR GO; GO:0061640; P:cytoskeleton-dependent cytokinesis; IBA:GO_Central. DR GO; GO:0030317; P:flagellated sperm motility; ISS:UniProtKB. DR GO; GO:0061484; P:hematopoietic stem cell homeostasis; ISS:UniProtKB. DR GO; GO:0008104; P:intracellular protein localization; IBA:GO_Central. DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB. DR GO; GO:0017157; P:regulation of exocytosis; IBA:GO_Central. DR GO; GO:0048515; P:spermatid differentiation; ISS:UniProtKB. DR CDD; cd01850; CDC_Septin; 1. DR DisProt; DP00537; -. DR DisProt; DP01325; -. [O43236-6] DR FunFam; 3.40.50.300:FF:000064; Septin 4; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR030379; G_SEPTIN_dom. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR016491; Septin. DR PANTHER; PTHR18884; SEPTIN; 1. DR Pfam; PF00735; Septin; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51719; G_SEPTIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell cycle; Cell division; KW Cell projection; Cilium; Coiled coil; Cytoplasm; Cytoplasmic vesicle; KW Differentiation; Direct protein sequencing; Disease variant; Flagellum; KW GTP-binding; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Spermatogenesis; Synapse; KW Ubl conjugation. FT CHAIN 1..996 FT /note="Septin-4" FT /id="PRO_0000173519" FT DOMAIN 659..932 FT /note="Septin-type G" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 1..115 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 428..448 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 669..676 FT /note="G1 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 726..729 FT /note="G3 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 807..810 FT /note="G4 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT COILED 965..996 FT /evidence="ECO:0000255" FT COMPBIAS 13..26 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 95..108 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 669..676 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 703 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 808..816 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 866 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 881 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT MOD_RES 635 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 636 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 843 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18318008, FT ECO:0007744|PubMed:24275569" FT MOD_RES 950 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P28661" FT MOD_RES 952 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P28661" FT VAR_SEQ 1..665 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062617" FT VAR_SEQ 1..538 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDEE -> MDRSLGWQGNSVPEDRTEAG (in isoform 1)" FT /id="VSP_062618" FT VAR_SEQ 1..538 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDEE -> M (in isoform 2 and isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656, FT ECO:0000303|PubMed:11167005, ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_062619" FT VAR_SEQ 1..537 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDE -> MRSSPALFSSRAAPQKPRKEGSQAAGLLVFSDSL (in FT isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062620" FT VAR_SEQ 1..535 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLK -> MPGFYSVMT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062621" FT VAR_SEQ 536..570 FT /note="DEEIKRFLEDTTDDGELSKFVKDFSGNASCHPPEA -> GLCFSLLWAHCGS FT LGDGRTGEEWHLCIYRAGSFRR (in isoform 8)" FT /id="VSP_062622" FT VAR_SEQ 571..996 FT /note="Missing (in isoform 8)" FT /id="VSP_062623" FT VAR_SEQ 785..811 FT /note="LRPLDVEFMKALHQRVNIVPILAKADT -> YGPSLRLLAPPGAVKGTGQEH FT QGQGCH (in isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656" FT /id="VSP_062624" FT VAR_SEQ 812..996 FT /note="Missing (in isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656" FT /id="VSP_062625" FT VARIANT 69..996 FT /note="Missing (in SPGF99; likely pathogenic; loss of FT protein expression)" FT /evidence="ECO:0000269|PubMed:36135717" FT /id="VAR_090727" FT VARIANT 88 FT /note="P -> T (in dbSNP:rs8071623)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334" FT /id="VAR_090728" FT VARIANT 241..996 FT /note="Missing (in SPGF99; likely pathogenic; loss of FT protein expression)" FT /evidence="ECO:0000269|PubMed:36135717" FT /id="VAR_090729" FT VARIANT 829 FT /note="E -> V (in dbSNP:rs17741424)" FT /id="VAR_051935" FT CONFLICT 187 FT /note="V -> A (in Ref. 8; BAC05054)" FT /evidence="ECO:0000305" FT CONFLICT 674 FT /note="G -> D (in Ref. 7; BAG37789)" FT /evidence="ECO:0000305" FT CONFLICT 900 FT /note="K -> E (in Ref. 7; BAG63517)" FT /evidence="ECO:0000305" FT HELIX 967..994 FT /evidence="ECO:0007829|PDB:6WB3" FT MUTAGEN O43236-6:137..139 FT /note="GKS->ENP: Loss of TGF-beta-induced apoptosis. No FT translocation to the nucleus following TGF-beta treatment. FT Loss of XIAP-binding." FT /evidence="ECO:0000269|PubMed:11146656, FT ECO:0000269|PubMed:15029247" SQ SEQUENCE 996 AA; 112439 MW; 8306167C9EF5CFF0 CRC64; MVKTNKPGAK VAVSAQRGSE VTTNTSPQQG HGYVLASSHR SAAVSLNPSH RRSEAAHPTT PHSASDYPRS VSLQSGPGHY AVPTPRGPET GPRTESSRHS SPHLKSQKTQ TLASHASSRQ WKVSPPREEA ARRGSESKSG REVGHHASSI PDAKSTHQLS FQDQKNNLQS QILEDDPPSK VQNPQGVRVP RRILSYPKDE AVQTEPIQRI TTTSEIRSPR SPSLLEHGSS CVSADYQTAQ RRVPVEESET GPYGPIPSKP KALYRNMNLD SLLKLSVLKD SDGVHRVSAR VDPESLHKYS AYPETKPSAK VLVSSQVESN VRTPIRGNSE VGRRVTISPG VQSVEPTHHV TVPSVSEGSH KSSMFVTPEP IYKQQTQKPP EITYMSQGPT PRYPELSQKP SIHAELELTP RPLPPRSLPR YGPDSSWWPL LNPEVETPQS QLTTPDFEPK CSPSLDLLLS GFKIDSSPFC EDLKFQREKA SLSPPSPPKE FPSWAPLSEV PQTPKHTCKQ PIQRFTAFFL DVSEEMYNRV IWWLKDEEIK RFLEDTTDDG ELSKFVKDFS GNASCHPPEA KTWASRPQVP EPRPQAPDLY DDDLEFRPPS RPQSSDNQQY FCAPAPLSPS ARPRSPWGKL DPYDSSEDDK EYVGFATLPN QVHRKSVKKG FDFTLMVAGE SGLGKSTLVN SLFLTDLYRD RKLLGAEERI MQTVEITKHA VDIEEKGVRL RLTIVDTPGF GDAVNNTECW KPVAEYIDQQ FEQYFRDESG LNRKNIQDNR VHCCLYFISP FGHGLRPLDV EFMKALHQRV NIVPILAKAD TLTPPEVDHK KRKIREEIEH FGIKIYQFPD CDSDEDEDFK LQDQALKESI PFAVIGSNTV VEARGRRVRG RLYPWGIVEV ENPGHCDFVK LRTMLVRTHM QDLKDVTRET HYENYRAQCI QSMTRLVVKE RNRNKLTRES GTDFPIPAVP PGTDPETEKL IREKDEELRR MQEMLHKIQK QMKENY // ID SNCAP_HUMAN Reviewed; 919 AA. AC Q9Y6H5; D3DSZ1; Q05BS1; Q1PSC2; Q49AC6; Q504U9; Q6L984; Q6L985; Q6L986; AC Q9HC59; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 22-JUL-2008, sequence version 2. DT 28-JAN-2026, entry version 201. DE RecName: Full=Synphilin-1; DE Short=Sph1; DE AltName: Full=Alpha-synuclein-interacting protein; GN Name=SNCAIP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH SNCA, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND VARIANT ALA-44. RC TISSUE=Brain; RX PubMed=10319874; DOI=10.1038/8820; RA Engelender S., Kaminsky Z., Guo X., Sharp A.H., Amaravi R.K., RA Kleiderlein J.J., Margolis R.L., Troncoso J.C., Lanahan A., Worley P.F., RA Dawson V.L., Dawson T.M., Ross C.A.; RT "Synphilin-1 associates with alpha-synuclein and promotes the formation of RT cytosolic inclusions."; RL Nat. Genet. 22:110-114(1999). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=10967135; DOI=10.1007/s003350010123; RA Engelender S., Wanner T., Kleiderlein J.J., Wakabayashi K., Tsuji S., RA Takahashi H., Ashworth R., Margolis R.L., Ross C.A.; RT "Organization of the human synphilin-1 gene, a candidate for Parkinson's RT disease."; RL Mamm. Genome 11:763-766(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH SNCA, RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=16595633; DOI=10.1073/pnas.0509707103; RA Eyal A., Szargel R., Avraham E., Liani E., Haskin J., Rott R., RA Engelender S.; RT "Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes RT neuronal death and is present in aggregates from alpha-synucleinopathy RT patients."; RL Proc. Natl. Acad. Sci. U.S.A. 103:5917-5922(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 4 AND 6), AND VARIANT ALA-44. RC TISSUE=Cerebellum, and Testis; RA Lim M.K., Ohsawa Y., Kawamura T., Asakawa S., Takayanagi A., Minoshima S., RA Shimizu N.; RT "Identification and characterization of alternatively spliced form of human RT synphilin-1."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 5). RC TISSUE=Brain, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH PRKN, AND UBIQUITINATION. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [8] RP INTERACTION WITH RNF19A, AND UBIQUITINATION. RX PubMed=12750386; DOI=10.1074/jbc.m302763200; RA Ito T., Niwa J., Hishikawa N., Ishigaki S., Doyu M., Sobue G.; RT "Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1."; RL J. Biol. Chem. 278:29106-29114(2003). RN [9] RP INTERACTION WITH SIAH1, AND DEGRADATION. RX PubMed=14506261; DOI=10.1074/jbc.m306347200; RA Nagano Y., Yamashita H., Takahashi T., Kishida S., Nakamura T., Iseki E., RA Hattori N., Mizuno Y., Kikuchi A., Matsumoto M.; RT "Siah-1 facilitates ubiquitination and degradation of synphilin-1."; RL J. Biol. Chem. 278:51504-51514(2003). RN [10] RP SUBCELLULAR LOCATION, UBIQUITINATION, PROTEASOMAL DEGRADATION, INTERACTION RP WITH SIAH1 AND SIAH2, AND MUTAGENESIS OF VAL-79 AND PRO-81. RX PubMed=15064394; DOI=10.1073/pnas.0401081101; RA Liani E., Eyal A., Avraham E., Shemer R., Szargel R., Berg D., RA Bornemann A., Riess O., Ross C.A., Rott R., Engelender S.; RT "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence RT in cellular inclusions and Lewy bodies imply a role in Parkinson's RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 101:5500-5505(2004). RN [11] RP FUNCTION, AND INTERACTION WITH SIAH1. RX PubMed=19224863; DOI=10.1074/jbc.m805990200; RA Szargel R., Rott R., Eyal A., Haskin J., Shani V., Balan L., Wolosker H., RA Engelender S.; RT "Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates RT alpha-synuclein monoubiquitylation and inclusion formation."; RL J. Biol. Chem. 284:11706-11716(2009). RN [12] RP STRUCTURE BY NMR OF 512-557, INTERACTION WITH SNCA, PROMOTION OF INCLUSION RP BODY FORMATION, AND SUBCELLULAR LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [13] RP VARIANT CYS-621, CHARACTERIZATION OF VARIANT CYS-621, AND POSSIBLE RP INVOLVEMENT IN SUSCEPTIBILITY TO PARKINSON DISEASE. RX PubMed=12761037; DOI=10.1093/hmg/ddg134; RA Marx F.P., Holzmann C., Strauss K.M., Li L., Eberhardt O., Gerhardt E., RA Cookson M.R., Hernandez D., Farrer M.J., Kachergus J., Engelender S., RA Ross C.A., Berger K., Schols L., Schulz J.B., Riess O., Kruger R.; RT "Identification and functional characterization of a novel R621C mutation RT in the synphilin-1 gene in Parkinson's disease."; RL Hum. Mol. Genet. 12:1223-1231(2003). RN [14] RP VARIANTS ALA-44; CYS-621 AND GLN-706, AND LACK OF ASSOCIATION WITH RP PARKINSON DISEASE. RX PubMed=18366718; DOI=10.1186/1471-2350-9-19; RA Myhre R., Klungland H., Farrer M.J., Aasly J.O.; RT "Genetic association study of synphilin-1 in idiopathic Parkinson's RT disease."; RL BMC Med. Genet. 9:19-19(2008). CC -!- FUNCTION: Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and CC inhibits proteasomal degradation of target proteins. Isoform 2 inhibits CC autoubiquitination and proteasomal degradation of SIAH1, and thereby CC increases cellular levels of SIAH. Isoform 2 modulates SNCA CC monoubiquitination by SIAH1. {ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19224863}. CC -!- SUBUNIT: Homodimer (Probable). Heterodimer of isoform 1 and isoform 2 CC (Probable). Interacts with SIAH1, SIAH2, SNCA, RNF19A and PRKN. Isoform CC 2 has a strong tendency to form aggregates and can sequester isoform 1. CC {ECO:0000269|PubMed:10319874, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12750386, ECO:0000269|PubMed:14506261, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:19762560, ECO:0000305}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10319874, CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16595633, CC ECO:0000269|PubMed:19762560}. Note=Detected in cytoplasmic inclusion CC bodies, together with SNCA. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=1a; CC IsoId=Q9Y6H5-1; Sequence=Displayed; CC Name=2; Synonyms=Synphilin-1A; CC IsoId=Q9Y6H5-2; Sequence=VSP_038839, VSP_038842, VSP_038845; CC Name=3; CC IsoId=Q9Y6H5-3; Sequence=VSP_038840, VSP_038845; CC Name=4; Synonyms=1b; CC IsoId=Q9Y6H5-4; Sequence=VSP_038841; CC Name=5; CC IsoId=Q9Y6H5-5; Sequence=VSP_038839, VSP_038842; CC Name=6; Synonyms=1c; CC IsoId=Q9Y6H5-6; Sequence=VSP_038840, VSP_038843, VSP_038844; CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level). Widely CC expressed, with highest levels in brain, heart and placenta. CC {ECO:0000269|PubMed:10319874, ECO:0000269|PubMed:16595633}. CC -!- PTM: Ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A and leading to CC its subsequent proteasomal degradation. In the absence of proteasomal CC degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion CC bodies. Isoform 2 is subject to limited ubiquitination that does not CC lead to proteasomal degradation. {ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12750386, ECO:0000269|PubMed:15064394}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:12761037}. Note=Disease CC susceptibility may be associated with variants affecting the gene CC represented in this entry. CC -!- MISCELLANEOUS: Constructs encoding portions of SNCA and SNCAIP co- CC transfected in mammalian cells promote cytosolic inclusions resembling CC the Lewy bodies of Parkinson disease. Coexpression of SNCA, SNCAIP, and CC PRKN result in the formation of Lewy body-like. ubiquitin-positive CC cytosolic inclusions. SNCAIP isoform 2 is particularly aggregation- CC prone. Familial mutations in PRKN disrupt the ubiquitination of SNCAIP CC and the formation of the ubiquitin-positive inclusions. These results CC provide a molecular basis for the ubiquitination of Lewy body- CC associated proteins and link PRKN and SNCA in a common pathogenic CC mechanism through their interaction with SNCAIP. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF076929; AAD30362.1; -; mRNA. DR EMBL; AF167306; AAG17478.1; -; Genomic_DNA. DR EMBL; AF167301; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167302; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167303; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167304; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167305; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; DQ227317; ABB51162.1; -; mRNA. DR EMBL; CH471086; EAW48889.1; -; Genomic_DNA. DR EMBL; AB110788; BAD19017.1; -; mRNA. DR EMBL; AB110789; BAD19018.1; -; mRNA. DR EMBL; AB110790; BAD19019.1; -; mRNA. DR EMBL; CH471086; EAW48890.1; -; Genomic_DNA. DR EMBL; BC033743; AAH33743.1; -; mRNA. DR EMBL; BC040552; AAH40552.1; -; mRNA. DR EMBL; BC094759; AAH94759.1; -; mRNA. DR CCDS; CCDS4131.1; -. [Q9Y6H5-1] DR CCDS; CCDS78054.1; -. [Q9Y6H5-3] DR RefSeq; NP_001229864.1; NM_001242935.3. [Q9Y6H5-2] DR RefSeq; NP_001295029.1; NM_001308100.2. [Q9Y6H5-3] DR RefSeq; NP_001295034.1; NM_001308105.1. [Q9Y6H5-4] DR RefSeq; NP_001295035.1; NM_001308106.1. DR RefSeq; NP_001295036.1; NM_001308107.2. [Q9Y6H5-5] DR RefSeq; NP_001295037.1; NM_001308108.1. DR RefSeq; NP_001295038.1; NM_001308109.1. DR RefSeq; NP_005451.2; NM_005460.4. [Q9Y6H5-1] DR RefSeq; XP_011542039.1; XM_011543737.3. [Q9Y6H5-3] DR RefSeq; XP_011542040.1; XM_011543738.3. [Q9Y6H5-3] DR RefSeq; XP_011542041.1; XM_011543739.2. [Q9Y6H5-3] DR RefSeq; XP_011542043.1; XM_011543741.3. [Q9Y6H5-3] DR RefSeq; XP_011542045.1; XM_011543743.3. [Q9Y6H5-3] DR RefSeq; XP_016865571.1; XM_017010082.2. [Q9Y6H5-1] DR RefSeq; XP_024302035.1; XM_024446267.2. [Q9Y6H5-1] DR RefSeq; XP_024302036.1; XM_024446268.2. [Q9Y6H5-1] DR RefSeq; XP_047273867.1; XM_047417911.1. [Q9Y6H5-3] DR RefSeq; XP_047273879.1; XM_047417923.1. [Q9Y6H5-1] DR RefSeq; XP_047273880.1; XM_047417924.1. [Q9Y6H5-1] DR RefSeq; XP_047273881.1; XM_047417925.1. [Q9Y6H5-1] DR RefSeq; XP_047273882.1; XM_047417926.1. [Q9Y6H5-1] DR RefSeq; XP_047273883.1; XM_047417927.1. [Q9Y6H5-1] DR RefSeq; XP_047273885.1; XM_047417929.1. [Q9Y6H5-6] DR RefSeq; XP_054209830.1; XM_054353855.1. [Q9Y6H5-3] DR RefSeq; XP_054209831.1; XM_054353856.1. [Q9Y6H5-3] DR RefSeq; XP_054209832.1; XM_054353857.1. [Q9Y6H5-3] DR RefSeq; XP_054209833.1; XM_054353858.1. [Q9Y6H5-3] DR RefSeq; XP_054209834.1; XM_054353859.1. [Q9Y6H5-3] DR RefSeq; XP_054209852.1; XM_054353877.1. [Q9Y6H5-1] DR RefSeq; XP_054209853.1; XM_054353878.1. [Q9Y6H5-1] DR RefSeq; XP_054209854.1; XM_054353879.1. [Q9Y6H5-1] DR RefSeq; XP_054209855.1; XM_054353880.1. [Q9Y6H5-1] DR RefSeq; XP_054209856.1; XM_054353881.1. [Q9Y6H5-1] DR RefSeq; XP_054209857.1; XM_054353882.1. [Q9Y6H5-1] DR RefSeq; XP_054209858.1; XM_054353883.1. [Q9Y6H5-1] DR RefSeq; XP_054209859.1; XM_054353884.1. [Q9Y6H5-1] DR RefSeq; XP_054209864.1; XM_054353889.1. [Q9Y6H5-6] DR PDB; 2KES; NMR; -; A=512-557. DR PDBsum; 2KES; -. DR AlphaFoldDB; Q9Y6H5; -. DR BMRB; Q9Y6H5; -. DR SMR; Q9Y6H5; -. DR BioGRID; 114986; 39. DR CORUM; Q9Y6H5; -. DR DIP; DIP-61155N; -. DR FunCoup; Q9Y6H5; 232. DR MINT; Q9Y6H5; -. DR STRING; 9606.ENSP00000261367; -. DR ChEMBL; CHEMBL1926494; -. DR GlyGen; Q9Y6H5; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9Y6H5; -. DR PhosphoSitePlus; Q9Y6H5; -. DR BioMuta; SNCAIP; -. DR DMDM; 205831000; -. DR jPOST; Q9Y6H5; -. DR MassIVE; Q9Y6H5; -. DR PaxDb; 9606-ENSP00000261368; -. DR PeptideAtlas; Q9Y6H5; -. DR ProteomicsDB; 86680; -. [Q9Y6H5-1] DR ProteomicsDB; 86681; -. [Q9Y6H5-2] DR ProteomicsDB; 86682; -. [Q9Y6H5-3] DR ProteomicsDB; 86683; -. [Q9Y6H5-4] DR ProteomicsDB; 86684; -. [Q9Y6H5-5] DR ProteomicsDB; 86685; -. [Q9Y6H5-6] DR Antibodypedia; 1015; 225 antibodies from 33 providers. DR DNASU; 9627; -. DR Ensembl; ENST00000261367.11; ENSP00000261367.7; ENSG00000064692.21. [Q9Y6H5-3] DR Ensembl; ENST00000261368.13; ENSP00000261368.8; ENSG00000064692.21. [Q9Y6H5-1] DR Ensembl; ENST00000395469.6; ENSP00000378852.2; ENSG00000064692.21. [Q9Y6H5-6] DR GeneID; 9627; -. DR KEGG; hsa:9627; -. DR MANE-Select; ENST00000261368.13; ENSP00000261368.8; NM_005460.4; NP_005451.2. DR UCSC; uc003ksw.2; human. [Q9Y6H5-1] DR AGR; HGNC:11139; -. DR CIViC; 9627; 1 evidence item across 1 molecular profile. DR ClinPGx; PA35987; -. DR CTD; 9627; -. DR DisGeNET; 9627; -. DR GeneCards; SNCAIP; -. DR HGNC; HGNC:11139; SNCAIP. DR HPA; ENSG00000064692; Tissue enhanced (cervix, endometrium, ovary). DR MalaCards; SNCAIP; -. DR MIM; 168600; phenotype. DR MIM; 603779; gene. DR OpenTargets; ENSG00000064692; -. DR VEuPathDB; HostDB:ENSG00000064692; -. DR eggNOG; KOG0504; Eukaryota. DR GeneTree; ENSGT00390000001485; -. DR HOGENOM; CLU_012404_0_0_1; -. DR InParanoid; Q9Y6H5; -. DR OMA; SQTQYCV; -. DR OrthoDB; 10057496at2759; -. DR PAN-GO; Q9Y6H5; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q9Y6H5; -. DR PathwayCommons; Q9Y6H5; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; Q9Y6H5; -. DR SIGNOR; Q9Y6H5; -. DR Agora; ENSG00000064692; -. DR BioGRID-ORCS; 9627; 11 hits in 1148 CRISPR screens. DR ChiTaRS; SNCAIP; human. DR EvolutionaryTrace; Q9Y6H5; -. DR GeneWiki; SNCAIP; -. DR GenomeRNAi; 9627; -. DR Pharos; Q9Y6H5; Tbio. DR PRO; PR:Q9Y6H5; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q9Y6H5; protein. DR Bgee; ENSG00000064692; Expressed in ventricular zone and 174 other cell types or tissues. DR ExpressionAtlas; Q9Y6H5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:HPA. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043025; C:neuronal cell body; NAS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; NAS:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; TAS:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0008219; P:cell death; IDA:CACAO. DR GO; GO:0042417; P:dopamine metabolic process; IDA:MGI. DR GO; GO:0090083; P:regulation of inclusion body assembly; IDA:BHF-UCL. DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IDA:MGI. DR FunFam; 1.25.40.20:FF:000112; synphilin-1 isoform X1; 1. DR Gene3D; 6.10.250.750; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR040133; SNCAIP. DR InterPro; IPR032027; SNCAIP_SNCA-bd. DR PANTHER; PTHR22882; SYNPHILIN-1; 1. DR PANTHER; PTHR22882:SF3; SYNPHILIN-1; 1. DR Pfam; PF12796; Ank_2; 2. DR Pfam; PF16700; SNCAIP_SNCA_bd; 1. DR SMART; SM00248; ANK; 4. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ANK repeat; Coiled coil; Cytoplasm; KW Neurodegeneration; Parkinson disease; Parkinsonism; KW Proteomics identification; Reference proteome; Repeat; Ubl conjugation. FT CHAIN 1..919 FT /note="Synphilin-1" FT /id="PRO_0000067068" FT REPEAT 349..380 FT /note="ANK 1" FT REPEAT 384..413 FT /note="ANK 2" FT REPEAT 419..448 FT /note="ANK 3" FT REPEAT 456..485 FT /note="ANK 4" FT REPEAT 603..632 FT /note="ANK 5" FT REPEAT 699..729 FT /note="ANK 6" FT REGION 80..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 108..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 287..313 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 549..615 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 666..713 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 728..919 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 515..552 FT /evidence="ECO:0000255" FT COMPBIAS 299..308 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 555..571 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 667..685 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 686..700 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 774..785 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 833..842 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 844..854 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 874..886 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..366 FT /note="Missing (in isoform 2 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038839" FT VAR_SEQ 19 FT /note="S -> SDNRSQGNRLQKLGLEDTDREDAMGFGSHRAKLTVVAALGACHCPEN FT E (in isoform 3 and isoform 6)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4" FT /id="VSP_038840" FT VAR_SEQ 335..394 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038841" FT VAR_SEQ 367..394 FT /note="QHLTSLMGEDCLNERNTEKLTPAGLAIK -> MTYLIQSHHSRRSQNCAEDV FT IRKTKTDQ (in isoform 2 and isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038842" FT VAR_SEQ 476..541 FT /note="LVEYGANVTMQNHAGEKPSQSAERQGHTLCSRYLVVVETCMSLASQVVKLTK FT QLKEQTVERVTLQN -> RLKIQGTWNGSETCLFTHHFSSYPPISSGLQCQGQEGVLFI FT PDQVGAATNKQVLFQNQLPETKSSY (in isoform 6)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038843" FT VAR_SEQ 542..919 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_038844" FT VAR_SEQ 919 FT /note="A -> EMYSSCINLSSNMLIEEHLCNDTRHNDINRKMKKSYSIKHIAEPESK FT ELFL (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16595633" FT /id="VSP_038845" FT VARIANT 44 FT /note="V -> A (in dbSNP:rs56285021)" FT /evidence="ECO:0000269|PubMed:10319874, FT ECO:0000269|PubMed:18366718, ECO:0000269|Ref.4" FT /id="VAR_065358" FT VARIANT 235 FT /note="E -> G (in dbSNP:rs6867105)" FT /id="VAR_048312" FT VARIANT 621 FT /note="R -> C (found in patients with symptoms of Parkinson FT disease; uncertain significance; reduced number of FT cytoplasmic inclusions in cells expressing C-621 compared FT with cells expressing wild-type (wt) protein when subjected FT to proteasomal inhibition; C-621 transfected cells are more FT susceptible to staurosporine-induced cell death than cells FT expressing wt protein; dbSNP:rs28937592)" FT /evidence="ECO:0000269|PubMed:12761037, FT ECO:0000269|PubMed:18366718" FT /id="VAR_025667" FT VARIANT 706 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:18366718" FT /id="VAR_065359" FT MUTAGEN 79 FT /note="V->N: Decreases interaction with SIAH1 and formation FT of cytoplasmic inclusion bodies; when associated with N- FT 81." FT /evidence="ECO:0000269|PubMed:15064394" FT MUTAGEN 81 FT /note="P->N: Decreases interaction with SIAH1 and formation FT of cytoplasmic inclusion bodies; when associated with N- FT 79." FT /evidence="ECO:0000269|PubMed:15064394" FT CONFLICT 188 FT /note="S -> F (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 614 FT /note="E -> G (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 696 FT /note="A -> G (in Ref. 6; AAH40552)" FT /evidence="ECO:0000305" FT CONFLICT 712 FT /note="D -> G (in Ref. 6; AAH94759)" FT /evidence="ECO:0000305" FT CONFLICT 801 FT /note="S -> P (in Ref. 6; AAH33743)" FT /evidence="ECO:0000305" FT CONFLICT 919 FT /note="A -> E (in Ref. 6; AAH94759)" FT /evidence="ECO:0000305" FT HELIX 512..554 FT /evidence="ECO:0007829|PDB:2KES" SQ SEQUENCE 919 AA; 100409 MW; 55C5316F250D0480 CRC64; MEAPEYLDLD EIDFSDDISY SVTSLKTIPE LCRRCDTQNE DRSVSSSSWN CGISTLITNT QKPTGIADVY SKFRPVKRVS PLKHQPETLE NNESDDQKNQ KVVEYQKGGE SDLGPQPQEL GPGDGVGGPP GKSSEPSTSL GELEHYDLDM DEILDVPYIK SSQQLASFTK VTSEKRILGL CTTINGLSGK ACSTGSSESS SSNMAPFCVL SPVKSPHLRK ASAVIHDQHK LSTEETEISP PLVKCGSAYE PENQSKDFLN KTFSDPHGRK VEKTTPDCQL RAFHLQSSAA ESKPEEQVSG LNRTSSQGPE ERSEYLKKVK SILNIVKEGQ ISLLPHLAAD NLDKIHDENG NNLLHIAASQ GHAECLQHLT SLMGEDCLNE RNTEKLTPAG LAIKNGQLEC VRWMVSETEA IAELSCSKDF PSLIHYAGCY GQEKILLWLL QFMQEQGISL DEVDQDGNSA VHVASQHGYL GCIQTLVEYG ANVTMQNHAG EKPSQSAERQ GHTLCSRYLV VVETCMSLAS QVVKLTKQLK EQTVERVTLQ NQLQQFLEAQ KSEGKSLPSS PSSPSSPASR KSQWKSPDAD DDSVAKSKPG VQEGIQVLGS LSASSRARPK AKDEDSDKIL RQLLGKEISE NVCTQEKLSL EFQDAQASSR NSKKIPLEKR ELKLARLRQL MQRSLSESDT DSNNSEDPKT TPVRKADRPR PQPIVESVES MDSAESLHLM IKKHTLASGG RRFPFSIKAS KSLDGHSPSP TSESSEPDLE SQYPGSGSIP PNQPSGDPQQ PSPDSTAAQK VATSPKSALK SPSSKRRTSQ NLKLRVTFEE PVVQMEQPSL ELNGEKDKDK GRTLQRTSTS NESGDQLKRP FGAFRSIMET LSGNQNNNNN YQAANQLKTS TLPLTSLGRK TDAKGNPASS ASKGKNKAA // ID SQSTM_HUMAN Reviewed; 440 AA. AC Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 237. DE RecName: Full=Sequestosome-1 {ECO:0000305}; DE AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575}; DE Short=EBIAP; DE Short=p60 {ECO:0000303|PubMed:8551575}; DE AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207}; DE AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207}; DE Short=p62 {ECO:0000303|PubMed:30266909}; GN Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280}; GN Synonyms=ORCA, OSIL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND RP 394-411, AND INTERACTION WITH EBI3. RC TISSUE=B-cell; RX PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996; RA Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., RA Birkenbach M.; RT "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr RT virus infection in B lymphocytes."; RL J. Virol. 70:1143-1153(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; RP 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND RP MUTAGENESIS OF TYR-9. RC TISSUE=Cervix carcinoma; RX PubMed=8650207; DOI=10.1073/pnas.93.12.5991; RA Joung I., Strominger J.L., Shin J.; RT "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck RT SH2 domain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Caudate nucleus, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Pancreas, Placenta, Skin, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION. RX PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7; RA Vadlamudi R.K., Shin J.; RT "Genomic structure and promoter analysis of the p62 gene encoding a non- RT proteasomal multiubiquitin chain binding protein."; RL FEBS Lett. 435:138-142(1998). RN [7] RP PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388. RX PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0; RA Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., RA Zatloukal K., Denk H.; RT "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. RT Demonstration of p62 as major constituent."; RL Am. J. Pathol. 154:1701-1710(1999). RN [8] RP INTERACTION WITH LCK AND RASA1. RX PubMed=8618896; DOI=10.1073/pnas.92.26.12338; RA Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.; RT "Phosphotyrosine-independent binding of a 62-kDa protein to the src RT homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of RT Ser-59 in the lck unique N-terminal region."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995). RN [9] RP INTERACTION WITH UBIQUITIN. RX PubMed=8702753; DOI=10.1074/jbc.271.34.20235; RA Vadlamudi R.K., Joung I., Strominger J.L., Shin J.; RT "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, RT belongs to a new class of ubiquitin-binding proteins."; RL J. Biol. Chem. 271:20235-20237(1996). RN [10] RP INTERACTION WITH NR2F2. RX PubMed=8910285; DOI=10.1074/jbc.271.44.27197; RA Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.; RT "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone RT receptor."; RL J. Biol. Chem. 271:27197-27200(1996). RN [11] RP INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION. RX PubMed=9566925; DOI=10.1128/mcb.18.5.3069; RA Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.; RT "Localization of atypical protein kinase C isoforms into lysosome-targeted RT endosomes through interaction with p62."; RL Mol. Cell. Biol. 18:3069-3080(1998). RN [12] RP INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND RP FUNCTION. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [13] RP INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [14] RP INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [15] RP INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [16] RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6; RA Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., RA Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.; RT "p62 Is a common component of cytoplasmic inclusions in protein aggregation RT diseases."; RL Am. J. Pathol. 160:255-263(2002). RN [17] RP INTERACTION WITH PAWR AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=11981755; DOI=10.1053/jhep.2002.32674; RA Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.; RT "Mallory body -- a disease-associated type of sequestosome."; RL Hepatology 35:1053-1062(2002). RN [19] RP INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=12471037; DOI=10.1074/jbc.m208468200; RA Geetha T., Wooten M.W.; RT "Association of the atypical protein kinase C-interacting protein p62/ZIP RT with nerve growth factor receptor TrkA regulates receptor trafficking and RT Erk5 signaling."; RL J. Biol. Chem. 278:4730-4739(2003). RN [20] RP INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF RP LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND RP GLU-82, AND DIMERIZATION. RX PubMed=12813044; DOI=10.1074/jbc.m303221200; RA Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., RA Michaelsen E., Bjoerkoey G., Johansen T.; RT "Interaction codes within the family of mammalian Phox and Bem1p domain- RT containing proteins."; RL J. Biol. Chem. 278:34568-34581(2003). RN [21] RP INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7; RP ASP-69 AND ASP-73. RX PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6; RA Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.; RT "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling RT complexes of atypical protein kinase C with Par6 and p62."; RL Mol. Cell 12:39-50(2003). RN [22] RP INDUCTION. RX PubMed=12700667; DOI=10.1038/sj.onc.1206325; RA Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.; RT "p62 overexpression in breast tumors and regulation by prostate-derived Ets RT factor in breast cancer cells."; RL Oncogene 22:2322-2333(2003). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029; RA Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K., RA Araga S., Yanagawa T., Ishii T., Nakashima K.; RT "Transcriptional activation of p62/A170/ZIP during the formation of the RT aggregates: possible mechanisms and the role in Lewy body formation in RT Parkinson's disease."; RL Brain Res. 1012:42-51(2004). RN [24] RP INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398; RP PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION. RX PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004; RA Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R., RA Wooten M.W.; RT "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in RT ubiquitin proteasome degradation."; RL Mol. Cell. Biol. 24:8055-8068(2004). RN [25] RP FUNCTION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH RP MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND RP ILE-431. RX PubMed=16286508; DOI=10.1083/jcb.200507002; RA Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A., RA Stenmark H., Johansen T.; RT "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a RT protective effect on huntingtin-induced cell death."; RL J. Cell Biol. 171:603-614(2005). RN [27] RP INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [28] RP INTERACTION WITH AJUBA AND LIMD1. RX PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005; RA Feng Y., Longmore G.D.; RT "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB RT activation by affecting the assembly and activity of the protein kinase RT Czeta/p62/TRAF6 signaling complex."; RL Mol. Cell. Biol. 25:4010-4022(2005). RN [29] RP INDUCTION, AND FUNCTION. RX PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011; RA Wang Z., Figueiredo-Pereira M.E.; RT "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of RT ubiquitinated proteins induced by prostaglandin J2 without reducing its RT neurotoxicity."; RL Mol. Cell. Neurosci. 29:222-231(2005). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [31] RP INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION. RX PubMed=15802564; DOI=10.1126/science.1110463; RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., RA Udd B., Gautel M.; RT "The kinase domain of titin controls muscle gene expression and protein RT turnover."; RL Science 308:1599-1603(2005). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [34] RP FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND RP MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337; RP TRP-338 AND SER-342. RX PubMed=17580304; DOI=10.1074/jbc.m702824200; RA Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H., RA Overvatn A., Bjorkoy G., Johansen T.; RT "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of RT ubiquitinated protein aggregates by autophagy."; RL J. Biol. Chem. 282:24131-24145(2007). RN [35] RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION). RX PubMed=24331465; DOI=10.1016/j.chom.2013.11.003; RA Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N., RA Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.; RT "The globally disseminated M1T1 clone of group A Streptococcus evades RT autophagy for intracellular replication."; RL Cell Host Microbe 14:675-682(2013). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [41] RP FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION. RX PubMed=20168092; DOI=10.4161/auto.6.3.11226; RA Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A., RA Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.; RT "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 RT bodies/ALIS and their degradation by autophagy."; RL Autophagy 6:330-344(2010). RN [42] RP INTERACTION WITH KEAP1. RX PubMed=20495340; DOI=10.4161/auto.6.5.12189; RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.; RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via RT autophagy."; RL Autophagy 6:614-621(2010). RN [43] RP FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347; RP THR-350; GLY-351 AND GLU-352. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [44] RP INTERACTION WITH FHOD3. RX PubMed=21149568; DOI=10.1083/jcb.201005060; RA Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.; RT "Formin follows function: a muscle-specific isoform of FHOD3 is regulated RT by CK2 phosphorylation and promotes myofibril maintenance."; RL J. Cell Biol. 191:1159-1172(2010). RN [45] RP INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION. RX PubMed=20357094; DOI=10.1128/jvi.02412-09; RA O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J., RA Campbell E.M.; RT "p62/sequestosome-1 associates with and sustains the expression of RT retroviral restriction factor TRIM5alpha."; RL J. Virol. 84:5997-6006(2010). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249; RP SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; RP LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425. RX PubMed=22084127; DOI=10.1001/archneurol.2011.250; RA Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., RA Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L., RA Heller S.L., Deng H.X., Siddique T.; RT "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:1440-1446(2011). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [49] RP IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR RP LOCATION. RX PubMed=21923101; DOI=10.1021/bi201137e; RA Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B., RA Layfield R., Searle M.S.; RT "Independent interactions of ubiquitin-binding domains in a ubiquitin- RT mediated ternary complex."; RL Biochemistry 50:9076-9087(2011). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207; RP THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF RP SER-403. RX PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039; RA Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.; RT "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic RT clearance of ubiquitinated proteins."; RL Mol. Cell 44:279-289(2011). RN [51] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [52] RP FUNCTION. RX PubMed=22622177; DOI=10.4161/auto.19381; RA Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D., RA Faure M., Fauvarque M.O.; RT "The deubiquitinating enzyme USP36 controls selective autophagy activation RT by ubiquitinated proteins."; RL Autophagy 8:767-779(2012). RN [53] RP INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION. RX PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015; RA Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.; RT "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the RT cells."; RL Biochim. Biophys. Acta 1823:316-326(2012). RN [54] RP INTERACTION WITH MAP1LC3A. RX PubMed=22421968; DOI=10.1038/cdd.2012.30; RA Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M., RA Carrier A., Iovanna J.L., Dusetti N.J.; RT "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins RT through the LC3-interacting region (LIR) and promotes autophagy-dependent RT cell death."; RL Cell Death Differ. 19:1525-1535(2012). RN [55] RP INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION. RX PubMed=22792322; DOI=10.1371/journal.pone.0040440; RA Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B., RA Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G., RA Reymond A., Pucci P., Merla G.; RT "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes RT the sequestration and clearance of ubiquitinated proteins into the RT aggresome."; RL PLoS ONE 7:E40440-E40440(2012). RN [56] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE RP ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [57] RP FUNCTION. RX PubMed=24128730; DOI=10.4161/auto.26085; RA Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.; RT "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody RT ring degradation by selective autophagy."; RL Autophagy 9:1955-1964(2013). RN [58] RP INTERACTION WITH SESN1 AND SESN2. RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002; RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., RA Kang D., Rhee S.G.; RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation RT of Keap1 and prevent oxidative liver damage."; RL Cell Metab. 17:73-84(2013). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [60] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND RP LEU-392. RX PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849; RG French Clinical and Genetic Research Network on FTD/FTD-ALS; RA Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G., RA Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T., RA Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.; RT "SQSTM1 mutations in French patients with frontotemporal dementia or RT frontotemporal dementia with amyotrophic lateral sclerosis."; RL JAMA Neurol. 70:1403-1410(2013). RN [61] RP LIR MOTIF. RX PubMed=23908376; DOI=10.1242/jcs.126128; RA Birgisdottir A.B., Lamark T., Johansen T.; RT "The LIR motif - crucial for selective autophagy."; RL J. Cell Sci. 126:3237-3247(2013). RN [62] RP INTERACTION WITH MAP1LC3B. RX PubMed=24089205; DOI=10.1038/nature12606; RA Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B., RA Zhong Q.; RT "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar RT satellites."; RL Nature 502:254-257(2013). RN [63] RP FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE. RX PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033; RA Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.; RT "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated RT sequestration and degradation."; RL Cell. Signal. 26:2470-2480(2014). RN [64] RP INTERACTION WITH TRIM5. RX PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013; RA Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C., RA Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B., RA Johansen T., Deretic V.; RT "TRIM proteins regulate autophagy and can target autophagic substrates by RT direct recognition."; RL Dev. Cell 30:394-409(2014). RN [65] RP INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1. RX PubMed=25040165; DOI=10.1111/febs.12905; RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S., RA Lee J.H.; RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of RT p62/sequestosome-1."; RL FEBS J. 281:3816-3827(2014). RN [66] RP INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338. RX PubMed=24668264; DOI=10.1002/embr.201338003; RA Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y., RA Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.; RT "Structural determinants in GABARAP required for the selective binding and RT recruitment of ALFY to LC3B-positive structures."; RL EMBO Rep. 15:557-565(2014). RN [67] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306 RP AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [68] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [69] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214. RX PubMed=20851865; DOI=10.3324/haematol.2010.029769; RA Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C., RA Crescenzi B., Santoro A., Chiaretti S., Mecucci C.; RT "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic RT leukemia."; RL Haematologica 95:2161-2163(2010). RN [70] RP INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL. RX PubMed=25114083; DOI=10.3233/jad-141512; RA Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K., RA Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E., RA Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.; RT "A phenotype of atypical apraxia of speech in a family carrying SQSTM1 RT mutation."; RL J. Alzheimers Dis. 43:625-630(2015). RN [71] RP FUNCTION, AND INTERACTION WITH PEX5. RX PubMed=26344566; DOI=10.1038/ncb3230; RA Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T., RA Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K., RA Pandita T.K., Kastan M.B., Walker C.L.; RT "ATM functions at the peroxisome to induce pexophagy in response to ROS."; RL Nat. Cell Biol. 17:1259-1269(2015). RN [72] RP INVOLVEMENT IN DMRV. RX PubMed=26208961; DOI=10.1212/wnl.0000000000001864; RA Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M., RA Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.; RT "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."; RL Neurology 85:665-674(2015). RN [73] RP INVOLVEMENT IN NADGP. RX PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026; RA Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P., RA Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S., RA Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H., RA Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V., RA Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C., RA Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J., RA Klopstock T.; RT "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset RT neurodegeneration with ataxia, dystonia, and gaze palsy."; RL Am. J. Hum. Genet. 99:735-743(2016). RN [74] RP FUNCTION, AND UBIQUITINATION. RX PubMed=27368102; DOI=10.1016/j.cell.2016.05.078; RA Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M., RA Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M., RA Neefjes J.; RT "An ER-associated pathway defines endosomal architecture for controlled RT cargo transport."; RL Cell 166:152-166(2016). RN [75] RP INTERACTION WITH TRIM11. RX PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019; RA Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.; RT "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent RT selective autophagy."; RL Cell Rep. 16:1988-2002(2016). RN [76] RP UBIQUITINATION, AND FUNCTION. RX PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005; RA Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C., RA Jani V., Lassen K.G., Xavier R.J.; RT "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial RT Autophagy."; RL Cell Rep. 17:2183-2194(2016). RN [77] RP FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420. RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030; RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.; RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain RT ubiquitination."; RL Cell Rep. 19:188-202(2017). RN [78] RP DOMAIN, AND UBIQUITINATION. RX PubMed=28322253; DOI=10.1038/cr.2017.40; RA Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H., RA Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H., RA Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.; RT "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor RT function and controls selective autophagy upon ubiquitin stress."; RL Cell Res. 27:657-674(2017). RN [79] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [80] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF RP SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411. RX PubMed=29507397; DOI=10.1038/s41422-018-0017-7; RA Sun D., Wu R., Zheng J., Li P., Yu L.; RT "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo RT segregation."; RL Cell Res. 28:405-415(2018). RN [81] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=29343546; DOI=10.15252/embj.201798308; RA Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M., RA Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C., RA Martens S.; RT "p62 filaments capture and present ubiquitinated cargos for autophagy."; RL EMBO J. 37:0-0(2018). RN [82] RP INTERACTION WITH TRIM16. RX PubMed=30143514; DOI=10.15252/embj.201798358; RA Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A., RA Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.; RT "TRIM16 controls assembly and degradation of protein aggregates by RT modulating the p62-NRF2 axis and autophagy."; RL EMBO J. 37:0-0(2018). RN [83] RP INTERACTION WITH LRRC25. RX PubMed=29288164; DOI=10.15252/embj.201796781; RA Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.; RT "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I RT for autophagic degradation."; RL EMBO J. 37:351-366(2018). RN [84] RP FUNCTION, INTERACTION WITH WDR81, AND DOMAIN. RX PubMed=28404643; DOI=10.1083/jcb.201608039; RA Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y., RA Luo S., Guo W., Yang C.; RT "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote RT aggrephagy."; RL J. Cell Biol. 216:1301-1320(2017). RN [85] RP INTERACTION WITH TRIM23. RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2; RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F., RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O., RA Moss J., Vaughan M., Gack M.U.; RT "TRIM23 mediates virus-induced autophagy via activation of TBK1."; RL Nat. Microbiol. 2:1543-1557(2017). RN [86] RP FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403. RX PubMed=29496741; DOI=10.15252/embj.201797858; RA Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C., RA Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R., RA Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M., RA Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.; RT "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent RT autophagy pathway activated by TBK1."; RL EMBO J. 37:0-0(2018). RN [87] RP INTERACTION WITH USP12. RX PubMed=30266909; DOI=10.1038/s41467-018-05653-z; RA Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K., RA Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P., RA Finkbeiner S.; RT "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and RT confer neuroprotection in models of Huntington's disease."; RL Nat. Commun. 9:3191-3191(2018). RN [88] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435, RP AND MUTAGENESIS OF LYS-420 AND LYS-435. RX PubMed=31857589; DOI=10.1038/s41467-019-13718-w; RA You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H., RA Peng C., Zhou T., Tang C., Liu W.; RT "Requirement for p62 acetylation in the aggregation of ubiquitylated RT proteins under nutrient stress."; RL Nat. Commun. 10:5792-5792(2019). RN [89] RP INTERACTION WITH ECSIT. RX PubMed=31281713; DOI=10.4110/in.2019.19.e16; RA Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.; RT "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the RT TRAF6-ECSIT Complex."; RL Immune Netw. 19:e16-e16(2019). RN [90] RP INTERACTION WITH CYLD. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [91] RP FUNCTION, AND INTERACTION WITH MOAP1. RX PubMed=33393215; DOI=10.15252/embr.202050854; RA Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.; RT "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and RT suppresses Nrf2 signaling."; RL EMBO Rep. 22:e50854-e50854(2021). RN [92] RP FUNCTION, AND UBIQUITINATION AT LYS-435. RX PubMed=33472082; DOI=10.1016/j.celrep.2020.108659; RA Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J., RA Berlin I.; RT "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal RT control over the endolysosomal pathway."; RL Cell Rep. 34:108659-108659(2021). RN [93] RP FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 RP (MICROBIAL INFECTION). RX PubMed=33509017; DOI=10.1080/15548627.2021.1874660; RA Ylae-Anttila P., Gupta S., Masucci M.G.; RT "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit RT selective autophagy."; RL Autophagy 17:3461-3474(2021). RN [94] RP SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION. RX PubMed=34471133; DOI=10.1038/s41467-021-25572-w; RA Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M., RA Martens S.; RT "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin RT condensate formation and autophagy initiation."; RL Nat. Commun. 12:5212-5212(2021). RN [95] RP INTERACTION WITH ASB6. RX PubMed=34164402; DOI=10.3389/fcell.2021.684885; RA Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.; RT "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to RT Regulate Cell Proliferation and Autophagy."; RL Front. Cell Dev. Biol. 9:684885-684885(2021). RN [96] RP FUNCTION. RX PubMed=34893540; DOI=10.1073/pnas.2107993118; RA Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J., RA Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.; RT "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [97] RP FUNCTION, AND INTERACTION WITH GRB2. RX PubMed=35831301; DOI=10.1038/s41420-022-01106-1; RA Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.; RT "Grb2 interacts with necrosome components and is involved in rasfonin- RT induced necroptosis."; RL Cell. Death. Discov. 8:319-319(2022). RN [98] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND RP SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407. RX PubMed=37306101; DOI=10.15252/embj.2022113349; RA Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y., RA Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T., RA Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y., RA Noda N.N., Komatsu M.; RT "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox- RT independent stress response."; RL EMBO J. 42:e113349-e113349(2023). RN [99] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND RP MUTAGENESIS OF 289-CYS-CYS-290. RX PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004; RA Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X., RA Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T., RA Neculai D., Sun Q., Kong E., Tate E.W., Yang A.; RT "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in RT mammalian autophagy."; RL Mol. Cell 83:3485-3501(2023). RN [100] RP INTERACTION WITH WDR83. RX PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023; RA Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.; RT "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases."; RL Mol. Cell 0:0-0(2023). RN [101] RP STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND RP DOMAIN. RX PubMed=12857745; DOI=10.1074/jbc.m307416200; RA Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.; RT "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and RT implications for mutations that cause Paget's disease of bone."; RL J. Biol. Chem. 278:37409-37412(2003). RN [102] RP STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN. RX PubMed=18083707; DOI=10.1074/jbc.m704973200; RA Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H., RA Layfield R., Searle M.S.; RT "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a RT novel conformational switch."; RL J. Biol. Chem. 283:5427-5440(2008). RN [103] RP STRUCTURE BY NMR OF 387-436. RX PubMed=17932931; DOI=10.1002/prot.21692; RA Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.; RT "Conformation and dynamics of the three-helix bundle UBA domain of p62 from RT experiment and simulation."; RL Proteins 71:227-240(2008). RN [104] RP STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND RP GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425. RX PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032; RA Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B., RA Williamson M.P., Layfield R., Searle M.S.; RT "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and RT regulates NF-kappaB signalling."; RL J. Mol. Biol. 396:178-194(2010). RN [105] RP VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274. RX PubMed=11992264; DOI=10.1086/340731; RA Laurin N., Brown J.P., Morissette J., Raymond V.; RT "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in RT Paget disease of bone."; RL Am. J. Hum. Genet. 70:1582-1588(2002). RN [106] RP VARIANT PDB3 LEU-392. RX PubMed=12374763; DOI=10.1093/hmg/11.22.2735; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M., RA Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W., RA Ralston S.H.; RT "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and RT sporadic Paget's disease."; RL Hum. Mol. Genet. 11:2735-2739(2002). RN [107] RP VARIANT PDB3 LEU-387. RX PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748; RA Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F., RA Singer F.R., Leach R.J.; RT "Three novel mutations in SQSTM1 identified in familial Paget's disease of RT bone."; RL J. Bone Miner. Res. 18:1748-1753(2003). RN [108] RP VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425. RX PubMed=15146436; DOI=10.1002/art.20224; RA Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C., RA Kneppers A.L.J., Papapoulos S.E.; RT "Familial Paget's disease in The Netherlands: occurrence, identification of RT new mutations in the sequestosome 1 gene, and their clinical RT associations."; RL Arthritis Rheum. 50:1650-1654(2004). RN [109] RP VARIANT PDB3 LEU-392. RX PubMed=15207768; DOI=10.1016/j.bone.2004.01.010; RA Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L., RA Kesting J.B., Andersen J., Shaw J.T.E.; RT "Identification of SQSTM1 mutations in familial Paget's disease in RT Australian pedigrees."; RL Bone 35:277-282(2004). RN [110] RP VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425. RX PubMed=15125799; DOI=10.1359/jbmr.040203; RA Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C., RA Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F., RA Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B., RA Melchiorre D., Matucci-Cerinic M., Brandi M.L.; RT "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an RT Italian series of patients affected by Paget's disease of bone (PDB)."; RL J. Bone Miner. Res. 19:1013-1017(2004). RN [111] RP VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF RP VARIANTS VAL-404; SER-411 AND ARG-425. RX PubMed=15176995; DOI=10.1359/jbmr.0403015; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C., RA Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W., RA Searle M.S., Layfield R., Ralston S.H.; RT "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype RT phenotype correlation, functional analysis, and structural consequences."; RL J. Bone Miner. Res. 19:1122-1127(2004). RN [112] RP VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17488105; DOI=10.1021/pr0700908; RA Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A., RA Hendrickson R.C., Stephenson J.L. Jr.; RT "Detection and validation of non-synonymous coding SNPs from orthogonal RT analysis of shotgun proteomics data."; RL J. Proteome Res. 6:2331-2340(2007). RN [113] RP INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; RP TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; RP ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND RP VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; RP GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; RP 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 RP DEL; THR-349 AND LEU-439. RX PubMed=24899140; DOI=10.1007/s00401-014-1298-7; RA van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W., RA Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K., RA Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M., RA Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A., RA Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I., RA Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S., RA Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H., RA Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C., RA Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B., RA Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I., RA Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A., RA Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A., RA Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P., RA Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R., RA De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.; RT "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar RT degeneration."; RL Acta Neuropathol. 128:397-410(2014). CC -!- FUNCTION: Molecular adapter required for selective macroautophagy CC (aggrephagy) by acting as a bridge between polyubiquitinated proteins CC and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, CC PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, CC PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the CC recruitment of ubiquitinated cargo proteins to autophagosomes via CC multiple domains that bridge proteins and organelles in different steps CC (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, CC PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, CC PubMed:37802024). SQSTM1 first mediates the assembly and removal of CC ubiquitinated proteins by undergoing liquid-liquid phase separation CC upon binding to ubiquitinated proteins via its UBA domain, leading to CC the formation of insoluble cytoplasmic inclusions, known as p62 bodies CC (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, CC PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). CC SQSTM1 then interacts with ATG8 family proteins on autophagosomes via CC its LIR motif, leading to p62 body recruitment to autophagosomes, CC followed by autophagic clearance of ubiquitinated proteins CC (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself CC degraded along with its ubiquitinated cargos (PubMed:16286508, CC PubMed:17580304, PubMed:37802024). Also required to recruit CC ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). CC Also involved in autophagy of peroxisomes (pexophagy) in response to CC reactive oxygen species (ROS) by acting as a bridge between CC ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts CC as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: CC interaction inactivates the BCR(KEAP1) complex by sequestering the CC complex in inclusion bodies, promoting nuclear accumulation of CC NFE2L2/NRF2 and subsequent expression of cytoprotective genes CC (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). CC Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to CC autophagosomes (PubMed:29496741). Involved in endosome organization by CC retaining vesicles in the perinuclear cloud: following ubiquitination CC by RNF26, attracts specific vesicle-associated adapters, forming a CC molecular bridge that restrains cognate vesicles in the perinuclear CC region and organizes the endosomal pathway for efficient cargo CC transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 CC into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal CC degradation (PubMed:25101860). May regulate the activation of NFKB1 by CC TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, CC PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, CC PubMed:19931284). May play a role in titin/TTN downstream signaling in CC muscle cells (PubMed:15802564). Adapter that mediates the interaction CC between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, CC ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177, CC ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102, CC ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082, CC ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133, CC ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. CC -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays CC (PubMed:12887891, PubMed:19931284). Dimerization interferes with CC ubiquitin binding (PubMed:19931284). Component of a ternary complex CC with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, CC PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 CC and CYLD (By similarity). Identified in a heterotrimeric complex with CC ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the CC same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) CC with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, CC including GABARAP, GABARAPL1 and GABARAPL2; these interactions are CC necessary for the recruitment MAP1 LC3 family members to inclusion CC bodies containing polyubiquitinated protein aggregates and for their CC degradation by autophagy (PubMed:16286508, PubMed:17580304, CC PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly CC with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, CC PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, CC NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, CC PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, CC PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with CC RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF- CC R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the CC proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with CC TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked CC polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 CC (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts CC with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, CC PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with CC UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct CC and regulates the interaction of SQSTM1 with ubiquitinated proteins CC (PubMed:28404643). Interacts with WDFY3; this interaction is required CC to recruit WDFY3 to cytoplasmic bodies and to PML bodies CC (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts CC with STING1; leading to relocalization of STING1 to autophagosomes CC (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with CC KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex CC by sequestering KEAP1 in inclusion bodies, promoting its degradation CC (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with CC MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester CC KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts CC with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; CC specifically binds PEX5 ubiquitinated at 'Lys-209' in response to CC reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 CC domain) with TNS2; the interaction leads to sequestration of TNS2 in CC cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and CC proteasomal degradation (PubMed:25101860). Interacts with IRS1; the CC interaction is disrupted by the presence of tensin TNS2 CC (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, CC PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting CC AIM2 recruitment to autophagosomes and autophagy-dependent degradation CC of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). CC Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 CC (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts CC with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction CC inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT CC complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By CC similarity). Interacts with WDR83 (PubMed:38103557). Interacts with CC GRB2 (PubMed:35831301). Interacts with USP12; the interaction is CC independent of USP12 deubiquitinase activity and may be involved in CC regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 CC (PubMed:34164402). {ECO:0000250|UniProtKB:O08623, CC ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531, CC ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044, CC ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, CC ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101, CC ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085, CC ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264, CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865, CC ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090, CC ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909, CC ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402, CC ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557, CC ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896, CC ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285, CC ECO:0000269|PubMed:9566925}. CC -!- INTERACTION: CC Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613; CC Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964; CC Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185; CC Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634; CC Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440; CC Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940; CC Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310; CC Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445; CC Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462; CC Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541; CC Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505; CC Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001; CC Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969; CC Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116; CC Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499; CC Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029; CC Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279; CC Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001; CC Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863; CC Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372; CC Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768; CC Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144; CC Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996; CC Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294; CC Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698; CC Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125; CC Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226; CC Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974; CC Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987; CC Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705; CC Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199; CC Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227; CC Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453; CC Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642; CC Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595; CC Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161; CC Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879; CC Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104; CC Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085; CC Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276; CC Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864; CC Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054; CC Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357; CC Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397; CC Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256; CC Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701; CC Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773; CC Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771; CC Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684; CC Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110; CC Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238; CC Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715; CC Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771; CC Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, CC ECO:0000269|PubMed:37802024}. Preautophagosomal structure CC {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML CC body {ECO:0000269|PubMed:20168092}. Late endosome CC {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome CC {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm, CC myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac CC muscle, localizes to the sarcomeric band (By similarity). Localizes to CC cytoplasmic membraneless inclusion bodies, known as p62 bodies, CC containing polyubiquitinated protein aggregates (PubMed:11786419, CC PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:37306101, PubMed:37802024). In CC neurodegenerative diseases, detected in Lewy bodies in Parkinson CC disease, neurofibrillary tangles in Alzheimer disease, and HTT CC aggregates in Huntington disease (PubMed:15158159). In protein CC aggregate diseases of the liver, found in large amounts in Mallory CC bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in CC hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). CC Enriched in Rosenthal fibers of pilocytic astrocytoma CC (PubMed:11786419). In the cytoplasm, observed in both membrane-free CC ubiquitin-containing protein aggregates (sequestosomes) and membrane- CC surrounded autophagosomes (PubMed:15953362, PubMed:17580304). CC Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum CC (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies CC (PubMed:20357094). When nuclear export is blocked by treatment with CC leptomycin B, accumulates in PML bodies (PubMed:20168092). CC {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, CC ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, CC ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, CC ECO:0000269|PubMed:37802024}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13501-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13501-2; Sequence=VSP_015841; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:8650207}. CC -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in CC levels in fully differentiated myotubes compared to undifferentiated CC myoblasts. {ECO:0000269|PubMed:25101860}. CC -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at CC protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is CC directly activated by NFE2L2/NRF2; creating a positive feedback loop CC (PubMed:20452972). {ECO:0000269|PubMed:12700667, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:9762895}. CC -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin CC chains of polyubiquitinated substrates (PubMed:12857745, CC PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the CC interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains CC are necessary and sufficient for the localization into the ubiquitin- CC containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253, CC ECO:0000269|PubMed:31857589}. CC -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions CC with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, CC PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and CC UBA domains are necessary and sufficient for the localization into the CC ubiquitin-containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}. CC -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1. CC {ECO:0000269|PubMed:10747026}. CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction CC with ATG8 family proteins. {ECO:0000269|PubMed:23908376}. CC -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer CC interface and increases binding affinity to ubiquitinated proteins (By CC similarity). Phosphorylation at Ser-407 also primes for subsequent CC phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 CC by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing CC the affinity between the UBA domain and polyubiquitin chains CC (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 CC is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by CC TBK1, leading to promote relocalization of 'Lys-63'-linked CC ubiquitinated STING1 to autophagosomes (PubMed:29496741). CC Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and CC inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear CC accumulation and expression of phase II detoxifying enzymes CC (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564). CC {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165, CC ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}. CC -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 CC attracts specific vesicle-associated adapters, forming a molecular CC bridge that restrains cognate vesicles in the perinuclear region and CC organizes the endosomal pathway for efficient cargo transport CC (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 CC increases its ability to bind polyubiquitin chains by destabilizing the CC UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 CC releases target vesicles for fast transport into the cell periphery CC (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, CC increasing SQSTM1 sequestering activity and promoting its degradation CC (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked CC polyubiquitination leading to xenophagic targeting of bacteria and CC inhibition of their replication (PubMed:27880896). CC {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896, CC ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357, CC ECO:0000269|PubMed:33472082}. CC -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity CC by destabilizing the UBA dimer interface and increases binding affinity CC to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 CC (PubMed:31857589). {ECO:0000269|PubMed:31857589}. CC -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for CC efficient autophagic degradation of SQSTM1-cargo complexes by promoting CC affinity for ATG8 proteins and recruitment of p62 bodies to CC autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 CC by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}. CC -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading CC to its degradation (PubMed:24331465). Degradation by SpeB prevents CC autophagy, promoting to S.pyogenes intracellular replication CC (PubMed:24331465). {ECO:0000269|PubMed:24331465}. CC -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; CC leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1- CC positive structures. {ECO:0000269|PubMed:33509017}. CC -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of CC bone remodeling characterized by increased bone turnover affecting one CC or more sites throughout the skeleton, primarily the axial skeleton. CC Osteoclastic overactivity followed by compensatory osteoblastic CC activity leads to a structurally disorganized mosaic of bone (woven CC bone), which is mechanically weaker, larger, less compact, more CC vascular, and more susceptible to fracture than normal adult lamellar CC bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, CC ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, CC ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, CC ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to CC form a shell surrounding aggregates of mutant HTT that may protect CC cells from apoptosis, possibly by recruiting autophagosomal components CC to the polyubiquitinated protein aggregates. CC {ECO:0000269|PubMed:16286508}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 CC (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia is characterized by frontal and temporal lobe CC atrophy associated with neuronal loss, gliosis, and dementia. Patients CC exhibit progressive changes in social, behavioral, and/or language CC function. Amyotrophic lateral sclerosis is characterized by the death CC of motor neurons in the brain, brainstem, and spinal cord, resulting in CC fatal paralysis. Some FTDALS3 patients may also develop Paget disease CC of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, CC ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, CC childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder CC characterized by gait abnormalities, ataxia, dysarthria, dystonia, CC vertical gaze palsy, and cognitive decline. Disease onset is in CC childhood or adolescence. NADGP transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An CC autosomal dominant myopathy with adult onset, characterized by muscle CC weakness of the distal upper and lower limbs, walking difficulties, and CC proximal weakness of the shoulder girdle muscles. Muscle biopsy shows CC rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a CC form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) CC with NUP214. {ECO:0000269|PubMed:20851865}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U41806; AAA93299.1; -; mRNA. DR EMBL; U46751; AAC52070.1; -; mRNA. DR EMBL; AK098077; BAG53577.1; -; mRNA. DR EMBL; AK312451; BAG35358.1; -; mRNA. DR EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000951; AAH00951.1; -; mRNA. DR EMBL; BC001874; AAH01874.1; -; mRNA. DR EMBL; BC003139; AAH03139.1; -; mRNA. DR EMBL; BC017222; AAH17222.1; -; mRNA. DR EMBL; BC019111; AAH19111.1; -; mRNA. DR EMBL; AF060494; AAC64516.1; -; Genomic_DNA. DR CCDS; CCDS34317.1; -. [Q13501-1] DR CCDS; CCDS47355.1; -. [Q13501-2] DR RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2] DR RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2] DR RefSeq; NP_003891.1; NM_003900.5. [Q13501-1] DR PDB; 1Q02; NMR; -; A=387-436. DR PDB; 2JY7; NMR; -; A=387-436. DR PDB; 2JY8; NMR; -; A=387-436. DR PDB; 2K0B; NMR; -; X=387-436. DR PDB; 2KNV; NMR; -; A/B=387-436. DR PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102. DR PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102. DR PDB; 4UF9; EM; 10.30 A; A/B/D=1-122. DR PDB; 5YP7; X-ray; 1.42 A; A/D=126-180. DR PDB; 5YP8; X-ray; 1.45 A; A/B=126-180. DR PDB; 5YPA; X-ray; 2.50 A; A/B=126-180. DR PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180. DR PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180. DR PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180. DR PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180. DR PDB; 5YPG; X-ray; 2.20 A; A/B=126-180. DR PDB; 5YPH; X-ray; 1.63 A; A/B=126-180. DR PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102. DR PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169. DR PDB; 6MIU; X-ray; 1.90 A; A/B=120-171. DR PDB; 6MJ7; X-ray; 1.41 A; A=120-171. DR PDB; 6TGY; EM; 3.50 A; A=1-122. DR PDB; 6TH3; EM; 4.00 A; A/B/C=1-122. DR PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172. DR PDBsum; 1Q02; -. DR PDBsum; 2JY7; -. DR PDBsum; 2JY8; -. DR PDBsum; 2K0B; -. DR PDBsum; 2KNV; -. DR PDBsum; 4MJS; -. DR PDBsum; 4UF8; -. DR PDBsum; 4UF9; -. DR PDBsum; 5YP7; -. DR PDBsum; 5YP8; -. DR PDBsum; 5YPA; -. DR PDBsum; 5YPB; -. DR PDBsum; 5YPC; -. DR PDBsum; 5YPE; -. DR PDBsum; 5YPF; -. DR PDBsum; 5YPG; -. DR PDBsum; 5YPH; -. DR PDBsum; 6JM4; -. DR PDBsum; 6KHZ; -. DR PDBsum; 6MIU; -. DR PDBsum; 6MJ7; -. DR PDBsum; 6TGY; -. DR PDBsum; 6TH3; -. DR PDBsum; 7R1O; -. DR AlphaFoldDB; Q13501; -. DR BMRB; Q13501; -. DR EMDB; EMD-10501; -. DR EMDB; EMD-10502; -. DR EMDB; EMD-2936; -. DR EMDB; EMD-2937; -. DR SMR; Q13501; -. DR BioGRID; 114397; 1356. DR CORUM; Q13501; -. DR DIP; DIP-34443N; -. DR ELM; Q13501; -. DR FunCoup; Q13501; 2230. DR IntAct; Q13501; 311. DR MINT; Q13501; -. DR STRING; 9606.ENSP00000374455; -. DR BindingDB; Q13501; -. DR ChEMBL; CHEMBL4295816; -. DR GuidetoPHARMACOLOGY; 3213; -. DR MoonDB; Q13501; Predicted. DR GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13501; -. DR PhosphoSitePlus; Q13501; -. DR SwissPalm; Q13501; -. DR BioMuta; SQSTM1; -. DR DMDM; 74735628; -. DR jPOST; Q13501; -. DR MassIVE; Q13501; -. DR PaxDb; 9606-ENSP00000374455; -. DR PeptideAtlas; Q13501; -. DR ProteomicsDB; 59496; -. [Q13501-1] DR ProteomicsDB; 59497; -. [Q13501-2] DR Pumba; Q13501; -. DR Antibodypedia; 761; 1362 antibodies from 49 providers. DR DNASU; 8878; -. DR YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers. DR Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2] DR Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1] DR Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1] DR Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1] DR GeneID; 8878; -. DR KEGG; hsa:8878; -. DR MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1. DR UCSC; uc003mkw.5; human. [Q13501-1] DR AGR; HGNC:11280; -. DR ClinPGx; PA36109; -. DR CTD; 8878; -. DR DisGeNET; 8878; -. DR GeneCards; SQSTM1; -. DR HGNC; HGNC:11280; SQSTM1. DR HPA; ENSG00000161011; Tissue enhanced (skeletal). DR MalaCards; SQSTM1; -. DR MIM; 167250; phenotype. DR MIM; 601530; gene. DR MIM; 616437; phenotype. DR MIM; 617145; phenotype. DR MIM; 617158; phenotype. DR OpenTargets; ENSG00000161011; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 603; Distal myopathy, Welander type. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR VEuPathDB; HostDB:ENSG00000161011; -. DR eggNOG; KOG4582; Eukaryota. DR GeneTree; ENSGT00390000002781; -. DR HOGENOM; CLU_038011_1_0_1; -. DR InParanoid; Q13501; -. DR OMA; NCNGWLT; -. DR OrthoDB; 441278at2759; -. DR PAN-GO; Q13501; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13501; -. DR PathwayCommons; Q13501; -. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9664873; Pexophagy. DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; Q13501; -. DR SIGNOR; Q13501; -. DR Agora; ENSG00000161011; -. DR BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens. DR CD-CODE; 1822EB5E; Synthetic Condensate 000092. DR CD-CODE; 5D6181E1; Synthetic Condensate 000293. DR CD-CODE; 718A9EC3; P62 body. DR CD-CODE; 98C8800A; Synthetic Condensate 000338. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; EF6CBD8C; Synthetic Condensate 000070. DR CD-CODE; F17BA747; P62 cluster. DR CD-CODE; F5639AB0; Synthetic Condensate 000096. DR ChiTaRS; SQSTM1; human. DR EvolutionaryTrace; Q13501; -. DR GeneWiki; Sequestosome_1; -. DR GenomeRNAi; 8878; -. DR Pharos; Q13501; Tbio. DR PRO; PR:Q13501; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13501; protein. DR Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues. DR ExpressionAtlas; Q13501; baseline and differential. DR GO; GO:0016235; C:aggresome; IBA:GO_Central. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0097413; C:Lewy body; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000932; C:P-body; IDA:UniProtKB. DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB. DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc. DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0035973; P:aggrephagy; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0006914; P:autophagy; IDA:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0033554; P:cellular response to stress; IDA:UniProt. DR GO; GO:0016197; P:endosomal transport; TAS:UniProtKB. DR GO; GO:0007032; P:endosome organization; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IDA:UniProtKB. DR GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB. DR GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL. DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd06402; PB1_p62; 1. DR CDD; cd14320; UBA_SQSTM; 1. DR CDD; cd02340; ZZ_NBR1_like; 1. DR DisProt; DP01111; -. DR FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1. DR FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1. DR FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1. DR Gene3D; 3.30.60.90; -; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00383; -. DR InterPro; IPR052260; Autophagy_Rcpt_SigReg. DR InterPro; IPR053793; PB1-like. DR InterPro; IPR000270; PB1_dom. DR InterPro; IPR034866; PB1_p62. DR InterPro; IPR033741; SQSTM_UBA. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR000433; Znf_ZZ. DR InterPro; IPR043145; Znf_ZZ_sf. DR PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1. DR PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1. DR Pfam; PF00564; PB1; 1. DR Pfam; PF16577; UBA_5; 1. DR Pfam; PF00569; ZZ; 1. DR SMART; SM00666; PB1; 1. DR SMART; SM00165; UBA; 1. DR SMART; SM00291; ZnF_ZZ; 1. DR SUPFAM; SSF54277; CAD & PB1 domains; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51745; PB1; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS01357; ZF_ZZ_1; 1. DR PROSITE; PS50135; ZF_ZZ_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; KW Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm; KW Cytoplasmic vesicle; Differentiation; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Endosome; Immunity; KW Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration; KW Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT CHAIN 2..440 FT /note="Sequestosome-1" FT /id="PRO_0000072176" FT DOMAIN 3..102 FT /note="PB1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081" FT DOMAIN 389..434 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 123..173 FT /note="ZZ-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT REGION 2..50 FT /note="Interaction with LCK" FT /evidence="ECO:0000269|PubMed:8650207" FT REGION 43..107 FT /note="Interaction with PRKCZ and dimerization" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 50..80 FT /note="Interaction with PAWR" FT /evidence="ECO:0000269|PubMed:11755531" FT REGION 122..224 FT /note="Interaction with GABRR3" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 170..220 FT /note="LIM protein-binding (LB)" FT REGION 196..235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..390 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..440 FT /note="Interaction with NTRK1" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 321..342 FT /note="MAP1LC3B-binding" FT /evidence="ECO:0000269|PubMed:17580304" FT REGION 347..352 FT /note="Interaction with KEAP1" FT /evidence="ECO:0000269|PubMed:20452972" FT MOTIF 228..233 FT /note="TRAF6-binding" FT MOTIF 336..341 FT /note="LIR" FT COMPBIAS 283..296 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 310..324 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 337..347 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 351..373 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 154 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 160 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT SITE 252..253 FT /note="Breakpoint for translocation to form the NUP214- FT SQSTM1 fusion protein" FT /evidence="ECO:0000269|PubMed:20851865" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:24275569" FT MOD_RES 148 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 176 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:20068231" FT MOD_RES 233 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 249 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 266 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 269 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 282 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 332 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 349 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 355 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 361 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 365 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64337" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 403 FT /note="Phosphoserine; by CK2, ULK1 and TBK1" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741, FT ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101" FT MOD_RES 407 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 420 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT MOD_RES 435 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT LIPID 289 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT LIPID 290 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT CROSSLNK 91 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 189 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 420 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:28380357" FT CROSSLNK 435 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000269|PubMed:33472082, FT ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..84 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015841" FT VARIANT 16 FT /note="A -> V (in FTDALS3; dbSNP:rs1554162295)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073899" FT VARIANT 17 FT /note="A -> V (in dbSNP:rs141502868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073900" FT VARIANT 33 FT /note="A -> V (in FTDALS3; dbSNP:rs200396166)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_073901" FT VARIANT 80 FT /note="D -> E (in FTDALS3; dbSNP:rs148366738)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073902" FT VARIANT 90 FT /note="V -> M (in FTDALS3; dbSNP:rs181263868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073903" FT VARIANT 103 FT /note="K -> R (in dbSNP:rs748170760)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073904" FT VARIANT 107 FT /note="R -> Q" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073905" FT VARIANT 107 FT /note="R -> W (in FTDALS3; dbSNP:rs771903158)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073906" FT VARIANT 108 FT /note="D -> Y" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073907" FT VARIANT 110 FT /note="R -> H (in dbSNP:rs1267306593)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073908" FT VARIANT 117 FT /note="A -> V (in dbSNP:rs147810437)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:24899140" FT /id="VAR_023590" FT VARIANT 118 FT /note="P -> S (in dbSNP:rs200152247)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073909" FT VARIANT 119 FT /note="R -> G (in dbSNP:rs548787835)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073910" FT VARIANT 125 FT /note="N -> S (in dbSNP:rs769325755)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073911" FT VARIANT 129 FT /note="D -> N (in FTDALS3; dbSNP:rs753212399)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073912" FT VARIANT 139 FT /note="R -> C (in dbSNP:rs750256905)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073913" FT VARIANT 153 FT /note="V -> I (in FTDALS3; dbSNP:rs145056421)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073914" FT VARIANT 180 FT /note="S -> L (in dbSNP:rs1582008478)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073915" FT VARIANT 212 FT /note="R -> C (in FTDALS3; dbSNP:rs201263163)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073916" FT VARIANT 217 FT /note="R -> H (in dbSNP:rs761822261)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073917" FT VARIANT 219 FT /note="G -> V (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073918" FT VARIANT 226 FT /note="S -> P (in FTDALS3; dbSNP:rs765200636)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073919" FT VARIANT 228 FT /note="P -> L (in FTDALS3; dbSNP:rs151191977)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073920" FT VARIANT 232 FT /note="P -> T (in FTDALS3; dbSNP:rs1225746517)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073921" FT VARIANT 238 FT /note="K -> E (confirmed at protein level; FT dbSNP:rs11548633)" FT /evidence="ECO:0000269|PubMed:17488105, FT ECO:0000269|PubMed:24899140" FT /id="VAR_068915" FT VARIANT 238 FT /note="Missing (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083" FT /id="VAR_073922" FT VARIANT 258 FT /note="D -> N (in FTDALS3; dbSNP:rs774986849)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073923" FT VARIANT 265..266 FT /note="RS -> SR" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073924" FT VARIANT 274 FT /note="E -> D (in dbSNP:rs55793208)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_061707" FT VARIANT 274 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:11992264" FT /id="VAR_023591" FT VARIANT 278 FT /note="T -> I (in dbSNP:rs200445838)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073925" FT VARIANT 308 FT /note="A -> V (in dbSNP:rs541356917)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073926" FT VARIANT 318 FT /note="S -> P (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073927" FT VARIANT 319 FT /note="E -> K (in dbSNP:rs61748794)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073928" FT VARIANT 321 FT /note="R -> C (in FTDALS3; likely benign; FT dbSNP:rs140226523)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073929" FT VARIANT 329 FT /note="D -> G (in FTDALS3; dbSNP:rs148294622)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073930" FT VARIANT 334 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073931" FT VARIANT 348 FT /note="P -> L (in FTDALS3; dbSNP:rs772889843)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073932" FT VARIANT 349 FT /note="S -> T (in dbSNP:rs774512680)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073933" FT VARIANT 370 FT /note="S -> P (in FTDALS3; dbSNP:rs143956614)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073934" FT VARIANT 381 FT /note="A -> V (in FTDALS3; dbSNP:rs772122047)" FT /evidence="ECO:0000269|PubMed:24042580" FT /id="VAR_073935" FT VARIANT 387 FT /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)" FT /evidence="ECO:0000269|PubMed:14584883, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023592" FT VARIANT 392 FT /note="P -> L (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; dbSNP:rs104893941)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745, FT ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023593" FT VARIANT 399 FT /note="S -> P (in PDB3; dbSNP:rs1561609625)" FT /evidence="ECO:0000269|PubMed:15146436" FT /id="VAR_023594" FT VARIANT 404 FT /note="M -> T (in PDB3; decreased ability to undergo FT liquid-liquid phase separation and formation of p62 body; FT dbSNP:rs1247551175)" FT /evidence="ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:29507397" FT /id="VAR_023595" FT VARIANT 404 FT /note="M -> V (in PDB3; loss of polyubiquitin-binding; FT dbSNP:rs771966860)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15176995" FT /id="VAR_023596" FT VARIANT 411 FT /note="G -> S (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; decreased ability to undergo liquid- FT liquid phase separation and formation of p62 body; FT dbSNP:rs143511494)" FT /evidence="ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397" FT /id="VAR_023597" FT VARIANT 425 FT /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin- FT binding and increased activation of NF-kappa-B; FT dbSNP:rs757212984)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127" FT /id="VAR_023598" FT VARIANT 430 FT /note="T -> P (in FTDALS3; dbSNP:rs770118706)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073936" FT VARIANT 439 FT /note="P -> L (in dbSNP:rs199854262)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073937" FT MUTAGEN 7 FT /note="K->A: Loss of interactions with PRKCZ, PRCKI and FT NBR1. Loss of dimerization; when associated with A-69." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 9 FT /note="Y->F: No effect on interaction with LCK." FT /evidence="ECO:0000269|PubMed:8650207" FT MUTAGEN 13 FT /note="K->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 21..22 FT /note="RR->AA: Loss of interaction with PRKCI. Alters FT dimerization." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 67 FT /note="Y->A: No effect on interaction with PRKCZ." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 69 FT /note="D->A: No effect on interactions with PRKCZ, PRKCI FT and NBR1. Loss of localization in cytoplasmic inclusion FT bodies. Loss of dimerization; when associated with A-7." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508" FT MUTAGEN 71 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 73 FT /note="D->A: No effect on interactions with PRKCZ and FT PRKCI." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 80 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 82 FT /note="E->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 289..290 FT /note="CC->SS: Abolished palmitoylation." FT /evidence="ECO:0000269|PubMed:37802024" FT MUTAGEN 323..324 FT /note="EE->AA: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 332 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 335..337 FT /note="DDD->ADA: 75% decrease in MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 338 FT /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts FT interaction with GABARAP." FT /evidence="ECO:0000269|PubMed:17580304, FT ECO:0000269|PubMed:24668264" FT MUTAGEN 342 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 347 FT /note="D->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 349 FT /note="S->A: Impaired phosphorylation by ULK1, leading to FT decreased p62 body formation." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 350 FT /note="T->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972, FT ECO:0000269|PubMed:37306101" FT MUTAGEN 351 FT /note="G->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 352 FT /note="E->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 398 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 403..407 FT /note="SMGFS->EMGFE: Mimics phosphorylation; increased FT phosphorylation at S-349." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 403 FT /note="S->A: Abolished phosphorylation by CK2, leading to FT decreased affinity for ubiquitinated proteins. Abolished FT ability to promote relocalization of 'Lys-63'-linked FT ubiquitinated STING1 to autophagosomes." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29496741" FT MUTAGEN 403 FT /note="S->E: Mimmics phosphorylation; increased affinity FT for ubiquitinated proteins, leading to increased p62 body FT formation and autophagic degradation." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29507397" FT MUTAGEN 406 FT /note="F->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 409 FT /note="E->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 410 FT /note="G->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 413 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 417 FT /note="L->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 420 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-435." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 420 FT /note="K->R: Decreased ubiquitination by the BCR(KEAP1) FT complex, leading to decreased sequestering activity. FT Strongly reduced acetylation; when associated with R-435." FT /evidence="ECO:0000269|PubMed:28380357, FT ECO:0000269|PubMed:31857589" FT MUTAGEN 431 FT /note="I->V: Partial loss of polyubiquitin-binding. Loss of FT localization to cytoplasmic inclusion bodies." FT /evidence="ECO:0000269|PubMed:15340068, FT ECO:0000269|PubMed:16286508" FT MUTAGEN 435 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-420." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 435 FT /note="K->R: Strongly reduced acetylation; when associated FT with R-420." FT /evidence="ECO:0000269|PubMed:31857589" FT CONFLICT 321 FT /note="R -> A (in Ref. 1; AAA93299)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 13..15 FT /evidence="ECO:0007829|PDB:6TGY" FT STRAND 19..24 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:6TGY" FT HELIX 43..54 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4MJS" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6KHZ" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:6MJ7" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 157..162 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 165..168 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:2JY7" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 412..419 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 420..422 FT /evidence="ECO:0007829|PDB:1Q02" FT HELIX 424..431 FT /evidence="ECO:0007829|PDB:1Q02" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:2JY8" FT INIT_MET Q13501-2:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q13501-2:2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 440 AA; 47687 MW; 462D94C171F337CD CRC64; MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK NYDIGAALDT IQYSKHPPPL // ID SYNJ1_HUMAN Reviewed; 1573 AA. AC O43426; O43425; O94984; Q4KMR1; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 222. DE RecName: Full=Synaptojanin-1; DE EC=3.1.3.36 {ECO:0000269|PubMed:23804563, ECO:0000269|PubMed:27435091}; DE AltName: Full=Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1; GN Name=SYNJ1; Synonyms=KIAA0910; 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), AND VARIANT ARG-295. RC TISSUE=Cerebellum; RX PubMed=9428629; DOI=10.1016/s0014-5793(97)01451-8; RA Haffner C., Takei K., Chen H., Ringstad N., Hudson A., Butler M.H., RA Salcini A.E., Di Fiore P.P., De Camilli P.; RT "Synaptojanin 1: localization on coated endocytic intermediates in nerve RT terminals and interaction of its 170 kDa isoform with Eps15."; RL FEBS Lett. 419:175-180(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Brain; RX PubMed=10048485; DOI=10.1093/dnares/5.6.355; RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N., RA Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XII. The RT complete sequences of 100 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 5:355-364(1998). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). 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 [6] RP INTERACTION WITH AMPH; SH3GL1; SH3GL2 AND SH3GL3, AND DOMAIN. RX PubMed=10542231; DOI=10.1074/jbc.274.45.32001; RA Cestra G., Castagnoli L., Dente L., Minenkova O., Petrelli A., Migone N., RA Hoffmueller U., Schneider-Mergener J., Cesareni G.; RT "The SH3 domains of endophilin and amphiphysin bind to the proline-rich RT region of synaptojanin 1 at distinct sites that display an unconventional RT binding specificity."; RL J. Biol. Chem. 274:32001-32007(1999). RN [7] RP INTERACTION WITH MYO1E. RX PubMed=17257598; DOI=10.1016/j.febslet.2007.01.021; RA Krendel M., Osterweil E.K., Mooseker M.S.; RT "Myosin 1E interacts with synaptojanin-1 and dynamin and is involved in RT endocytosis."; RL FEBS Lett. 581:644-650(2007). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830; THR-1220; SER-1551 AND RP SER-1565, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1318, 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-830; THR-1220; SER-1292; RP SER-1345 AND SER-1565, 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 [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1220, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [13] RP FUNCTION, INVOLVEMENT IN DEE53, VARIANTS DEE53 CYS-849; ILE-981 AND RP SER-1018, CHARACTERIZATION OF VARIANTS DEE53 CYS-849; ILE-981 AND SER-1018, RP AND CATALYTIC ACTIVITY. RX PubMed=27435091; DOI=10.1093/brain/aww180; RG AR working group of the EuroEPINOMICS RES Consortium; RA Hardies K., Cai Y., Jardel C., Jansen A.C., Cao M., May P., Djemie T., RA Hachon Le Camus C., Keymolen K., Deconinck T., Bhambhani V., Long C., RA Sajan S.A., Helbig K.L., Suls A., Balling R., Helbig I., De Jonghe P., RA Depienne C., De Camilli P., Weckhuysen S.; RT "Loss of SYNJ1 dual phosphatase activity leads to early onset refractory RT seizures and progressive neurological decline."; RL Brain 139:2420-2430(2016). RN [14] RP STRUCTURE BY NMR OF 894-971. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of RNA binding domain in synaptojanin 1."; RL Submitted (OCT-2006) to the PDB data bank. RN [15] RP VARIANT PARK20 GLN-219, CHARACTERIZATION OF VARIANT PARK20 GLN-219, RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=23804563; DOI=10.1002/humu.22372; RA Krebs C.E., Karkheiran S., Powell J.C., Cao M., Makarov V., Darvish H., RA Di Paolo G., Walker R.H., Shahidi G.A., Buxbaum J.D., De Camilli P., RA Yue Z., Paisan-Ruiz C.; RT "The Sac1 domain of SYNJ1 identified mutated in a family with early-onset RT progressive Parkinsonism with generalized seizures."; RL Hum. Mutat. 34:1200-1207(2013). RN [16] RP VARIANTS PARK20 GLN-219 AND ARG-1383. RX PubMed=23804577; DOI=10.1002/humu.22373; RA Quadri M., Fang M., Picillo M., Olgiati S., Breedveld G.J., Graafland J., RA Wu B., Xu F., Erro R., Amboni M., Pappata S., Quarantelli M., Annesi G., RA Quattrone A., Chien H.F., Barbosa E.R., Oostra B.A., Barone P., Wang J., RA Bonifati V.; RT "Mutation in the SYNJ1 gene associated with autosomal recessive, early- RT onset Parkinsonism."; RL Hum. Mutat. 34:1208-1215(2013). RN [17] RP VARIANT PARK20 PRO-420. RX PubMed=27496670; DOI=10.1016/j.parkreldis.2016.07.014; RA Kirola L., Behari M., Shishir C., Thelma B.K.; RT "Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of RT an Indian family with autosomal recessive juvenile Parkinsonism."; RL Parkinsonism Relat. Disord. 31:124-128(2016). CC -!- FUNCTION: Phosphatase that acts on various phosphoinositides, including CC phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)- CC bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate CC (PubMed:23804563, PubMed:27435091). Has a role in clathrin-mediated CC endocytosis (By similarity). Hydrolyzes PIP2 bound to actin regulatory CC proteins resulting in the rearrangement of actin filaments downstream CC of tyrosine kinase and ASH/GRB2 (By similarity). CC {ECO:0000250|UniProtKB:O18964, ECO:0000250|UniProtKB:Q62910, CC ECO:0000269|PubMed:23804563, ECO:0000269|PubMed:27435091}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5- CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol 4-phosphate) + phosphate; Xref=Rhea:RHEA:22764, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178, CC ChEBI:CHEBI:58456; EC=3.1.3.36; CC Evidence={ECO:0000269|PubMed:23804563, ECO:0000269|PubMed:27435091}; CC -!- SUBUNIT: Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2 and CC PACSIN3 (By similarity). Interacts with AMPH, SH3GL1, SH3GL2 and SH3GL3 CC (PubMed:10542231). Interacts with MYO1E (via SH3 domain) CC (PubMed:17257598). Interacts with BIN1 and DNM1 (By similarity). CC Interacts with EPS15 (By similarity). {ECO:0000250|UniProtKB:O18964, CC ECO:0000250|UniProtKB:Q62910, ECO:0000250|UniProtKB:Q8CHC4, CC ECO:0000269|PubMed:10542231, ECO:0000269|PubMed:17257598}. CC -!- INTERACTION: CC O43426; P49418: AMPH; NbExp=5; IntAct=EBI-2821539, EBI-7121510; CC O43426; Q15811: ITSN1; NbExp=2; IntAct=EBI-2821539, EBI-602041; CC O43426; Q99961: SH3GL1; NbExp=3; IntAct=EBI-2821539, EBI-697911; CC O43426; Q99962: SH3GL2; NbExp=2; IntAct=EBI-2821539, EBI-77938; CC O43426; Q9Y5X1: SNX9; NbExp=7; IntAct=EBI-2821539, EBI-77848; CC O43426; O94875: SORBS2; NbExp=2; IntAct=EBI-2821539, EBI-311323; CC O43426; Q6ZQ03: Fnbp4; Xeno; NbExp=2; IntAct=EBI-2821539, EBI-6261106; CC O43426; P62994: Grb2; Xeno; NbExp=2; IntAct=EBI-2821539, EBI-401775; CC O43426; Q9Z0W5: Pacsin1; Xeno; NbExp=2; IntAct=EBI-2821539, EBI-1550185; CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region CC {ECO:0000250|UniProtKB:O18964}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=Synaptojanin-170; CC IsoId=O43426-1; Sequence=Displayed; CC Name=2; Synonyms=Synaptojanin-145; CC IsoId=O43426-2; Sequence=VSP_002682, VSP_002683; CC Name=3; CC IsoId=O43426-4; Sequence=VSP_041578, VSP_002682, VSP_002683; CC Name=4; CC IsoId=O43426-5; Sequence=VSP_035709, VSP_035710, VSP_035711; CC -!- DOMAIN: Interacts with EPS15 (a clathrin coat-associated protein) via a CC C-terminal domain containing three Asn-Pro-Phe (NPF) repeats. CC {ECO:0000250|UniProtKB:Q62910}. CC -!- DOMAIN: The C-terminal proline-rich region mediates binding to a CC variety of SH3 domain-containing proteins including AMPH, SH3GL1, CC SH3GL2 and SH3GL3. {ECO:0000269|PubMed:10542231}. CC -!- DISEASE: Parkinson disease 20, early-onset (PARK20) [MIM:615530]: An CC early-onset form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability, as well as by a clinically CC significant response to treatment with levodopa. The pathology involves CC the loss of dopaminergic neurons in the substantia nigra and the CC presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. PARK20 CC is characterized by young adult-onset of parkinsonism. Additional CC features may include seizures, cognitive decline, abnormal eye CC movements, and dystonia. {ECO:0000269|PubMed:23804563, CC ECO:0000269|PubMed:23804577, ECO:0000269|PubMed:27496670}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Developmental and epileptic encephalopathy 53 (DEE53) CC [MIM:617389]: A form of epileptic encephalopathy, a heterogeneous group CC of severe early-onset epilepsies characterized by refractory seizures, CC neurodevelopmental impairment, and poor prognosis. Development is CC normal prior to seizure onset, after which cognitive and motor delays CC become apparent. DEE53 inheritance is autosomal recessive. CC {ECO:0000269|PubMed:27435091}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the synaptojanin family. {ECO:0000305}. CC -!- SIMILARITY: In the central section; belongs to the inositol 1,4,5- CC trisphosphate 5-phosphatase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA74933.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF009039; AAC51921.1; -; mRNA. DR EMBL; AF009040; AAC51922.1; -; mRNA. DR EMBL; AB020717; BAA74933.2; ALT_INIT; mRNA. DR EMBL; AP000275; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000276; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000277; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000278; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000279; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC098395; AAH98395.1; -; mRNA. DR CCDS; CCDS33540.3; -. [O43426-2] DR CCDS; CCDS54483.1; -. [O43426-4] DR RefSeq; NP_001153774.1; NM_001160302.2. [O43426-4] DR RefSeq; NP_001153778.1; NM_001160306.1. DR RefSeq; NP_003886.3; NM_003895.3. DR RefSeq; NP_982271.3; NM_203446.3. [O43426-2] DR RefSeq; XP_047297005.1; XM_047441049.1. [O43426-4] DR RefSeq; XP_054180924.1; XM_054324949.1. [O43426-4] DR PDB; 1W80; X-ray; 1.90 A; P=1477-1488, Q=1458-1469. DR PDB; 2DNR; NMR; -; A=894-971. DR PDB; 2VJ0; X-ray; 1.60 A; P=1477-1488. DR PDB; 7A0V; X-ray; 2.30 A; A/C/E=528-873. DR PDB; 7A17; X-ray; 2.73 A; A=528-873, C/E=529-873. DR PDBsum; 1W80; -. DR PDBsum; 2DNR; -. DR PDBsum; 2VJ0; -. DR PDBsum; 7A0V; -. DR PDBsum; 7A17; -. DR AlphaFoldDB; O43426; -. DR SMR; O43426; -. DR BioGRID; 114388; 89. DR ELM; O43426; -. DR FunCoup; O43426; 1139. DR IntAct; O43426; 47. DR MINT; O43426; -. DR STRING; 9606.ENSP00000409667; -. DR ChEMBL; CHEMBL4523136; -. DR DrugCentral; O43426; -. DR DEPOD; SYNJ1; -. DR GlyCosmos; O43426; 5 sites, 1 glycan. DR GlyGen; O43426; 7 sites, 1 O-linked glycan (6 sites). DR iPTMnet; O43426; -. DR MetOSite; O43426; -. DR PhosphoSitePlus; O43426; -. DR SwissPalm; O43426; -. DR BioMuta; SYNJ1; -. DR jPOST; O43426; -. DR MassIVE; O43426; -. DR PaxDb; 9606-ENSP00000409667; -. DR PeptideAtlas; O43426; -. DR ProteomicsDB; 48937; -. [O43426-1] DR ProteomicsDB; 48938; -. [O43426-2] DR ProteomicsDB; 48939; -. [O43426-4] DR ProteomicsDB; 48940; -. [O43426-5] DR Pumba; O43426; -. DR Antibodypedia; 2183; 163 antibodies from 28 providers. DR DNASU; 8867; -. DR Ensembl; ENST00000357345.8; ENSP00000349903.3; ENSG00000159082.19. [O43426-4] DR Ensembl; ENST00000674204.1; ENSP00000501504.1; ENSG00000159082.19. [O43426-2] DR Ensembl; ENST00000674308.1; ENSP00000501426.1; ENSG00000159082.19. [O43426-1] DR Ensembl; ENST00000674351.1; ENSP00000501530.1; ENSG00000159082.19. [O43426-2] DR GeneID; 8867; -. DR KEGG; hsa:8867; -. DR MANE-Select; ENST00000674351.1; ENSP00000501530.1; NM_203446.3; NP_982271.3. [O43426-2] DR UCSC; uc002yqf.2; human. [O43426-1] DR AGR; HGNC:11503; -. DR ClinPGx; PA36285; -. DR CTD; 8867; -. DR DisGeNET; 8867; -. DR GeneCards; SYNJ1; -. DR HGNC; HGNC:11503; SYNJ1. DR HPA; ENSG00000159082; Tissue enhanced (brain, retina). DR MalaCards; SYNJ1; -. DR MIM; 604297; gene. DR MIM; 615530; phenotype. DR MIM; 617389; phenotype. DR OpenTargets; ENSG00000159082; -. DR Orphanet; 391411; Atypical juvenile parkinsonism. DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000159082; -. DR eggNOG; KOG0566; Eukaryota. DR GeneTree; ENSGT00940000157964; -. DR InParanoid; O43426; -. DR OMA; FERHMSM; -. DR OrthoDB; 1925875at2759; -. DR PAN-GO; O43426; 8 GO annotations based on evolutionary models. DR PhylomeDB; O43426; -. DR BioCyc; MetaCyc:HS08354-MONOMER; -. DR PathwayCommons; O43426; -. DR Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane. DR Reactome; R-HSA-1855183; Synthesis of IP2, IP, and Ins in the cytosol. DR Reactome; R-HSA-1855204; Synthesis of IP3 and IP4 in the cytosol. DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis. DR SignaLink; O43426; -. DR SIGNOR; O43426; -. DR Agora; ENSG00000159082; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 8867; 9 hits in 1169 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SYNJ1; human. DR EvolutionaryTrace; O43426; -. DR GenomeRNAi; 8867; -. DR Pharos; O43426; Tchem. DR PRO; PR:O43426; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; O43426; protein. DR Bgee; ENSG00000159082; Expressed in Brodmann (1909) area 23 and 193 other cell types or tissues. DR ExpressionAtlas; O43426; baseline and differential. DR GO; GO:0030132; C:clathrin coat of coated pit; ISS:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0030117; C:membrane coat; ISS:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; IDA:ParkinsonsUK-UCL. DR GO; GO:0097060; C:synaptic membrane; ISS:BHF-UCL. DR GO; GO:0043195; C:terminal bouton; ISS:ParkinsonsUK-UCL. DR GO; GO:0012506; C:vesicle membrane; ISS:ParkinsonsUK-UCL. DR GO; GO:0052658; F:inositol-1,4,5-trisphosphate 5-phosphatase activity; IBA:GO_Central. DR GO; GO:0034596; F:phosphatidylinositol phosphate 4-phosphatase activity; TAS:Reactome. DR GO; GO:0034595; F:phosphatidylinositol phosphate 5-phosphatase activity; ISS:ParkinsonsUK-UCL. DR GO; GO:0052629; F:phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity; TAS:Reactome. DR GO; GO:0043813; F:phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity; TAS:Reactome. DR GO; GO:0004438; F:phosphatidylinositol-3-phosphate phosphatase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0043812; F:phosphatidylinositol-4-phosphate phosphatase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW. DR GO; GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome. DR GO; GO:0007612; P:learning; IMP:ParkinsonsUK-UCL. DR GO; GO:0061024; P:membrane organization; TAS:Reactome. DR GO; GO:0006836; P:neurotransmitter transport; ISS:ParkinsonsUK-UCL. DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome. DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0046488; P:phosphatidylinositol metabolic process; ISS:ParkinsonsUK-UCL. DR GO; GO:1904980; P:positive regulation of endosome organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0048488; P:synaptic vesicle endocytosis; IGI:ParkinsonsUK-UCL. DR GO; GO:0016082; P:synaptic vesicle priming; ISS:ParkinsonsUK-UCL. DR GO; GO:0048489; P:synaptic vesicle transport; ISS:ParkinsonsUK-UCL. DR GO; GO:0016191; P:synaptic vesicle uncoating; ISS:ParkinsonsUK-UCL. DR CDD; cd09098; INPP5c_Synj1; 1. DR CDD; cd12719; RRM_SYNJ1; 1. DR FunFam; 3.30.70.330:FF:000076; Synaptojanin-1 isoform 1; 1. DR FunFam; 3.60.10.10:FF:000003; Synaptojanin-1 isoform 1; 1. DR Gene3D; 3.30.70.330; -; 1. DR Gene3D; 3.60.10.10; Endonuclease/exonuclease/phosphatase; 1. DR IDEAL; IID00691; -. DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf. DR InterPro; IPR046985; IP5. DR InterPro; IPR000300; IPPc. DR InterPro; IPR012677; Nucleotide-bd_a/b_plait_sf. DR InterPro; IPR035979; RBD_domain_sf. DR InterPro; IPR000504; RRM_dom. DR InterPro; IPR002013; SAC_dom. DR InterPro; IPR015047; SYNJ1/2_RRM. DR InterPro; IPR034971; SYNJ1_RRM. DR PANTHER; PTHR11200; INOSITOL 5-PHOSPHATASE; 1. DR PANTHER; PTHR11200:SF158; SYNAPTOJANIN-1; 1. DR Pfam; PF08952; DUF1866; 1. DR Pfam; PF22669; Exo_endo_phos2; 1. DR Pfam; PF02383; Syja_N; 1. DR SMART; SM01165; DUF1866; 1. DR SMART; SM00128; IPPc; 1. DR SUPFAM; SSF56219; DNase I-like; 1. DR SUPFAM; SSF54928; RNA-binding domain, RBD; 1. DR PROSITE; PS50102; RRM; 1. DR PROSITE; PS50275; SAC; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; KW Endocytosis; Epilepsy; Hydrolase; Lipid metabolism; Methylation; KW Neurodegeneration; Parkinson disease; Parkinsonism; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; RNA-binding. FT CHAIN 1..1573 FT /note="Synaptojanin-1" FT /id="PRO_0000209730" FT DOMAIN 119..442 FT /note="SAC" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00183" FT DOMAIN 902..971 FT /note="RRM" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00176" FT REPEAT 1396..1398 FT /note="1" FT REPEAT 1406..1408 FT /note="2" FT REPEAT 1417..1419 FT /note="3" FT REGION 500..899 FT /note="Catalytic" FT /evidence="ECO:0000255" FT REGION 1029..1322 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1341..1360 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1370..1463 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1396..1419 FT /note="3 X 3 AA repeats of N-P-F" FT /evidence="ECO:0000250|UniProtKB:Q62910" FT REGION 1535..1573 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1029..1054 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1108..1130 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1221..1234 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1293..1304 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1313..1322 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1382..1407 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1536..1555 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 820 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8CHC4" FT MOD_RES 830 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 1053 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q62910" FT MOD_RES 1150 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8CHC4" FT MOD_RES 1178 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q62910" FT MOD_RES 1201 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q8CHC4" FT MOD_RES 1220 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 1292 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1318 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 1345 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1349 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8CHC4" FT MOD_RES 1551 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1565 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 451 FT /note="K -> KAGK (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_035709" FT VAR_SEQ 504..511 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_035710" FT VAR_SEQ 525..1573 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_035711" FT VAR_SEQ 1144..1159 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10048485" FT /id="VSP_041578" FT VAR_SEQ 1306..1311 FT /note="VKTNGI -> QEQPSG (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:10048485, FT ECO:0000303|PubMed:9428629" FT /id="VSP_002682" FT VAR_SEQ 1312..1573 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:10048485, FT ECO:0000303|PubMed:9428629" FT /id="VSP_002683" FT VARIANT 219 FT /note="R -> Q (in PARK20; impairs the phosphatase activity FT of the enzyme toward phosphatidylinositol-3-phosphate and FT phosphatidylinositol-4-phosphate; dbSNP:rs398122403)" FT /evidence="ECO:0000269|PubMed:23804563, FT ECO:0000269|PubMed:23804577" FT /id="VAR_070905" FT VARIANT 295 FT /note="K -> R (in dbSNP:rs2254562)" FT /evidence="ECO:0000269|PubMed:9428629" FT /id="VAR_047308" FT VARIANT 420 FT /note="R -> P (in PARK20; dbSNP:rs1060499619)" FT /evidence="ECO:0000269|PubMed:27496670" FT /id="VAR_078803" FT VARIANT 849 FT /note="Y -> C (in DEE53; decreased inositol phosphate FT phosphatase activity; dbSNP:rs1057524877)" FT /evidence="ECO:0000269|PubMed:27435091" FT /id="VAR_078804" FT VARIANT 981 FT /note="M -> I (in DEE53; likely benign; no effect on FT inositol phosphate phosphatase activity; FT dbSNP:rs115683257)" FT /evidence="ECO:0000269|PubMed:27435091" FT /id="VAR_078805" FT VARIANT 1018 FT /note="Y -> S (in DEE53; likely benign; no effect on FT inositol phosphate phosphatase activity)" FT /evidence="ECO:0000269|PubMed:27435091" FT /id="VAR_078806" FT VARIANT 1366 FT /note="V -> A (in dbSNP:rs9980589)" FT /id="VAR_047309" FT VARIANT 1383 FT /note="S -> R (in PARK20; uncertain significance; the FT patient also carries a heterozygous PINK1 truncating FT mutation; dbSNP:rs769099271)" FT /evidence="ECO:0000269|PubMed:23804577" FT /id="VAR_070906" FT VARIANT 1547 FT /note="P -> L (in dbSNP:rs2230767)" FT /id="VAR_049603" FT CONFLICT 1093..1108 FT /note="Missing (in Ref. 1; BAA74933)" FT /evidence="ECO:0000305" FT CONFLICT 1366 FT /note="V -> VNT (in Ref. 1; AAC51922)" FT /evidence="ECO:0000305" FT STRAND 531..541 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 559..562 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 565..569 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 572..574 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 575..577 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 583..590 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 597..601 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 606..619 FT /evidence="ECO:0007829|PDB:7A0V" FT TURN 620..622 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 626..633 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 636..642 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 644..649 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 650..661 FT /evidence="ECO:0007829|PDB:7A0V" FT TURN 662..665 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 666..678 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 681..689 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 697..710 FT /evidence="ECO:0007829|PDB:7A0V" FT TURN 714..716 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 719..721 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 722..730 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 739..747 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 751..755 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 759..765 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 790..793 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 796..798 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 806..812 FT /evidence="ECO:0007829|PDB:7A0V" FT HELIX 815..825 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 845..851 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 856..859 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 862..870 FT /evidence="ECO:0007829|PDB:7A0V" FT STRAND 895..901 FT /evidence="ECO:0007829|PDB:2DNR" FT TURN 905..907 FT /evidence="ECO:0007829|PDB:2DNR" FT HELIX 912..923 FT /evidence="ECO:0007829|PDB:2DNR" FT STRAND 928..933 FT /evidence="ECO:0007829|PDB:2DNR" FT STRAND 935..944 FT /evidence="ECO:0007829|PDB:2DNR" FT HELIX 945..950 FT /evidence="ECO:0007829|PDB:2DNR" FT HELIX 951..954 FT /evidence="ECO:0007829|PDB:2DNR" FT STRAND 962..968 FT /evidence="ECO:0007829|PDB:2DNR" SQ SEQUENCE 1573 AA; 173103 MW; D50B249B1EBFFC18 CRC64; MAFSKGFRIY HKLDPPPFSL IVETRHKEEC LMFESGAVAV LSSAEKEAIK GTYSKVLDAY GLLGVLRLNL GDTMLHYLVL VTGCMSVGKI QESEVFRVTS TEFISLRIDS SDEDRISEVR KVLNSGNFYF AWSASGISLD LSLNAHRSMQ EQTTDNRFFW NQSLHLHLKH YGVNCDDWLL RLMCGGVEIR TIYAAHKQAK ACLISRLSCE RAGTRFNVRG TNDDGHVANF VETEQVVYLD DSVSSFIQIR GSVPLFWEQP GLQVGSHRVR MSRGFEANAP AFDRHFRTLK NLYGKQIIVN LLGSKEGEHM LSKAFQSHLK ASEHAADIQM VNFDYHQMVK GGKAEKLHSV LKPQVQKFLD YGFFYFNGSE VQRCQSGTVR TNCLDCLDRT NSVQAFLGLE MLAKQLEALG LAEKPQLVTR FQEVFRSMWS VNGDSISKIY AGTGALEGKA KLKDGARSVT RTIQNNFFDS SKQEAIDVLL LGNTLNSDLA DKARALLTTG SLRVSEQTLQ SASSKVLKSM CENFYKYSKP KKIRVCVGTW NVNGGKQFRS IAFKNQTLTD WLLDAPKLAG IQEFQDKRSK PTDIFAIGFE EMVELNAGNI VSASTTNQKL WAVELQKTIS RDNKYVLLAS EQLVGVCLFV FIRPQHAPFI RDVAVDTVKT GMGGATGNKG AVAIRMLFHT TSLCFVCSHF AAGQSQVKER NEDFIEIARK LSFPMGRMLF SHDYVFWCGD FNYRIDLPNE EVKELIRQQN WDSLIAGDQL INQKNAGQVF RGFLEGKVTF APTYKYDLFS DDYDTSEKCR TPAWTDRVLW RRRKWPFDRS AEDLDLLNAS FQDESKILYT WTPGTLLHYG RAELKTSDHR PVVALIDIDI FEVEAEERQN IYKEVIAVQG PPDGTVLVSI KSSLPENNFF DDALIDELLQ QFASFGEVIL IRFVEDKMWV TFLEGSSALN VLSLNGKELL NRTITIALKS PDWIKNLEEE MSLEKISIAL PSSTSSTLLG EDAEVAADFD MEGDVDDYSA EVEELLPQHL QPSSSSGLGT SPSSSPRTSP CQSPTISEGP VPSLPIRPSR APSRTPGPPS AQSSPIDAQP ATPLPQKDPA QPLEPKRPPP PRPVAPPTRP APPQRPPPPS GARSPAPTRK EFGGIGAPPS PGVARREMEA PKSPGTTRKD NIGRSQPSPQ AGLAGPGPAG YSTARPTIPP RAGVISAPQS HARASAGRLT PESQSKTSET SKGSTFLPEP LKPQAAFPPQ SSLPPPAQRL QEPLVPVAAP MPQSGPQPNL ETPPQPPPRS RSSHSLPSEA SSQPQVKTNG ISDGKRESPL KIDPFEDLSF NLLAVSKAQL SVQTSPVPTP DPKRLIQLPS ATQSNVLSSV SCMPTMPPIP ARSQSQENMR SSPNPFITGL TRTNPFSDRT AAPGNPFRAK SEESEATSWF SKEEPVTISP FPSLQPLGHN KSRASSSLDG FKDSFDLQGQ STLKISNPKG WVTFEEEEDF GVKGKSKSAC SDLLGNQPSS FSGSNLTLND DWNKGTNVSF CVLPSRRPPP PPVPLLPPGT SPPVDPFTTL ASKASPTLDF TER // ID SYT11_HUMAN Reviewed; 431 AA. AC Q9BT88; Q14998; Q5W0D4; Q68CT5; Q8IXU3; Q96SU2; DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 204. DE RecName: Full=Synaptotagmin-11 {ECO:0000305}; DE AltName: Full=Synaptotagmin XI; DE Short=SytXI; GN Name=SYT11 {ECO:0000312|HGNC:HGNC:19239}; Synonyms=KIAA0080; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-48. 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 SEQUENCE REVISION. RA Ohara O., Nagase T., Kikuno R., Nomura N.; RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-48. 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 MRNA], AND VARIANT HIS-48. 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS HIS-48 AND VAL-231. RC TISSUE=Brain, and Lymph; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH PRKN, UBIQUITINATION, AND SUBCELLULAR LOCATION. 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 [8] RP FUNCTION, AND UBIQUITINATION. 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). CC -!- FUNCTION: Synaptotagmin family member involved in vesicular and CC membrane trafficking which does not bind Ca(2+). Inhibits clathrin- CC mediated and bulk endocytosis, functions to ensure precision in vesicle CC retrieval. Plays an important role in dopamine transmission by CC regulating endocytosis and the vesicle-recycling process. Essential CC component of a neuronal vesicular trafficking pathway that differs from CC the synaptic vesicle trafficking pathway but is crucial for development CC and synaptic plasticity. In macrophages and microglia, inhibits the CC conventional cytokine secretion, of at least IL6 and TNF, and CC phagocytosis. In astrocytes, regulates lysosome exocytosis, mechanism CC required for the repair of injured astrocyte cell membrane (By CC similarity). Required for the ATP13A2-mediated regulation of the CC autophagy-lysosome pathway (PubMed:27278822). CC {ECO:0000250|UniProtKB:Q9R0N3, ECO:0000269|PubMed:27278822}. CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00041}; CC -!- SUBUNIT: Homodimer. Can also form heterodimers. Interacts with PRKN CC (PubMed:12925569). Interacts (via C2 2 domain) with AGO2 and SND1; the CC interaction with SND1 is direct. Interacts with KIF1A; the interaction CC increases in presence of calcium (By similarity). CC {ECO:0000250|UniProtKB:O08835, ECO:0000250|UniProtKB:Q9R0N3, CC ECO:0000269|PubMed:12925569}. CC -!- INTERACTION: CC Q9BT88; Q92624: APPBP2; NbExp=3; IntAct=EBI-751770, EBI-743771; CC Q9BT88; Q9NQ11: ATP13A2; NbExp=2; IntAct=EBI-751770, EBI-6308763; CC Q9BT88; O60260-5: PRKN; NbExp=6; IntAct=EBI-751770, EBI-21251460; CC Q9BT88; O43765: SGTA; NbExp=7; IntAct=EBI-751770, EBI-347996; CC Q9BT88; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-751770, EBI-744081; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle membrane CC {ECO:0000305|PubMed:12925569}; Single-pass membrane protein CC {ECO:0000305}. Perikaryon {ECO:0000250|UniProtKB:Q9R0N3}. Golgi CC apparatus, trans-Golgi network membrane {ECO:0000250|UniProtKB:Q9R0N3}; CC Single-pass membrane protein {ECO:0000250|UniProtKB:Q9R0N3}. Recycling CC endosome membrane {ECO:0000250|UniProtKB:Q9R0N3}; Single-pass membrane CC protein {ECO:0000250|UniProtKB:Q9R0N3}. Lysosome membrane CC {ECO:0000250|UniProtKB:Q9R0N3}; Single-pass membrane protein CC {ECO:0000250|UniProtKB:Q9R0N3}. Cytoplasmic vesicle, phagosome CC {ECO:0000250|UniProtKB:Q9R0N3}. Cell projection, axon CC {ECO:0000269|PubMed:12925569}. Cell projection, dendrite CC {ECO:0000269|PubMed:12925569}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9R0N3}. Recycling endosome membrane CC {ECO:0000250|UniProtKB:O08835}; Single-pass membrane protein CC {ECO:0000250|UniProtKB:O08835}. Cytoplasmic vesicle, clathrin-coated CC vesicle membrane {ECO:0000250|UniProtKB:O08835}; Single-pass membrane CC protein {ECO:0000250|UniProtKB:O08835}. Perikaryon CC {ECO:0000269|PubMed:12925569}. Note=Localized in vesicles that travels CC in axonal and dendritic shafts in both anterograde and retrograde CC directions. In macrophages and microglia, recruited in phagosomes at CC early stages of phagocytosis (By similarity). Found in the core of the CC Lewy bodies in the brain of sporadic Parkinson disease patients CC (PubMed:12925569). {ECO:0000250|UniProtKB:Q9R0N3, CC ECO:0000269|PubMed:12925569}. CC -!- DOMAIN: The second C2 domain/C2B is required for the inhibitory role in CC both clathrin-mediated and bulk endocytosis. The transmembrane domain CC and the first C2 domain/C2A are critical for the inhibitory role in CC clathrin-mediated endocytosis or bulk endocytosis, respectively. CC {ECO:0000250|UniProtKB:O08835}. CC -!- DOMAIN: Unlike in other synaptotagmin family members, the first C2 CC domain/C2A does not bind Ca(2+) neither mediates Ca(2+)-dependent CC phospholipid binding. An aspartate-to-serine substitution in this CC domain inactivates Ca(2+)/phospho-lipid binding. CC {ECO:0000250|UniProtKB:O08835}. CC -!- PTM: Ubiquitinated, at least by PRKN, and targeted to the proteasome CC complex for degradation (PubMed:12925569, PubMed:27278822). CC Ubiquitination is inhibited by ATP13A2 (PubMed:27278822). CC {ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:27278822}. CC -!- SIMILARITY: Belongs to the synaptotagmin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA07527.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D38522; BAA07527.2; ALT_INIT; mRNA. DR EMBL; AK027540; BAB55186.1; -; mRNA. DR EMBL; AK074931; BAC11300.1; -; mRNA. DR EMBL; CR749792; CAH18653.1; -; mRNA. DR EMBL; AL139128; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC004291; AAH04291.1; -; mRNA. DR EMBL; BC013690; AAH13690.1; -; mRNA. DR EMBL; BC039205; AAH39205.1; -; mRNA. DR CCDS; CCDS1122.1; -. DR RefSeq; NP_689493.3; NM_152280.4. DR AlphaFoldDB; Q9BT88; -. DR SMR; Q9BT88; -. DR BioGRID; 116815; 34. DR ELM; Q9BT88; -. DR FunCoup; Q9BT88; 625. DR IntAct; Q9BT88; 66. DR MINT; Q9BT88; -. DR STRING; 9606.ENSP00000357307; -. DR iPTMnet; Q9BT88; -. DR PhosphoSitePlus; Q9BT88; -. DR SwissPalm; Q9BT88; -. DR BioMuta; SYT11; -. DR DMDM; 215273917; -. DR jPOST; Q9BT88; -. DR MassIVE; Q9BT88; -. DR PaxDb; 9606-ENSP00000357307; -. DR PeptideAtlas; Q9BT88; -. DR ProteomicsDB; 78960; -. DR Antibodypedia; 34201; 204 antibodies from 28 providers. DR DNASU; 23208; -. DR Ensembl; ENST00000368324.5; ENSP00000357307.4; ENSG00000132718.10. DR GeneID; 23208; -. DR KEGG; hsa:23208; -. DR MANE-Select; ENST00000368324.5; ENSP00000357307.4; NM_152280.5; NP_689493.3. DR UCSC; uc001fmg.4; human. DR AGR; HGNC:19239; -. DR ClinPGx; PA134898675; -. DR CTD; 23208; -. DR DisGeNET; 23208; -. DR GeneCards; SYT11; -. DR HGNC; HGNC:19239; SYT11. DR HPA; ENSG00000132718; Group enriched (brain, retina). DR MIM; 608741; gene. DR OpenTargets; ENSG00000132718; -. DR VEuPathDB; HostDB:ENSG00000132718; -. DR eggNOG; KOG1028; Eukaryota. DR GeneTree; ENSGT00940000159088; -. DR HOGENOM; CLU_023008_7_3_1; -. DR InParanoid; Q9BT88; -. DR OMA; MDEQNQG; -. DR OrthoDB; 270970at2759; -. DR PAN-GO; Q9BT88; 14 GO annotations based on evolutionary models. DR PhylomeDB; Q9BT88; -. DR PathwayCommons; Q9BT88; -. DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis. DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis. DR SignaLink; Q9BT88; -. DR SIGNOR; Q9BT88; -. DR Agora; ENSG00000132718; -. DR BioGRID-ORCS; 23208; 25 hits in 1141 CRISPR screens. DR ChiTaRS; SYT11; human. DR GeneWiki; SYT11; -. DR GenomeRNAi; 23208; -. DR Pharos; Q9BT88; Tbio. DR PRO; PR:Q9BT88; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9BT88; protein. DR Bgee; ENSG00000132718; Expressed in ventricular zone and 165 other cell types or tissues. DR GO; GO:0030424; C:axon; ISS:ParkinsonsUK-UCL. DR GO; GO:0030665; C:clathrin-coated vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; ISS:UniProtKB. DR GO; GO:0043197; C:dendritic spine; ISS:ParkinsonsUK-UCL. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0032009; C:early phagosome; ISS:UniProtKB. DR GO; GO:0060076; C:excitatory synapse; ISS:ParkinsonsUK-UCL. DR GO; GO:0070382; C:exocytic vesicle; IBA:GO_Central. DR GO; GO:0060077; C:inhibitory synapse; ISS:ParkinsonsUK-UCL. DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005764; C:lysosome; ISS:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0001891; C:phagocytic cup; IEA:Ensembl. DR GO; GO:0045335; C:phagocytic vesicle; ISS:ParkinsonsUK-UCL. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; ISS:ParkinsonsUK-UCL. DR GO; GO:0048787; C:presynaptic active zone membrane; ISS:ParkinsonsUK-UCL. DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0045202; C:synapse; IBA:GO_Central. DR GO; GO:0008021; C:synaptic vesicle; ISS:ParkinsonsUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB. DR GO; GO:0031982; C:vesicle; ISS:UniProtKB. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0061891; F:calcium ion sensor activity; IBA:GO_Central. DR GO; GO:0005544; F:calcium-dependent phospholipid binding; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0000149; F:SNARE binding; IBA:GO_Central. DR GO; GO:0031369; F:translation initiation factor binding; IEA:Ensembl. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1990927; P:calcium ion regulated lysosome exocytosis; ISS:ParkinsonsUK-UCL. DR GO; GO:0099502; P:calcium-dependent activation of synaptic vesicle fusion; IBA:GO_Central. DR GO; GO:0051650; P:establishment of vesicle localization; ISS:UniProtKB. DR GO; GO:0007612; P:learning; ISS:UniProtKB. DR GO; GO:0007613; P:memory; ISS:UniProtKB. DR GO; GO:0001818; P:negative regulation of cytokine production; ISS:UniProtKB. DR GO; GO:0033602; P:negative regulation of dopamine secretion; ISS:UniProtKB. DR GO; GO:0045806; P:negative regulation of endocytosis; ISS:UniProtKB. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISS:UniProtKB. DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB. DR GO; GO:0046929; P:negative regulation of neurotransmitter secretion; TAS:ParkinsonsUK-UCL. DR GO; GO:0050765; P:negative regulation of phagocytosis; ISS:UniProtKB. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:UniProtKB. DR GO; GO:0001778; P:plasma membrane repair; ISS:ParkinsonsUK-UCL. DR GO; GO:1905171; P:positive regulation of protein localization to phagocytic vesicle; ISS:ParkinsonsUK-UCL. DR GO; GO:0017158; P:regulation of calcium ion-dependent exocytosis; IBA:GO_Central. DR GO; GO:1900424; P:regulation of defense response to bacterium; IEA:Ensembl. DR GO; GO:1905162; P:regulation of phagosome maturation; IC:ParkinsonsUK-UCL. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:0006906; P:vesicle fusion; IBA:GO_Central. DR GO; GO:0016192; P:vesicle-mediated transport; IBA:GO_Central. DR CDD; cd08388; C2A_Synaptotagmin-4-11; 1. DR CDD; cd08404; C2B_Synaptotagmin-4; 1. DR FunFam; 2.60.40.150:FF:000039; Synaptotagmin 11; 1. DR FunFam; 2.60.40.150:FF:000051; Synaptotagmin 11; 1. DR Gene3D; 2.60.40.150; C2 domain; 2. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR001565; Synaptotagmin. DR PANTHER; PTHR10024; SYNAPTOTAGMIN; 1. DR PANTHER; PTHR10024:SF115; SYNAPTOTAGMIN-11; 1. DR Pfam; PF00168; C2; 2. DR PRINTS; PR00399; SYNAPTOTAGMN. DR SMART; SM00239; C2; 2. DR SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 2. DR PROSITE; PS50004; C2; 2. PE 1: Evidence at protein level; KW Calcium; Cell projection; Cytoplasmic vesicle; Endosome; Golgi apparatus; KW Lysosome; Membrane; Metal-binding; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Synapse; KW Transmembrane; Transmembrane helix; Ubl conjugation. FT CHAIN 1..431 FT /note="Synaptotagmin-11" FT /id="PRO_0000183969" FT TOPO_DOM 1..15 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 16..36 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 37..431 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 157..279 FT /note="C2 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 291..426 FT /note="C2 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT REGION 134..154 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 140..151 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 250 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT BINDING 253 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT BINDING 256 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT MOD_RES 134 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9R0N3" FT VARIANT 48 FT /note="Q -> H (in dbSNP:rs822522)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005, FT ECO:0000269|PubMed:7584044" FT /id="VAR_047656" FT VARIANT 231 FT /note="G -> V (in dbSNP:rs17853892)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_047657" FT CONFLICT 50 FT /note="N -> S (in Ref. 3; BAB55186)" FT /evidence="ECO:0000305" FT CONFLICT 268 FT /note="V -> A (in Ref. 3; BAB55186)" FT /evidence="ECO:0000305" FT CONFLICT 359 FT /note="F -> L (in Ref. 4; CAH18653)" FT /evidence="ECO:0000305" FT CONFLICT 370 FT /note="D -> G (in Ref. 4; CAH18653)" FT /evidence="ECO:0000305" SQ SEQUENCE 431 AA; 48297 MW; 5C8667D2C23D758E CRC64; MAEITNIRPS FDVSPVVAGL IGASVLVVCV SVTVFVWSCC HQQAEKKQKN PPYKFIHMLK GISIYPETLS NKKKIIKVRR DKDGPGREGG RRNLLVDAAE AGLLSRDKDP RGPSSGSCID QLPIKMDYGE ELRSPITSLT PGESKTTSPS SPEEDVMLGS LTFSVDYNFP KKALVVTIQE AHGLPVMDDQ TQGSDPYIKM TILPDKRHRV KTRVLRKTLD PVFDETFTFY GIPYSQLQDL VLHFLVLSFD RFSRDDVIGE VMVPLAGVDP STGKVQLTRD IIKRNIQKCI SRGELQVSLS YQPVAQRMTV VVLKARHLPK MDITGLSGNP YVKVNVYYGR KRIAKKKTHV KKCTLNPIFN ESFIYDIPTD LLPDISIEFL VIDFDRTTKN EVVGRLILGA HSVTASGAEH WREVCESPRK PVAKWHSLSE Y // ID SYUA_HUMAN Reviewed; 140 AA. AC P37840; A8K2A4; Q13701; Q4JHI3; Q6IAU6; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 28-JAN-2026, entry version 259. DE RecName: Full=Alpha-synuclein; DE AltName: Full=Non-A beta component of AD amyloid; DE AltName: Full=Non-A4 component of amyloid precursor; DE Short=NACP; GN Name=SNCA; Synonyms=NACP, PARK1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 61-95. RC TISSUE=Brain; RX PubMed=8248242; DOI=10.1073/pnas.90.23.11282; RA Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., RA Otero D.A., Kondo J., Ihara Y., Saitoh T.; RT "Molecular cloning of cDNA encoding an unrecognized component of amyloid in RT Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5). RX PubMed=7601450; DOI=10.1016/0888-7543(95)80208-4; RA Campion D., Martin C., Heilig R., Charbonnier F., Moreau V., Flaman J.-M., RA Petit J.-L., Hannequin D., Brice A., Frebourg T.; RT "The NACP/synuclein gene: chromosomal assignment and screening for RT alterations in Alzheimer disease."; RL Genomics 26:254-257(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4). RC TISSUE=Brain; RX PubMed=7802671; DOI=10.1006/bbrc.1994.2816; RA Ueda K., Saitoh T., Mori H.; RT "Tissue-dependent alternative splicing of mRNA for NACP, the precursor of RT non-A beta component of Alzheimer's disease amyloid."; RL Biochem. Biophys. Res. Commun. 205:1366-1372(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Xia Y., Silva R.D., Chen X.H., Saitoh T.; RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4). RX PubMed=11156617; DOI=10.1101/gr.165801; RA Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R., RA Orrison B.M., Polymeropoulos M.H., Nussbaum R.L.; RT "Human and mouse alpha-synuclein genes: comparative genomic sequence RT analysis and identification of a novel gene regulatory element."; RL Genome Res. 11:78-86(2001). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Hu X., Xu Y., Peng X., Yuan J., Qiang B.; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PROTEIN SEQUENCE OF 59-96, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [13] RP TISSUE SPECIFICITY. RX PubMed=8194594; DOI=10.1016/0014-5793(94)00395-5; RA Jakes R., Spillantini M.G., Goedert M.; RT "Identification of two distinct synucleins from human brain."; RL FEBS Lett. 345:27-32(1994). RN [14] RP PHOSPHORYLATION AT SER-87 AND SER-129 BY CK1 AND CK2. RX PubMed=10617630; DOI=10.1074/jbc.275.1.390; RA Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T., RA Meijer L., Kahle P.J., Haass C.; RT "Constitutive phosphorylation of the Parkinson's disease associated alpha- RT synuclein."; RL J. Biol. Chem. 275:390-397(2000). RN [15] RP PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE. RX PubMed=10852916; DOI=10.1074/jbc.m003542200; RA Pronin A.N., Morris A.J., Surguchov A., Benovic J.L.; RT "Synucleins are a novel class of substrates for G protein-coupled receptor RT kinases."; RL J. Biol. Chem. 275:26515-26522(2000). RN [16] RP PHOSPHORYLATION AT TYR-125 BY FYN. RX PubMed=11162638; DOI=10.1006/bbrc.2000.4253; RA Nakamura T., Yamashita H., Takahashi T., Nakamura S.; RT "Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125."; RL Biochem. Biophys. Res. Commun. 280:1085-1092(2001). RN [17] RP INTERACTION WITH PHOSPHOLIPASE D. RX PubMed=11821392; DOI=10.1074/jbc.m110414200; RA Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y., Wolozin B., RA Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H., Hahn S.J., RA Kim M.S., Jo Y.H., Min do S.; RT "Alpha-synuclein interacts with phospholipase D isozymes and inhibits RT pervanadate-induced phospholipase D activation in human embryonic kidney- RT 293 cells."; RL J. Biol. Chem. 277:12334-12342(2002). RN [18] RP PHOSPHORYLATION AT SER-129. RX PubMed=11813001; DOI=10.1038/ncb748; RA Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., RA Goldberg M.S., Shen J., Takio K., Iwatsubo T.; RT "alpha-Synuclein is phosphorylated in synucleinopathy lesions."; RL Nat. Cell Biol. 4:160-164(2002). RN [19] RP INTERACTION WITH HISTONES, AND SUBCELLULAR LOCATION. RX PubMed=12859192; DOI=10.1021/bi0341152; RA Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S., RA Di Monte D.A., Uversky V.N., Fink A.L.; RT "Nuclear localization of alpha-synuclein and its interaction with RT histones."; RL Biochemistry 42:8465-8471(2003). RN [20] RP ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS. RX PubMed=12859200; DOI=10.1021/bi027363r; RA Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H., RA Ischiropoulos H., Trojanowski J.Q., Lee V.M.; RT "Role of alpha-synuclein carboxy-terminus on fibril formation in vitro."; RL Biochemistry 42:8530-8540(2003). RN [21] RP REVIEW. RX PubMed=12558071; DOI=10.2174/1566524033361690; RA Alves da Costa C.; RT "Recent advances on alpha-synuclein cell biology: functions and RT dysfunctions."; RL Curr. Mol. Med. 3:17-24(2003). RN [22] RP MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION OF RP VARIANT THR-53, AND PHOSPHORYLATION AT TYR-125. RX PubMed=12893833; DOI=10.1074/jbc.m213217200; RA Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H., Avraham H., RA Avraham S., Yasuda M., Matsumoto M.; RT "Identification and characterization of a novel Pyk2/related adhesion focal RT tyrosine kinase-associated protein that inhibits alpha-synuclein RT phosphorylation."; RL J. Biol. Chem. 278:42225-42233(2003). RN [23] RP INTERACTION WITH RPH3A AND RAB3A. RX PubMed=15207266; DOI=10.1016/j.nbd.2004.01.001; RA Dalfo E., Barrachina M., Rosa J.L., Ambrosio S., Ferrer I.; RT "Abnormal alpha-synuclein interactions with rab3a and rabphilin in diffuse RT Lewy body disease."; RL Neurobiol. Dis. 16:92-97(2004). RN [24] RP SUBCELLULAR LOCATION. RX PubMed=15282274; DOI=10.1523/jneurosci.1594-04.2004; RA Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D., Edwards R.H.; RT "Lipid rafts mediate the synaptic localization of alpha-synuclein."; RL J. Neurosci. 24:6715-6723(2004). RN [25] RP FIBRILS FORMATION, DOMAIN NAC, AND MUTAGENESIS OF 67-GLY--VAL-71; RP 71-VAL--VAL-82; 76-ALA-VAL-77; VAL-77; ALA-78 AND 85-ALA--PHE-94. RX PubMed=19722699; DOI=10.1021/bi900539p; RA Waxman E.A., Mazzulli J.R., Giasson B.I.; RT "Characterization of hydrophobic residue requirements for alpha-synuclein RT fibrillization."; RL Biochemistry 48:9427-9436(2009). RN [26] RP FUNCTION, AND INTERACTION WITH VAMP2 AND SNAP25. RX PubMed=20798282; DOI=10.1126/science.1195227; RA Burre J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Suedhof T.C.; RT "Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro."; RL Science 329:1663-1667(2010). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [28] RP COPPER-BINDING, AND MUTAGENESIS OF ASP-2 AND HIS-50. RX PubMed=21319811; DOI=10.1021/bi101912q; RA Dudzik C.G., Walter E.D., Millhauser G.L.; RT "Coordination features and affinity of the Cu(2)+ site in the alpha- RT synuclein protein of Parkinson's disease."; RL Biochemistry 50:1771-1777(2011). RN [29] RP SUBUNIT. RX PubMed=21841800; DOI=10.1038/nature10324; RA Bartels T., Choi J.G., Selkoe D.J.; RT "alpha-Synuclein occurs physiologically as a helically folded tetramer that RT resists aggregation."; RL Nature 477:107-110(2011). RN [30] RP INTERACTION WITH SERF1A. RX PubMed=22854022; DOI=10.1016/j.celrep.2012.06.012; RA Falsone S.F., Meyer N.H., Schrank E., Leitinger G., Pham C.L., RA Fodero-Tavoletti M.T., Holmberg M., Dulle M., Scicluna B., Gesslbauer B., RA Rueckert H.M., Wagner G.E., Merle D.A., Nollen E.A., Kungl A.J., Hill A.F., RA Cappai R., Zangger K.; RT "SERF protein is a direct modifier of amyloid fiber assembly."; RL Cell Rep. 2:358-371(2012). RN [31] RP ACETYLATION AT MET-1. RX PubMed=22407793; DOI=10.1002/pro.2056; RA Trexler A.J., Rhoades E.; RT "N-Terminal acetylation is critical for forming alpha-helical oligomer of RT alpha-synuclein."; RL Protein Sci. 21:601-605(2012). RN [32] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC6A3. RX PubMed=26442590; DOI=10.1074/jbc.m115.691592; RA Butler B., Saha K., Rana T., Becker J.P., Sambo D., Davari P., RA Goodwin J.S., Khoshbouei H.; RT "Dopamine Transporter Activity Is Modulated by alpha-Synuclein."; RL J. Biol. Chem. 290:29542-29554(2015). RN [33] RP INTERACTION WITH STXBP1, AND SUBCELLULAR LOCATION. RX PubMed=27597756; DOI=10.1083/jcb.201512016; RA Chai Y.J., Sierecki E., Tomatis V.M., Gormal R.S., Giles N., Morrow I.C., RA Xia D., Goetz J., Parton R.G., Collins B.M., Gambin Y., Meunier F.A.; RT "Munc18-1 is a molecular chaperone for alpha-synuclein, controlling its RT self-replicating aggregation."; RL J. Cell Biol. 214:705-718(2016). RN [34] RP FUNCTION. RX PubMed=28288128; DOI=10.1038/nn.4529; RA Logan T., Bendor J., Toupin C., Thorn K., Edwards R.H.; RT "alpha-Synuclein promotes dilation of the exocytotic fusion pore."; RL Nat. Neurosci. 20:681-689(2017). RN [35] RP FUNCTION. RX PubMed=30404828; DOI=10.1242/jcs.213017; RA Huang C.C., Chiu T.Y., Lee T.Y., Hsieh H.J., Lin C.C., Kao L.S.; RT "Soluble alpha-synuclein facilitates priming and fusion by releasing Ca2+ RT from the thapsigargin-sensitive Ca2+ pool in PC12 cells."; RL J. Cell Sci. 131:0-0(2018). RN [36] RP INTERACTION WITH DDX10, AND SUBCELLULAR LOCATION. RX PubMed=33657088; DOI=10.1371/journal.pgen.1009407; RA Popova B., Wang D., Paetz C., Akkermann D., Lazaro D.F., Galka D., RA Kolog Gulko M., Bohnsack M.T., Moebius W., Bohnsack K.E., Outeiro T.F., RA Braus G.H.; RT "DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of alpha-synuclein RT toxicity and oligomerization."; RL PLoS Genet. 17:e1009407-e1009407(2021). RN [37] RP INTERACTION WITH SERF1A, AND SUBCELLULAR LOCATION. RX PubMed=31034892; DOI=10.1016/j.jmb.2019.04.031; RA Merle D.A., Witternigg A., Tam-Amersdorfer C., Hartlmueller C., RA Spreitzer E., Schrank E., Wagner-Lichtenegger S., Werzer O., Zangger K., RA Kungl A.J., Madl T., Meyer N.H., Falsone S.F.; RT "Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered RT Protein Complex."; RL J. Mol. Biol. 431:2581-2598(2019). RN [38] RP STRUCTURE BY NMR IN COMPLEX WITH DETERGENT MICELLES. RX PubMed=15615727; DOI=10.1074/jbc.m411805200; RA Ulmer T.S., Bax A., Cole N.B., Nussbaum R.L.; RT "Structure and dynamics of micelle-bound human alpha-synuclein."; RL J. Biol. Chem. 280:9595-9603(2005). RN [39] RP STRUCTURE BY NMR OF 1-12, INTERACTION WITH SNCAIP, AND SUBCELLULAR RP LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 1-57 AND 58-79. RX PubMed=21462277; DOI=10.1002/pro.630; RA Zhao M., Cascio D., Sawaya M.R., Eisenberg D.; RT "Structures of segments of alpha-synuclein fused to maltose-binding protein RT suggest intermediate states during amyloid formation."; RL Protein Sci. 20:996-1004(2011). RN [41] RP STRUCTURE BY NMR OF 1-19, AND INTERACTION WITH CALM1. RX PubMed=23607618; DOI=10.1021/bi400199p; RA Gruschus J.M., Yap T.L., Pistolesi S., Maltsev A.S., Lee J.C.; RT "NMR structure of calmodulin complexed to an N-terminally acetylated alpha- RT synuclein peptide."; RL Biochemistry 52:3436-3445(2013). RN [42] RP STRUCTURE BY ELECTRON MICROSCOPY (1.41 ANGSTROMS) OF 47-56 AND 68-78. RX PubMed=26352473; DOI=10.1038/nature15368; RA Rodriguez J.A., Ivanova M.I., Sawaya M.R., Cascio D., Reyes F.E., Shi D., RA Sangwan S., Guenther E.L., Johnson L.M., Zhang M., Jiang L., Arbing M.A., RA Nannenga B.L., Hattne J., Whitelegge J., Brewster A.S., Messerschmidt M., RA Boutet S., Sauter N.K., Gonen T., Eisenberg D.S.; RT "Structure of the toxic core of alpha-synuclein from invisible crystals."; RL Nature 525:486-490(2015). RN [43] RP STRUCTURE BY NMR. RX PubMed=27018801; DOI=10.1038/nsmb.3194; RA Tuttle M.D., Comellas G., Nieuwkoop A.J., Covell D.J., Berthold D.A., RA Kloepper K.D., Courtney J.M., Kim J.K., Barclay A.M., Kendall A., Wan W., RA Stubbs G., Schwieters C.D., Lee V.M., George J.M., Rienstra C.M.; RT "Solid-state NMR structure of a pathogenic fibril of full-length human RT alpha-synuclein."; RL Nat. Struct. Mol. Biol. 23:409-415(2016). RN [44] RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS). RX PubMed=30190461; DOI=10.1038/s41467-018-05971-2; RA Li B., Ge P., Murray K.A., Sheth P., Zhang M., Nair G., Sawaya M.R., RA Shin W.S., Boyer D.R., Ye S., Eisenberg D.S., Zhou Z.H., Jiang L.; RT "Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a RT common structural kernel."; RL Nat. Commun. 9:3609-3609(2018). RN [45] RP VARIANT PARK1 THR-53. RX PubMed=9197268; DOI=10.1126/science.276.5321.2045; RA Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., RA Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., RA Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., RA Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I., Nussbaum R.L.; RT "Mutation in the alpha-synuclein gene identified in families with RT Parkinson's disease."; RL Science 276:2045-2047(1997). RN [46] RP VARIANT PARK1 PRO-30. RX PubMed=9462735; DOI=10.1038/ng0298-106; RA Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S., RA Przuntek H., Epplen J.T., Schoels L., Riess O.; RT "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's RT disease."; RL Nat. Genet. 18:106-108(1998). RN [47] RP VARIANT PARK1/DLB LYS-46. RX PubMed=14755719; DOI=10.1002/ana.10795; RA Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., RA Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., RA Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G.; RT "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body RT dementia."; RL Ann. Neurol. 55:164-173(2004). RN [48] RP CHARACTERIZATION OF VARIANT LYS-46. RX PubMed=15498564; DOI=10.1016/j.febslet.2004.09.038; RA Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B., Crowther R.A., RA Goedert M.; RT "Mutation E46K increases phospholipid binding and assembly into filaments RT of human alpha-synuclein."; RL FEBS Lett. 576:363-368(2004). RN [49] RP VARIANT PARK1 GLN-50. RX PubMed=23457019; DOI=10.1002/mds.25421; RA Appel-Cresswell S., Vilarino-Guell C., Encarnacion M., Sherman H., Yu I., RA Shah B., Weir D., Thompson C., Szu-Tu C., Trinh J., Aasly J.O., Rajput A., RA Rajput A.H., Jon Stoessl A., Farrer M.J.; RT "Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's RT disease."; RL Mov. Disord. 28:811-813(2013). RN [50] RP VARIANT PARK1 GLN-50, AND CHARACTERIZATION OF VARIANT PARK1 GLN-50. RX PubMed=23427326; DOI=10.1212/wnl.0b013e31828727ba; RA Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M., RA Millhauser G.L., Houlden H., Schapira A.H.; RT "A novel alpha-synuclein missense mutation in Parkinson disease."; RL Neurology 80:1062-1064(2013). RN [51] RP CHARACTERIZATION OF VARIANT PARK1 GLN-50, SUBCELLULAR LOCATION, SUBUNIT, RP AND PHOSPHORYLATION AT SER-129. RX PubMed=24936070; DOI=10.1074/jbc.m114.553297; RA Khalaf O., Fauvet B., Oueslati A., Dikiy I., Mahul-Mellier A.L., RA Ruggeri F.S., Mbefo M.K., Vercruysse F., Dietler G., Lee S.J., Eliezer D., RA Lashuel H.A.; RT "The H50Q mutation enhances alpha-synuclein aggregation, secretion, and RT toxicity."; RL J. Biol. Chem. 289:21856-21876(2014). RN [52] RP CHARACTERIZATION OF VARIANTS PARK1 PRO-30; LYS-46; GLN-50 AND THR-53, RP MUTAGENESIS OF GLU-35 AND GLU-57, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=25561023; DOI=10.1021/cn500332w; RA Tsigelny I.F., Sharikov Y., Kouznetsova V.L., Greenberg J.P., Wrasidlo W., RA Overk C., Gonzalez T., Trejo M., Spencer B., Kosberg K., Masliah E.; RT "Molecular determinants of alpha-synuclein mutants' oligomerization and RT membrane interactions."; RL ACS Chem. Neurosci. 6:403-416(2015). CC -!- FUNCTION: Neuronal protein that plays several roles in synaptic CC activity such as regulation of synaptic vesicle trafficking and CC subsequent neurotransmitter release (PubMed:20798282, PubMed:26442590, CC PubMed:28288128, PubMed:30404828). Participates as a monomer in CC synaptic vesicle exocytosis by enhancing vesicle priming, fusion and CC dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). CC Mechanistically, acts by increasing local Ca(2+) release from CC microdomains which is essential for the enhancement of ATP-induced CC exocytosis (PubMed:30404828). Also acts as a molecular chaperone in its CC multimeric membrane-bound state, assisting in the folding of synaptic CC fusion components called SNAREs (Soluble NSF Attachment Protein CC REceptors) at presynaptic plasma membrane in conjunction with cysteine CC string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity CC is important to sustain normal SNARE-complex assembly during aging CC (PubMed:20798282). Also plays a role in the regulation of the dopamine CC neurotransmission by associating with the dopamine transporter (DAT1) CC and thereby modulating its activity (PubMed:26442590). CC {ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:26442590, CC ECO:0000269|PubMed:28288128, ECO:0000269|PubMed:30404828}. CC -!- SUBUNIT: Soluble monomer. Homotetramer (PubMed:21841800). A dynamic CC intracellular population of tetramers and monomers coexists normally CC and the tetramer plays an essential role in maintaining homeostasis CC (PubMed:21841800). Interacts with UCHL1 (By similarity). Interacts with CC phospholipase D and histones. Interacts (via N-terminus) with CC synphilin-1/SNCAIP; this interaction promotes formation of SNCA CC inclusions in the cytoplasm (PubMed:19762560). Interacts with CALM1 CC (PubMed:23607618). Interacts with STXBP1; this interaction controls CC SNCA self-replicating aggregation (PubMed:27597756). Interacts with CC SNARE components VAMP2 and SNAP25; these interactions allows SNARE CC complex assembly and integrity (PubMed:20798282). Interacts with RPH3A CC and RAB3A (PubMed:15207266). Interacts with SERF1A; this interaction CC promotes the aggregation of SNCA (PubMed:22854022, PubMed:31034892). CC Interacts with SEPTIN4 (By similarity). Interacts with DDX10; this CC interaction causes DDX10 mislocalization to the nucleoplasm and CC cytoplasmic inclusions (PubMed:33657088). CC {ECO:0000250|UniProtKB:O55042, ECO:0000250|UniProtKB:P37377, CC ECO:0000269|PubMed:15207266, ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:21841800, CC ECO:0000269|PubMed:22854022, ECO:0000269|PubMed:23607618, CC ECO:0000269|PubMed:27597756, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. CC -!- INTERACTION: CC P37840; Q6PCB6: ABHD17C; NbExp=3; IntAct=EBI-985879, EBI-22011868; CC P37840; P00519: ABL1; NbExp=3; IntAct=EBI-985879, EBI-375543; CC P37840; P00519-1: ABL1; NbExp=6; IntAct=EBI-985879, EBI-5278159; CC P37840; P00519-2: ABL1; NbExp=5; IntAct=EBI-985879, EBI-9254597; CC P37840; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-985879, EBI-25840993; CC P37840; P63010-2: AP2B1; NbExp=3; IntAct=EBI-985879, EBI-11529439; CC P37840; O00203: AP3B1; NbExp=3; IntAct=EBI-985879, EBI-1044383; CC P37840; P02647: APOA1; NbExp=3; IntAct=EBI-985879, EBI-701692; CC P37840; P02649: APOE; NbExp=11; IntAct=EBI-985879, EBI-1222467; CC P37840; P05067: APP; NbExp=6; IntAct=EBI-985879, EBI-77613; CC P37840; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-985879, EBI-10694449; CC P37840; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-985879, EBI-2875816; CC P37840; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-985879, EBI-10186132; CC P37840; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-985879, EBI-707573; CC P37840; P18847: ATF3; NbExp=3; IntAct=EBI-985879, EBI-712767; CC P37840; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-985879, EBI-1048913; CC P37840; P46379-2: BAG6; NbExp=3; IntAct=EBI-985879, EBI-10988864; CC P37840; Q07812: BAX; NbExp=4; IntAct=EBI-985879, EBI-516580; CC P37840; Q07817: BCL2L1; NbExp=3; IntAct=EBI-985879, EBI-78035; CC P37840; O15392: BIRC5; NbExp=3; IntAct=EBI-985879, EBI-518823; CC P37840; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-985879, EBI-2837444; CC P37840; Q5SZD1: C6orf141; NbExp=3; IntAct=EBI-985879, EBI-10697767; CC P37840; P62158: CALM3; NbExp=3; IntAct=EBI-985879, EBI-397435; CC P37840; Q8N5S9-2: CAMKK1; NbExp=3; IntAct=EBI-985879, EBI-25850646; CC P37840; P55212: CASP6; NbExp=3; IntAct=EBI-985879, EBI-718729; CC P37840; Q7Z7K6: CENPV; NbExp=4; IntAct=EBI-985879, EBI-1210604; CC P37840; Q9HD42: CHMP1A; NbExp=3; IntAct=EBI-985879, EBI-1057156; CC P37840; Q16740: CLPP; NbExp=3; IntAct=EBI-985879, EBI-1056029; CC P37840; P10909: CLU; NbExp=4; IntAct=EBI-985879, EBI-1104674; CC P37840; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-985879, EBI-350590; CC P37840; Q8IUI8: CRLF3; NbExp=3; IntAct=EBI-985879, EBI-2872414; CC P37840; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-985879, EBI-9087876; CC P37840; P99999: CYCS; NbExp=3; IntAct=EBI-985879, EBI-446479; CC P37840; O75398: DEAF1; NbExp=3; IntAct=EBI-985879, EBI-718185; CC P37840; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-985879, EBI-25842538; CC P37840; O60479: DLX3; NbExp=3; IntAct=EBI-985879, EBI-3908248; CC P37840; A0AVK6: E2F8; NbExp=3; IntAct=EBI-985879, EBI-7779316; CC P37840; O75530-2: EED; NbExp=3; IntAct=EBI-985879, EBI-11132357; CC P37840; O00472: ELL2; NbExp=3; IntAct=EBI-985879, EBI-395274; CC P37840; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-985879, EBI-9246952; CC P37840; O00471: EXOC5; NbExp=3; IntAct=EBI-985879, EBI-949824; CC P37840; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-985879, EBI-396453; CC P37840; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-985879, EBI-10226858; CC P37840; Q6PIV2: FOXR1; NbExp=3; IntAct=EBI-985879, EBI-10253815; CC P37840; P02792: FTL; NbExp=3; IntAct=EBI-985879, EBI-713279; CC P37840; P06241: FYN; NbExp=3; IntAct=EBI-985879, EBI-515315; CC P37840; P06241-3: FYN; NbExp=3; IntAct=EBI-985879, EBI-10691738; CC P37840; P62879: GNB2; NbExp=3; IntAct=EBI-985879, EBI-356942; CC P37840; P49841: GSK3B; NbExp=2; IntAct=EBI-985879, EBI-373586; CC P37840; P68431: H3C12; NbExp=3; IntAct=EBI-985879, EBI-79722; CC P37840; Q71DI3: H3C15; NbExp=3; IntAct=EBI-985879, EBI-750650; CC P37840; Q969S8: HDAC10; NbExp=3; IntAct=EBI-985879, EBI-301762; CC P37840; Q9HCC6: HES4; NbExp=3; IntAct=EBI-985879, EBI-2680288; CC P37840; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-985879, EBI-25845242; CC P37840; P09017: HOXC4; NbExp=3; IntAct=EBI-985879, EBI-3923226; CC P37840; P08107: HSPA1B; NbExp=7; IntAct=EBI-985879, EBI-629985; CC P37840; P42858: HTT; NbExp=4; IntAct=EBI-985879, EBI-466029; CC P37840; P80217-2: IFI35; NbExp=3; IntAct=EBI-985879, EBI-12823003; CC P37840; Q16352: INA; NbExp=3; IntAct=EBI-985879, EBI-366258; CC P37840; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-985879, EBI-21911304; CC P37840; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-985879, EBI-2127319; CC P37840; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-985879, EBI-2796400; CC P37840; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-985879, EBI-714379; CC P37840; Q92876: KLK6; NbExp=3; IntAct=EBI-985879, EBI-2432309; CC P37840; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-985879, EBI-1044640; CC P37840; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-985879, EBI-11985629; CC P37840; P13473-2: LAMP2; NbExp=3; IntAct=EBI-985879, EBI-21591415; CC P37840; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-985879, EBI-1108377; CC P37840; Q9H2C1: LHX5; NbExp=3; IntAct=EBI-985879, EBI-25835523; CC P37840; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-985879, EBI-10258746; CC P37840; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-985879, EBI-739832; CC P37840; Q8N448: LNX2; NbExp=3; IntAct=EBI-985879, EBI-2340947; CC P37840; A2RU56: LOC401296; NbExp=3; IntAct=EBI-985879, EBI-9088215; CC P37840; Q5S007: LRRK2; NbExp=6; IntAct=EBI-985879, EBI-5323863; CC P37840; O95777: LSM8; NbExp=3; IntAct=EBI-985879, EBI-347779; CC P37840; P07948: LYN; NbExp=3; IntAct=EBI-985879, EBI-79452; CC P37840; Q8TD91-2: MAGEC3; NbExp=3; IntAct=EBI-985879, EBI-10694180; CC P37840; P10636-6: MAPT; NbExp=3; IntAct=EBI-985879, EBI-7796455; CC P37840; P10636-8: MAPT; NbExp=12; IntAct=EBI-985879, EBI-366233; CC P37840; Q8N6F8: METTL27; NbExp=3; IntAct=EBI-985879, EBI-8487781; CC P37840; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-985879, EBI-4397720; CC P37840; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-985879, EBI-21250407; CC P37840; Q8N594: MPND; NbExp=3; IntAct=EBI-985879, EBI-2512452; CC P37840; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-985879, EBI-9092052; CC P37840; P00414: MT-CO3; NbExp=3; IntAct=EBI-985879, EBI-3932264; CC P37840; P02795: MT2A; NbExp=3; IntAct=EBI-985879, EBI-996616; CC P37840; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-985879, EBI-10698053; CC P37840; O00746: NME4; NbExp=3; IntAct=EBI-985879, EBI-744871; CC P37840; O15381-5: NVL; NbExp=3; IntAct=EBI-985879, EBI-18577082; CC P37840; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-985879, EBI-25888682; CC P37840; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-985879, EBI-1058491; CC P37840; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-985879, EBI-25830200; CC P37840; Q6VY07: PACS1; NbExp=3; IntAct=EBI-985879, EBI-2555014; CC P37840; O96013-2: PAK4; NbExp=3; IntAct=EBI-985879, EBI-21659863; CC P37840; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-985879, EBI-17159452; CC P37840; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-985879, EBI-6309018; CC P37840; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-985879, EBI-716063; CC P37840; O75925: PIAS1; NbExp=3; IntAct=EBI-985879, EBI-629434; CC P37840; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-985879, EBI-12891828; CC P37840; P17252: PRKCA; NbExp=3; IntAct=EBI-985879, EBI-1383528; CC P37840; Q02156: PRKCE; NbExp=3; IntAct=EBI-985879, EBI-706254; CC P37840; O60260-5: PRKN; NbExp=8; IntAct=EBI-985879, EBI-21251460; CC P37840; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-985879, EBI-5280197; CC P37840; P62191: PSMC1; NbExp=3; IntAct=EBI-985879, EBI-357598; CC P37840; P17980: PSMC3; NbExp=6; IntAct=EBI-985879, EBI-359720; CC P37840; Q9UI14: RABAC1; NbExp=4; IntAct=EBI-985879, EBI-712367; CC P37840; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-985879, EBI-14093916; CC P37840; P62826: RAN; NbExp=3; IntAct=EBI-985879, EBI-286642; CC P37840; Q13702-2: RAPSN; NbExp=3; IntAct=EBI-985879, EBI-22012855; CC P37840; P57052: RBM11; NbExp=3; IntAct=EBI-985879, EBI-741332; CC P37840; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-985879, EBI-714023; CC P37840; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-985879, EBI-21535400; CC P37840; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-985879, EBI-25829984; CC P37840; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-985879, EBI-749039; CC P37840; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-985879, EBI-914207; CC P37840; Q96D59: RNF183; NbExp=3; IntAct=EBI-985879, EBI-743938; CC P37840; Q8N488: RYBP; NbExp=3; IntAct=EBI-985879, EBI-752324; CC P37840; O75446: SAP30; NbExp=3; IntAct=EBI-985879, EBI-632609; CC P37840; O00560: SDCBP; NbExp=3; IntAct=EBI-985879, EBI-727004; CC P37840; O43236: SEPTIN4; NbExp=3; IntAct=EBI-985879, EBI-1047513; CC P37840; O75920-2: SERF1B; NbExp=4; IntAct=EBI-985879, EBI-21283682; CC P37840; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-985879, EBI-10182463; CC P37840; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-985879, EBI-358545; CC P37840; Q01959: SLC6A3; NbExp=3; IntAct=EBI-985879, EBI-6661445; CC P37840; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-985879, EBI-9845742; CC P37840; P37840: SNCA; NbExp=51; IntAct=EBI-985879, EBI-985879; CC P37840; Q9Y6H5: SNCAIP; NbExp=22; IntAct=EBI-985879, EBI-717182; CC P37840; Q9Y6H5-2: SNCAIP; NbExp=2; IntAct=EBI-985879, EBI-15577909; CC P37840; Q16143: SNCB; NbExp=3; IntAct=EBI-985879, EBI-727106; CC P37840; P00441: SOD1; NbExp=9; IntAct=EBI-985879, EBI-990792; CC P37840; P23497-2: SP100; NbExp=3; IntAct=EBI-985879, EBI-6589365; CC P37840; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-985879, EBI-11959123; CC P37840; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-985879, EBI-7067260; CC P37840; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-985879, EBI-8345366; CC P37840; Q13501: SQSTM1; NbExp=3; IntAct=EBI-985879, EBI-307104; CC P37840; O75886: STAM2; NbExp=3; IntAct=EBI-985879, EBI-373258; CC P37840; Q16623: STX1A; NbExp=2; IntAct=EBI-985879, EBI-712466; CC P37840; Q9BR01-2: SULT4A1; NbExp=3; IntAct=EBI-985879, EBI-25831443; CC P37840; Q92797-2: SYMPK; NbExp=3; IntAct=EBI-985879, EBI-21560407; CC P37840; Q16650: TBR1; NbExp=3; IntAct=EBI-985879, EBI-1047158; CC P37840; Q13569: TDG; NbExp=3; IntAct=EBI-985879, EBI-348333; CC P37840; P28347-2: TEAD1; NbExp=3; IntAct=EBI-985879, EBI-12151837; CC P37840; Q15554-4: TERF2; NbExp=3; IntAct=EBI-985879, EBI-25840535; CC P37840; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-985879, EBI-74615; CC P37840; O94811: TPPP; NbExp=8; IntAct=EBI-985879, EBI-3927802; CC P37840; P19474: TRIM21; NbExp=3; IntAct=EBI-985879, EBI-81290; CC P37840; P68363: TUBA1B; NbExp=3; IntAct=EBI-985879, EBI-487083; CC P37840; P07437: TUBB; NbExp=3; IntAct=EBI-985879, EBI-350864; CC P37840; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-985879, EBI-1797313; CC P37840; P62987: UBA52; NbExp=3; IntAct=EBI-985879, EBI-357304; CC P37840; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-985879, EBI-749370; CC P37840; O15205: UBD; NbExp=3; IntAct=EBI-985879, EBI-6657186; CC P37840; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-985879, EBI-11530712; CC P37840; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-985879, EBI-17761788; CC P37840; O75604-3: USP2; NbExp=3; IntAct=EBI-985879, EBI-10696113; CC P37840; P63027: VAMP2; NbExp=5; IntAct=EBI-985879, EBI-520113; CC P37840; P40337-2: VHL; NbExp=3; IntAct=EBI-985879, EBI-12157263; CC P37840; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-985879, EBI-11141397; CC P37840; O00308: WWP2; NbExp=3; IntAct=EBI-985879, EBI-743923; CC P37840; Q04917: YWHAH; NbExp=4; IntAct=EBI-985879, EBI-306940; CC P37840; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-985879, EBI-25842419; CC P37840; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-985879, EBI-2682299; CC P37840; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-985879, EBI-8834821; CC P37840; Q8N895: ZNF366; NbExp=3; IntAct=EBI-985879, EBI-2813661; CC P37840; Q8N988-2: ZNF557; NbExp=3; IntAct=EBI-985879, EBI-10699005; CC P37840; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-985879, EBI-8490788; CC P37840; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-985879, EBI-12021938; CC P37840; A8K878; NbExp=3; IntAct=EBI-985879, EBI-25831303; CC P37840; P0DTC9: N; Xeno; NbExp=2; IntAct=EBI-985879, EBI-25475856; CC P37840; Q61327: Slc6a3; Xeno; NbExp=5; IntAct=EBI-985879, EBI-7839708; CC P37840-1; P37840-1: SNCA; NbExp=21; IntAct=EBI-9684465, EBI-9684465; CC P37840-1; Q04917: YWHAH; NbExp=9; IntAct=EBI-9684465, EBI-306940; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:26442590, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. Membrane {ECO:0000269|PubMed:24936070}. CC Nucleus {ECO:0000269|PubMed:12859192, ECO:0000269|PubMed:24936070}. CC Synapse {ECO:0000269|PubMed:15282274}. Secreted CC {ECO:0000269|PubMed:24936070}. Cell projection, axon CC {ECO:0000250|UniProtKB:O55042}. Note=Membrane-bound in dopaminergic CC neurons (PubMed:15282274). Expressed and colocalized with SEPTIN4 in CC dopaminergic axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:O55042, CC ECO:0000269|PubMed:15282274}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=NACP140; CC IsoId=P37840-1; Sequence=Displayed; CC Name=2-4; Synonyms=NACP112; CC IsoId=P37840-2; Sequence=VSP_006364; CC Name=2-5; CC IsoId=P37840-3; Sequence=VSP_006363; CC -!- TISSUE SPECIFICITY: Highly expressed in presynaptic terminals in the CC central nervous system. Expressed principally in brain. CC {ECO:0000269|PubMed:8194594}. CC -!- DOMAIN: The 'non A-beta component of Alzheimer disease amyloid plaque' CC domain (NAC domain) is involved in fibrils formation. The middle CC hydrophobic region forms the core of the filaments. The C-terminus may CC regulate aggregation and determine the diameter of the filaments. CC {ECO:0000269|PubMed:19722699}. CC -!- PTM: Phosphorylated, predominantly on serine residues. Phosphorylation CC by CK1 appears to occur on residues distinct from the residue CC phosphorylated by other kinases. Phosphorylation of Ser-129 is CC selective and extensive in synucleinopathy lesions. In vitro, CC phosphorylation at Ser-129 promoted insoluble fibril formation. CC Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic CC stress. {ECO:0000269|PubMed:10617630, ECO:0000269|PubMed:10852916, CC ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11813001, CC ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:24936070}. CC -!- PTM: Hallmark lesions of neurodegenerative synucleinopathies contain CC alpha-synuclein that is modified by nitration of tyrosine residues and CC possibly by dityrosine cross-linking to generated stable oligomers. CC -!- PTM: Ubiquitinated. The predominant conjugate is the diubiquitinated CC form. {ECO:0000250|UniProtKB:P37377}. CC -!- PTM: Acetylation at Met-1 seems to be important for proper folding and CC native oligomeric structure. {ECO:0000269|PubMed:22407793}. CC -!- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant CC polymerization into fibrils, are associated with several CC neurodegenerative diseases (synucleinopathies). SNCA fibrillar CC aggregates represent the major non A-beta component of Alzheimer CC disease amyloid plaque, and a major component of Lewy body inclusions. CC They are also found within Lewy body (LB)-like intraneuronal CC inclusions, glial inclusions and axonal spheroids in neurodegeneration CC with brain iron accumulation type 1. CC -!- DISEASE: Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601]: CC A complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability. Additional CC features are characteristic postural abnormalities, dysautonomia, CC dystonic cramps, and dementia. The pathology of Parkinson disease CC involves the loss of dopaminergic neurons in the substantia nigra and CC the presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. The CC disease is progressive and usually manifests after the age of 50 years, CC although early-onset cases (before 50 years) are known. The majority of CC the cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:14755719, CC ECO:0000269|PubMed:23427326, ECO:0000269|PubMed:23457019, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:9197268, ECO:0000269|PubMed:9462735}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543]: CC A complex neurodegenerative disorder with manifestations ranging from CC typical Parkinson disease to dementia with Lewy bodies. Clinical CC features include parkinsonian symptoms (resting tremor, rigidity, CC postural instability and bradykinesia), dementia, diffuse Lewy body CC pathology, autonomic dysfunction, hallucinations and paranoia. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Dementia, Lewy body (DLB) [MIM:127750]: A neurodegenerative CC disorder characterized by mental impairment leading to dementia, CC parkinsonism, fluctuating cognitive function, visual hallucinations, CC falls, syncopal episodes, and sensitivity to neuroleptic medication. CC Brainstem or cortical intraneuronal accumulations of aggregated CC proteins (Lewy bodies) are the only essential pathologic features. CC Patients may also have hippocampal and neocortical senile plaques, CC sometimes in sufficient number to fulfill the diagnostic criteria for CC Alzheimer disease. {ECO:0000269|PubMed:14755719}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the synuclein family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L08850; AAA16117.1; -; mRNA. DR EMBL; L36674; AAA98493.1; -; mRNA. DR EMBL; L36675; AAA98487.1; -; mRNA. DR EMBL; D31839; BAA06625.1; -; mRNA. DR EMBL; U46901; AAC02114.1; -; Genomic_DNA. DR EMBL; U46897; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46898; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46899; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; AF163864; AAG30302.1; -; Genomic_DNA. DR EMBL; AF163864; AAG30303.1; -; Genomic_DNA. DR EMBL; AY049786; AAL15443.1; -; mRNA. DR EMBL; AK290169; BAF82858.1; -; mRNA. DR EMBL; CR457058; CAG33339.1; -; mRNA. DR EMBL; DQ088379; AAY88735.1; -; Genomic_DNA. DR EMBL; CH471057; EAX06036.1; -; Genomic_DNA. DR EMBL; BC013293; AAH13293.1; -; mRNA. DR EMBL; BC108275; AAI08276.1; -; mRNA. DR CCDS; CCDS3634.1; -. [P37840-1] DR CCDS; CCDS43252.1; -. [P37840-2] DR PIR; A49669; A49669. DR PIR; S56746; S56746. DR RefSeq; NP_000336.1; NM_000345.4. [P37840-1] DR RefSeq; NP_001139526.1; NM_001146054.2. [P37840-1] DR RefSeq; NP_001139527.1; NM_001146055.2. [P37840-1] DR RefSeq; NP_001362214.1; NM_001375285.1. [P37840-1] DR RefSeq; NP_001362215.1; NM_001375286.1. [P37840-1] DR RefSeq; NP_001362216.1; NM_001375287.1. [P37840-1] DR RefSeq; NP_001362217.1; NM_001375288.1. [P37840-1] DR RefSeq; NP_009292.1; NM_007308.3. [P37840-2] DR PDB; 1XQ8; NMR; -; A=1-140. DR PDB; 2JN5; NMR; -; A=1-12. DR PDB; 2KKW; NMR; -; A=1-140. DR PDB; 2M55; NMR; -; B=1-19. DR PDB; 2N0A; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 2X6M; X-ray; 1.62 A; B=132-140. DR PDB; 3Q25; X-ray; 1.90 A; A=1-19. DR PDB; 3Q26; X-ray; 1.54 A; A=10-42. DR PDB; 3Q27; X-ray; 1.30 A; A=32-57. DR PDB; 3Q28; X-ray; 1.60 A; A=58-79. DR PDB; 3Q29; X-ray; 2.30 A; A/C=1-19. DR PDB; 4BXL; NMR; -; C=35-56. DR PDB; 4R0U; X-ray; 1.38 A; A=72-78. DR PDB; 4R0W; X-ray; 1.50 A; A=70-76. DR PDB; 4RIK; X-ray; 1.85 A; A=69-77. DR PDB; 4RIL; EM; 1.43 A; A=68-78. DR PDB; 4ZNN; EM; 1.41 A; A=47-56. DR PDB; 5CRW; X-ray; 1.60 A; B=31-41. DR PDB; 6A6B; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J/K/L=37-99. DR PDB; 6CT7; X-ray; 1.90 A; S/T=1-10. DR PDB; 6CU7; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6CU8; EM; 3.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6H6B; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-121. DR PDB; 6I42; X-ray; 1.38 A; B=48-60. DR PDB; 6L1T; EM; 3.22 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6L1U; EM; 3.37 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-140. DR PDB; 6L4S; EM; 3.37 A; A/B/C/D/E/F=45-99. DR PDB; 6LRQ; EM; 3.49 A; A/B/C/D/E/F=1-140. DR PDB; 6OSJ; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSL; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSM; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6PEO; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 6PES; EM; 3.60 A; A/B/C/D/E/V/W/X/Y/Z=1-140. DR PDB; 6RT0; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6RTB; EM; 3.46 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SST; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SSX; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6UFR; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYO; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYP; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYQ; EM; 3.09 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7C1D; EM; 3.80 A; A/B/C/D/E/F=1-140. DR PDB; 7E0F; EM; 3.02 A; A/B/C/D/E/F=1-140. DR PDB; 7L7H; EM; 4.00 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7LC9; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L=41-140. DR PDB; 7NCA; EM; 3.47 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCG; EM; 3.43 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCH; EM; 3.84 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCI; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCJ; EM; 4.23 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCK; EM; 3.18 A; A/B/C/D/E/F=1-140. DR PDB; 7OZG; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7OZH; EM; 3.02 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7STX; EM; 3.14 A; C=1-5. DR PDB; 7UAK; EM; 3.38 A; A/B/C/D/E/F=1-140. DR PDB; 7V47; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7V48; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7V49; EM; 3.40 A; A/B/C=1-140. DR PDB; 7V4A; EM; 3.20 A; A/B/C=1-140. DR PDB; 7V4B; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7V4C; EM; 3.30 A; A/B/F=1-140. DR PDB; 7V4D; EM; 3.50 A; A/B/C/D/E/F=1-140. DR PDB; 7WMM; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7WNZ; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=36-100. DR PDB; 7WO0; EM; 2.70 A; A/B/C/D/E/F/G/O/P/Q/R/S/T/U=35-99. DR PDB; 7XJX; EM; 2.70 A; A/B/C/D/E/F=1-140. DR PDB; 7XO0; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO1; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO2; EM; 3.00 A; A/B/C/D/E/I=1-140. DR PDB; 7XO3; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7YK2; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YK8; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7YNF; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 7YNG; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7YNL; EM; 2.60 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7YNM; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNN; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNO; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNP; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNQ; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNR; EM; 2.90 A; A/B/C/D/E/F=1-140. DR PDB; 7YNS; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7YNT; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8A4L; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J/K/L/M/O/P=1-140. DR PDB; 8A9L; EM; 2.16 A; A=1-140. DR PDB; 8ADS; EM; 3.05 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADU; EM; 3.24 A; A/B/C/D/E=1-140. DR PDB; 8ADV; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADW; EM; 2.95 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8AEX; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8B9V; X-ray; 2.16 A; A=110-119. DR PDB; 8BQV; EM; 2.00 A; A=1-140. DR PDB; 8BQW; EM; 2.30 A; A/C=1-140. DR PDB; 8CE7; EM; 2.70 A; A/C=1-140. DR PDB; 8CEB; EM; 2.70 A; A/C=1-140. DR PDB; 8CYR; EM; 4.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYS; EM; 3.10 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYT; EM; 3.00 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYV; EM; 3.50 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYW; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYX; EM; 3.00 A; A/B/C/D/E/I/J/K/L/M=1-140. DR PDB; 8CYY; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ0; EM; 2.90 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ1; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ2; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ3; EM; 3.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ6; EM; 3.20 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8FPT; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8G0L; EM; 3.39 A; C=1-5. DR PDB; 8GF7; EM; 4.80 A; A/B/C/D/E/F=7-96. DR PDB; 8H03; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8H04; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8H05; EM; 3.40 A; A/B/C=1-140. DR PDB; 8HZB; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZC; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZS; EM; 3.30 A; A/B/C/D/E/F=1-140. DR PDB; 8JEX; EM; 3.10 A; A/B/G/H/K/P=1-140. DR PDB; 8JEY; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 8JJV; X-ray; 1.23 A; B=43-56. DR PDB; 8JLY; X-ray; 1.29 A; B=43-56. DR PDB; 8OG0; X-ray; 1.71 A; P=136-140. DR PDB; 8OJR; NMR; -; A=1-25. DR PDB; 8OL8; NMR; -; A=2-12. DR PDB; 8OQI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PIX; EM; 3.41 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PJO; EM; 2.31 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PK2; EM; 3.26 A; A/B/C/D/E=1-140. DR PDB; 8PK4; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8QPZ; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J/K/L=8-140. DR PDB; 8RI9; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 8RQM; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8RRR; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8UKA; EM; 3.90 A; A/B/C/D/E/a/b/c/d/e=1-140. DR PDB; 8X7B; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7M; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7P; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7Q; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7R; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8XWD; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2P; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2Q; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8ZLI; EM; 3.40 A; A/B/C/D/E/F/I/J/K/L=45-99. DR PDB; 8ZLO; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/O/T=45-99. DR PDB; 8ZLP; EM; 3.50 A; A/B/C/F/G/H=1-98. DR PDB; 8ZMY; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-98. DR PDB; 8ZVY; X-ray; 1.72 A; C/D=121-140. DR PDB; 8ZWH; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWI; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWJ; EM; 3.10 A; A/B/C/D/E/G=1-140. DR PDB; 8ZWK; EM; 3.40 A; A/B/C/D/E/F=1-140. DR PDB; 9C5R; EM; 2.61 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 9CD9; EM; 3.20 A; E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z=1-140. DR PDB; 9CDA; EM; 3.30 A; K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b=1-140. DR PDB; 9CK3; EM; 2.04 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 9CX6; EM; 3.20 A; G/H=1-140. DR PDB; 9D5C; EM; 4.80 A; A/B/C/F/G/H=1-96. DR PDB; 9EUU; EM; 1.93 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9FYP; EM; 2.23 A; I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9HGR; EM; 2.70 A; A/B=1-140. DR PDB; 9HGS; EM; 3.00 A; C=1-140. DR PDB; 9HXA; EM; 3.70 A; A/C=1-140. DR PDB; 9IJP; EM; 3.10 A; B/C/E/G/I/L=1-140. DR PDB; 9O4B; EM; 2.59 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDBsum; 1XQ8; -. DR PDBsum; 2JN5; -. DR PDBsum; 2KKW; -. DR PDBsum; 2M55; -. DR PDBsum; 2N0A; -. DR PDBsum; 2X6M; -. DR PDBsum; 3Q25; -. DR PDBsum; 3Q26; -. DR PDBsum; 3Q27; -. DR PDBsum; 3Q28; -. DR PDBsum; 3Q29; -. DR PDBsum; 4BXL; -. DR PDBsum; 4R0U; -. DR PDBsum; 4R0W; -. DR PDBsum; 4RIK; -. DR PDBsum; 4RIL; -. DR PDBsum; 4ZNN; -. DR PDBsum; 5CRW; -. DR PDBsum; 6A6B; -. DR PDBsum; 6CT7; -. DR PDBsum; 6CU7; -. DR PDBsum; 6CU8; -. DR PDBsum; 6H6B; -. DR PDBsum; 6I42; -. DR PDBsum; 6L1T; -. DR PDBsum; 6L1U; -. DR PDBsum; 6L4S; -. DR PDBsum; 6LRQ; -. DR PDBsum; 6OSJ; -. DR PDBsum; 6OSL; -. DR PDBsum; 6OSM; -. DR PDBsum; 6PEO; -. DR PDBsum; 6PES; -. DR PDBsum; 6RT0; -. DR PDBsum; 6RTB; -. DR PDBsum; 6SST; -. DR PDBsum; 6SSX; -. DR PDBsum; 6UFR; -. DR PDBsum; 6XYO; -. DR PDBsum; 6XYP; -. DR PDBsum; 6XYQ; -. DR PDBsum; 7C1D; -. DR PDBsum; 7E0F; -. DR PDBsum; 7L7H; -. DR PDBsum; 7LC9; -. DR PDBsum; 7NCA; -. DR PDBsum; 7NCG; -. DR PDBsum; 7NCH; -. DR PDBsum; 7NCI; -. DR PDBsum; 7NCJ; -. DR PDBsum; 7NCK; -. DR PDBsum; 7OZG; -. DR PDBsum; 7OZH; -. DR PDBsum; 7STX; -. DR PDBsum; 7UAK; -. DR PDBsum; 7V47; -. DR PDBsum; 7V48; -. DR PDBsum; 7V49; -. DR PDBsum; 7V4A; -. DR PDBsum; 7V4B; -. DR PDBsum; 7V4C; -. DR PDBsum; 7V4D; -. DR PDBsum; 7WMM; -. DR PDBsum; 7WNZ; -. DR PDBsum; 7WO0; -. DR PDBsum; 7XJX; -. DR PDBsum; 7XO0; -. DR PDBsum; 7XO1; -. DR PDBsum; 7XO2; -. DR PDBsum; 7XO3; -. DR PDBsum; 7YK2; -. DR PDBsum; 7YK8; -. DR PDBsum; 7YNF; -. DR PDBsum; 7YNG; -. DR PDBsum; 7YNL; -. DR PDBsum; 7YNM; -. DR PDBsum; 7YNN; -. DR PDBsum; 7YNO; -. DR PDBsum; 7YNP; -. DR PDBsum; 7YNQ; -. DR PDBsum; 7YNR; -. DR PDBsum; 7YNS; -. DR PDBsum; 7YNT; -. DR PDBsum; 8A4L; -. DR PDBsum; 8A9L; -. DR PDBsum; 8ADS; -. DR PDBsum; 8ADU; -. DR PDBsum; 8ADV; -. DR PDBsum; 8ADW; -. DR PDBsum; 8AEX; -. DR PDBsum; 8B9V; -. DR PDBsum; 8BQV; -. DR PDBsum; 8BQW; -. DR PDBsum; 8CE7; -. DR PDBsum; 8CEB; -. DR PDBsum; 8CYR; -. DR PDBsum; 8CYS; -. DR PDBsum; 8CYT; -. DR PDBsum; 8CYV; -. DR PDBsum; 8CYW; -. DR PDBsum; 8CYX; -. DR PDBsum; 8CYY; -. DR PDBsum; 8CZ0; -. DR PDBsum; 8CZ1; -. DR PDBsum; 8CZ2; -. DR PDBsum; 8CZ3; -. DR PDBsum; 8CZ6; -. DR PDBsum; 8FPT; -. DR PDBsum; 8G0L; -. DR PDBsum; 8GF7; -. DR PDBsum; 8H03; -. DR PDBsum; 8H04; -. DR PDBsum; 8H05; -. DR PDBsum; 8HZB; -. DR PDBsum; 8HZC; -. DR PDBsum; 8HZS; -. DR PDBsum; 8JEX; -. DR PDBsum; 8JEY; -. DR PDBsum; 8JJV; -. DR PDBsum; 8JLY; -. DR PDBsum; 8OG0; -. DR PDBsum; 8OJR; -. DR PDBsum; 8OL8; -. DR PDBsum; 8OQI; -. DR PDBsum; 8PIX; -. DR PDBsum; 8PJO; -. DR PDBsum; 8PK2; -. DR PDBsum; 8PK4; -. DR PDBsum; 8QPZ; -. DR PDBsum; 8RI9; -. DR PDBsum; 8RQM; -. DR PDBsum; 8RRR; -. DR PDBsum; 8UKA; -. DR PDBsum; 8X7B; -. DR PDBsum; 8X7L; -. DR PDBsum; 8X7M; -. DR PDBsum; 8X7O; -. DR PDBsum; 8X7P; -. DR PDBsum; 8X7Q; -. DR PDBsum; 8X7R; -. DR PDBsum; 8XWD; -. DR PDBsum; 8Y2P; -. DR PDBsum; 8Y2Q; -. DR PDBsum; 8ZLI; -. DR PDBsum; 8ZLO; -. DR PDBsum; 8ZLP; -. DR PDBsum; 8ZMY; -. DR PDBsum; 8ZVY; -. DR PDBsum; 8ZWH; -. DR PDBsum; 8ZWI; -. DR PDBsum; 8ZWJ; -. DR PDBsum; 8ZWK; -. DR PDBsum; 9C5R; -. DR PDBsum; 9CD9; -. DR PDBsum; 9CDA; -. DR PDBsum; 9CK3; -. DR PDBsum; 9CX6; -. DR PDBsum; 9D5C; -. DR PDBsum; 9EUU; -. DR PDBsum; 9FYP; -. DR PDBsum; 9HGR; -. DR PDBsum; 9HGS; -. DR PDBsum; 9HXA; -. DR PDBsum; 9IJP; -. DR PDBsum; 9O4B; -. DR AlphaFoldDB; P37840; -. DR BMRB; P37840; -. DR EMDB; EMD-0148; -. DR EMDB; EMD-0801; -. DR EMDB; EMD-0803; -. DR EMDB; EMD-0833; -. DR EMDB; EMD-0958; -. DR EMDB; EMD-10305; -. DR EMDB; EMD-10307; -. DR EMDB; EMD-10650; -. DR EMDB; EMD-10651; -. DR EMDB; EMD-10652; -. DR EMDB; EMD-12264; -. DR EMDB; EMD-12265; -. DR EMDB; EMD-12266; -. DR EMDB; EMD-12267; -. DR EMDB; EMD-12268; -. DR EMDB; EMD-12269; -. DR EMDB; EMD-13123; -. DR EMDB; EMD-13124; -. DR EMDB; EMD-15148; -. DR EMDB; EMD-15285; -. DR EMDB; EMD-15369; -. DR EMDB; EMD-15370; -. DR EMDB; EMD-15371; -. DR EMDB; EMD-15372; -. DR EMDB; EMD-15388; -. DR EMDB; EMD-16188; -. DR EMDB; EMD-16189; -. DR EMDB; EMD-16600; -. DR EMDB; EMD-16603; -. DR EMDB; EMD-17111; -. DR EMDB; EMD-17693; -. DR EMDB; EMD-17714; -. DR EMDB; EMD-17723; -. DR EMDB; EMD-17726; -. DR EMDB; EMD-18570; -. DR EMDB; EMD-19184; -. DR EMDB; EMD-19446; -. DR EMDB; EMD-19462; -. DR EMDB; EMD-19986; -. DR EMDB; EMD-20183; -. DR EMDB; EMD-20185; -. DR EMDB; EMD-20186; -. DR EMDB; EMD-20328; -. DR EMDB; EMD-20331; -. DR EMDB; EMD-20759; -. DR EMDB; EMD-23212; -. DR EMDB; EMD-23270; -. DR EMDB; EMD-25438; -. DR EMDB; EMD-26427; -. DR EMDB; EMD-27082; -. DR EMDB; EMD-27083; -. DR EMDB; EMD-27084; -. DR EMDB; EMD-27085; -. DR EMDB; EMD-27086; -. DR EMDB; EMD-27087; -. DR EMDB; EMD-27088; -. DR EMDB; EMD-27089; -. DR EMDB; EMD-27090; -. DR EMDB; EMD-27091; -. DR EMDB; EMD-27092; -. DR EMDB; EMD-27093; -. DR EMDB; EMD-29657; -. DR EMDB; EMD-29980; -. DR EMDB; EMD-30269; -. DR EMDB; EMD-30931; -. DR EMDB; EMD-3094; -. DR EMDB; EMD-3095; -. DR EMDB; EMD-31702; -. DR EMDB; EMD-31703; -. DR EMDB; EMD-31704; -. DR EMDB; EMD-31705; -. DR EMDB; EMD-31706; -. DR EMDB; EMD-31707; -. DR EMDB; EMD-31708; -. DR EMDB; EMD-32615; -. DR EMDB; EMD-32636; -. DR EMDB; EMD-32637; -. DR EMDB; EMD-33236; -. DR EMDB; EMD-33332; -. DR EMDB; EMD-33333; -. DR EMDB; EMD-33334; -. DR EMDB; EMD-33335; -. DR EMDB; EMD-33884; -. DR EMDB; EMD-33890; -. DR EMDB; EMD-33960; -. DR EMDB; EMD-33961; -. DR EMDB; EMD-33965; -. DR EMDB; EMD-33966; -. DR EMDB; EMD-33967; -. DR EMDB; EMD-33968; -. DR EMDB; EMD-33969; -. DR EMDB; EMD-33970; -. DR EMDB; EMD-33971; -. DR EMDB; EMD-35087; -. DR EMDB; EMD-35088; -. DR EMDB; EMD-35090; -. DR EMDB; EMD-36202; -. DR EMDB; EMD-36203; -. DR EMDB; EMD-38097; -. DR EMDB; EMD-38103; -. DR EMDB; EMD-38104; -. DR EMDB; EMD-38105; -. DR EMDB; EMD-38106; -. DR EMDB; EMD-38107; -. DR EMDB; EMD-38108; -. DR EMDB; EMD-38733; -. DR EMDB; EMD-38862; -. DR EMDB; EMD-38863; -. DR EMDB; EMD-42350; -. DR EMDB; EMD-45221; -. DR EMDB; EMD-45464; -. DR EMDB; EMD-45465; -. DR EMDB; EMD-45639; -. DR EMDB; EMD-45650; -. DR EMDB; EMD-45651; -. DR EMDB; EMD-45979; -. DR EMDB; EMD-47820; -. DR EMDB; EMD-4994; -. DR EMDB; EMD-4996; -. DR EMDB; EMD-50077; -. DR EMDB; EMD-50860; -. DR EMDB; EMD-50888; -. DR EMDB; EMD-52165; -. DR EMDB; EMD-52166; -. DR EMDB; EMD-52458; -. DR EMDB; EMD-54402; -. DR EMDB; EMD-60226; -. DR EMDB; EMD-60231; -. DR EMDB; EMD-60232; -. DR EMDB; EMD-60262; -. DR EMDB; EMD-60527; -. DR EMDB; EMD-60528; -. DR EMDB; EMD-60529; -. DR EMDB; EMD-60530; -. DR EMDB; EMD-60637; -. DR EMDB; EMD-61330; -. DR EMDB; EMD-61355; -. DR EMDB; EMD-61356; -. DR EMDB; EMD-61357; -. DR EMDB; EMD-61383; -. DR EMDB; EMD-61384; -. DR EMDB; EMD-61394; -. DR EMDB; EMD-6482; -. DR EMDB; EMD-6988; -. DR EMDB; EMD-70093; -. DR EMDB; EMD-70295; -. DR EMDB; EMD-7618; -. DR EMDB; EMD-7619; -. DR PCDDB; P37840; -. DR SMR; P37840; -. DR BioGRID; 112506; 1553. DR CORUM; P37840; -. DR DIP; DIP-35354N; -. DR FunCoup; P37840; 336. DR IntAct; P37840; 474. DR MINT; P37840; -. DR STRING; 9606.ENSP00000500990; -. DR BindingDB; P37840; -. DR ChEMBL; CHEMBL6152; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB04209; Dequalinium. DR DrugBank; DB02709; Resveratrol. DR DrugCentral; P37840; -. DR GuidetoPHARMACOLOGY; 3285; -. DR TCDB; 1.C.77.1.1; the synuclein (synuclein) family. DR GlyConnect; 2893; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; P37840; 5 sites, 1 glycan. DR GlyGen; P37840; 7 sites, 2 O-linked glycans (7 sites). DR iPTMnet; P37840; -. DR MetOSite; P37840; -. DR PhosphoSitePlus; P37840; -. DR SwissPalm; P37840; -. DR BioMuta; SNCA; -. DR DMDM; 586067; -. DR jPOST; P37840; -. DR MassIVE; P37840; -. DR PaxDb; 9606-ENSP00000338345; -. DR PeptideAtlas; P37840; -. DR ProteomicsDB; 55279; -. [P37840-1] DR ProteomicsDB; 55280; -. [P37840-2] DR ProteomicsDB; 55281; -. [P37840-3] DR Pumba; P37840; -. DR TopDownProteomics; P37840-1; -. [P37840-1] DR ABCD; P37840; 22 sequenced antibodies. DR Antibodypedia; 14688; 3097 antibodies from 56 providers. DR DNASU; 6622; -. DR Ensembl; ENST00000336904.7; ENSP00000338345.3; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000345009.8; ENSP00000343683.4; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000394986.5; ENSP00000378437.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000394989.6; ENSP00000378440.2; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000394991.8; ENSP00000378442.4; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000420646.6; ENSP00000396241.2; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000505199.5; ENSP00000421485.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000506244.5; ENSP00000422238.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000508895.5; ENSP00000426955.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000618500.4; ENSP00000484044.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000673718.1; ENSP00000500990.1; ENSG00000145335.18. [P37840-1] DR GeneID; 6622; -. DR KEGG; hsa:6622; -. DR MANE-Select; ENST00000394991.8; ENSP00000378442.4; NM_000345.4; NP_000336.1. DR UCSC; uc003hso.3; human. [P37840-1] DR AGR; HGNC:11138; -. DR ClinPGx; PA35986; -. DR CTD; 6622; -. DR DisGeNET; 6622; -. DR GeneCards; SNCA; -. DR GeneReviews; SNCA; -. DR HGNC; HGNC:11138; SNCA. DR HPA; ENSG00000145335; Group enriched (bone marrow, brain). DR MalaCards; SNCA; -. DR MIM; 127750; phenotype. DR MIM; 163890; gene. DR MIM; 168600; phenotype. DR MIM; 168601; phenotype. DR MIM; 605543; phenotype. DR OpenTargets; ENSG00000145335; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 171695; Parkinsonian-pyramidal syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000145335; -. DR eggNOG; ENOG502S0Q7; Eukaryota. DR GeneTree; ENSGT00950000183175; -. DR HOGENOM; CLU_129378_1_0_1; -. DR InParanoid; P37840; -. DR OMA; LPQEGMM; -. DR OrthoDB; 9900372at2759; -. DR PAN-GO; P37840; 8 GO annotations based on evolutionary models. DR PhylomeDB; P37840; -. DR PathwayCommons; P37840; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P37840; -. DR SIGNOR; P37840; -. DR Agora; ENSG00000145335; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 6622; 12 hits in 1150 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SNCA; human. DR EvolutionaryTrace; P37840; -. DR GeneWiki; Alpha-synuclein; -. DR GenomeRNAi; 6622; -. DR Pharos; P37840; Tchem. DR PRO; PR:P37840; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P37840; protein. DR Bgee; ENSG00000145335; Expressed in trabecular bone tissue and 205 other cell types or tissues. DR ExpressionAtlas; P37840; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ParkinsonsUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central. DR GO; GO:0005640; C:nuclear outer membrane; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0032991; C:protein-containing complex; IMP:UniProtKB. DR GO; GO:0005840; C:ribosome; IEA:Ensembl. DR GO; GO:0099512; C:supramolecular fiber; IDA:UniProtKB. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IPI:ARUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IPI:UniProtKB. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0070840; F:dynein complex binding; IPI:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:BHF-UCL. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0019894; F:kinesin binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; EXP:DisProt. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IEA:Ensembl. DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB. DR GO; GO:0043274; F:phospholipase binding; IEA:Ensembl. DR GO; GO:0005543; F:phospholipid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051219; F:phosphoprotein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl. DR GO; GO:0004860; F:protein kinase inhibitor activity; TAS:ARUK-UCL. DR GO; GO:0140311; F:protein sequestering activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0000149; F:SNARE binding; IDA:UniProtKB. DR GO; GO:0048156; F:tau protein binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0141108; F:transporter regulator activity; IGI:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; EXP:DisProt. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:1990000; P:amyloid fibril formation; EXP:DisProt. DR GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl. DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB. DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IEA:Ensembl. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0042416; P:dopamine biosynthetic process; TAS:UniProtKB. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0006749; P:glutathione metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0042775; P:mitochondrial ATP synthesis coupled electron transport; IEA:Ensembl. DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:1904715; P:negative regulation of chaperone-mediated autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl. DR GO; GO:0051585; P:negative regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB. DR GO; GO:0045920; P:negative regulation of exocytosis; IMP:UniProtKB. DR GO; GO:0031115; P:negative regulation of microtubule polymerization; IDA:BHF-UCL. DR GO; GO:1902957; P:negative regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051622; P:negative regulation of norepinephrine uptake; IDA:UniProtKB. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0051612; P:negative regulation of serotonin uptake; IDA:UniProtKB. DR GO; GO:0070495; P:negative regulation of thrombin-activated receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ParkinsonsUK-UCL. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0006638; P:neutral lipid metabolic process; IEA:Ensembl. DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB. DR GO; GO:0045921; P:positive regulation of exocytosis; IMP:UniProtKB. DR GO; GO:1903285; P:positive regulation of hydrogen peroxide catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:ParkinsonsUK-UCL. DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0001921; P:positive regulation of receptor recycling; IDA:UniProtKB. DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:UniProtKB. DR GO; GO:0035543; P:positive regulation of SNARE complex assembly; IDA:CACAO. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB. DR GO; GO:0050812; P:regulation of acyl-CoA biosynthetic process; IEA:Ensembl. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:UniProtKB. DR GO; GO:0014048; P:regulation of glutamate secretion; IEA:Ensembl. DR GO; GO:0040012; P:regulation of locomotion; IEA:Ensembl. DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl. DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:BHF-UCL. DR GO; GO:0051621; P:regulation of norepinephrine uptake; IGI:ARUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1903421; P:regulation of synaptic vesicle recycling; TAS:ParkinsonsUK-UCL. DR GO; GO:1904307; P:response to desipramine; IEA:Ensembl. DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB. DR GO; GO:0010040; P:response to iron(II) ion; IDA:UniProtKB. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0032026; P:response to magnesium ion; IDA:UniProtKB. DR GO; GO:0034341; P:response to type II interferon; IDA:UniProtKB. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0035493; P:SNARE complex assembly; IDA:UniProtKB. DR GO; GO:0097435; P:supramolecular fiber organization; TAS:UniProtKB. DR GO; GO:0050808; P:synapse organization; IBA:GO_Central. DR GO; GO:0048488; P:synaptic vesicle endocytosis; ISS:UniProtKB. DR GO; GO:0016079; P:synaptic vesicle exocytosis; IDA:UniProtKB. DR GO; GO:0016082; P:synaptic vesicle priming; IMP:UniProtKB. DR GO; GO:0048489; P:synaptic vesicle transport; IEA:Ensembl. DR DisProt; DP00070; -. DR FunFam; 1.10.287.700:FF:000001; Alpha-synuclein; 1. DR Gene3D; 1.10.287.700; Helix hairpin bin; 1. DR IDEAL; IID00302; -. DR InterPro; IPR001058; Synuclein. DR InterPro; IPR002460; Synuclein_alpha. DR PANTHER; PTHR13820:SF5; ALPHA-SYNUCLEIN; 1. DR PANTHER; PTHR13820; SYNUCLEIN; 1. DR Pfam; PF01387; Synuclein; 1. DR PRINTS; PR01212; ASYNUCLEIN. DR PRINTS; PR01211; SYNUCLEIN. DR SUPFAM; SSF118375; Synuclein; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Amyloid; Cell projection; Copper; Cytoplasm; Direct protein sequencing; KW Disease variant; Membrane; Metal-binding; Neurodegeneration; Nucleus; KW Parkinson disease; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Synapse; Ubl conjugation. FT CHAIN 1..140 FT /note="Alpha-synuclein" FT /id="PRO_0000184022" FT REPEAT 20..30 FT /note="1" FT REPEAT 31..41 FT /note="2" FT REPEAT 42..56 FT /note="3; approximate" FT REPEAT 57..67 FT /note="4" FT REGION 20..67 FT /note="4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V- FT X(4)" FT REGION 100..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 111..140 FT /note="Interaction with SERF1A" FT /evidence="ECO:0000269|PubMed:22854022" FT COMPBIAS 112..140 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 2 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT BINDING 50 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:22407793" FT MOD_RES 87 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:10617630" FT MOD_RES 125 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:11162638, FT ECO:0000269|PubMed:12893833" FT MOD_RES 129 FT /note="Phosphoserine; by BARK1, PLK2, CK2, CK1 and GRK5" FT /evidence="ECO:0000269|PubMed:10617630, FT ECO:0000269|PubMed:11813001, ECO:0000269|PubMed:24936070" FT VAR_SEQ 41..54 FT /note="Missing (in isoform 2-5)" FT /evidence="ECO:0000303|PubMed:7601450" FT /id="VSP_006363" FT VAR_SEQ 103..130 FT /note="Missing (in isoform 2-4)" FT /evidence="ECO:0000303|PubMed:7601450, FT ECO:0000303|PubMed:7802671" FT /id="VSP_006364" FT VARIANT 30 FT /note="A -> P (in PARK1; no effect on oligomerization; FT dbSNP:rs104893878)" FT /evidence="ECO:0000269|PubMed:25561023, FT ECO:0000269|PubMed:9462735" FT /id="VAR_007957" FT VARIANT 46 FT /note="E -> K (in PARK1 and DLB; significant increase in FT binding to negatively charged phospholipid liposomes; FT increases oligomerization; dbSNP:rs104893875)" FT /evidence="ECO:0000269|PubMed:14755719, FT ECO:0000269|PubMed:15498564, ECO:0000269|PubMed:25561023" FT /id="VAR_022703" FT VARIANT 50 FT /note="H -> Q (in PARK1; no effect on protein structure; no FT effect on phosphorylation of the protein; no effect on FT membrane- and lipid-binding; increases oligomerization; FT increases fibril formation; increases secretion of the FT protein; impairs copper-binding; dbSNP:rs201106962)" FT /evidence="ECO:0000269|PubMed:23427326, FT ECO:0000269|PubMed:23457019, ECO:0000269|PubMed:24936070, FT ECO:0000269|PubMed:25561023" FT /id="VAR_070171" FT VARIANT 53 FT /note="A -> T (in PARK1; no effect on osmotic stress- FT induced phosphorylation; increases oligomerization; FT dbSNP:rs104893877)" FT /evidence="ECO:0000269|PubMed:12893833, FT ECO:0000269|PubMed:25561023, ECO:0000269|PubMed:9197268" FT /id="VAR_007454" FT MUTAGEN 2 FT /note="D->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 35 FT /note="E->K: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 39 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 50 FT /note="H->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 57 FT /note="E->K: Increases oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 67..71 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 71..82 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76..77 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT MUTAGEN 77 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 78 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 85..94 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 125 FT /note="Y->F: Abolishes osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 133 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 136 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT HELIX 3..11 FT /evidence="ECO:0007829|PDB:3Q25" FT STRAND 16..18 FT /evidence="ECO:0007829|PDB:7YK8" FT HELIX 21..32 FT /evidence="ECO:0007829|PDB:3Q26" FT STRAND 34..36 FT /evidence="ECO:0007829|PDB:8A4L" FT STRAND 38..40 FT /evidence="ECO:0007829|PDB:7V48" FT HELIX 41..44 FT /evidence="ECO:0007829|PDB:3Q27" FT STRAND 45..49 FT /evidence="ECO:0007829|PDB:8PJO" FT STRAND 52..55 FT /evidence="ECO:0007829|PDB:8JJV" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:8RQM" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:9FYP" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:3Q28" FT STRAND 70..72 FT /evidence="ECO:0007829|PDB:7YNP" FT STRAND 73..83 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:8AEX" FT STRAND 88..96 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 110..113 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 120..122 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 124..126 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 133..136 FT /evidence="ECO:0007829|PDB:2N0A" SQ SEQUENCE 140 AA; 14460 MW; 6BB2F12128931663 CRC64; MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP DNEAYEMPSE EGYQDYEPEA // ID TERA_HUMAN Reviewed; 806 AA. AC P55072; B2R5T8; Q0V924; Q2TAI5; Q969G7; Q9UCD5; V9HW80; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 248. DE RecName: Full=Transitional endoplasmic reticulum ATPase; DE Short=TER ATPase; DE EC=3.6.4.6 {ECO:0000269|PubMed:26471729}; DE AltName: Full=15S Mg(2+)-ATPase p97 subunit; DE AltName: Full=Valosin-containing protein; DE Short=VCP; GN Name=VCP; GN Synonyms=HEL-220 {ECO:0000312|EMBL:ACI46036.1}, GN HEL-S-70 {ECO:0000312|EMBL:ACI46044.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W., RA Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S., Phan H., RA Velasco N., Garnes J., Danganan L., Poundstone P., Christensen M., RA Georgescu A., Avila J., Liu S., Attix C., Andreise T., Trankheim M., RA Amico-Keller G., Coefield J., Duarte S., Lucas S., Bruce R., Thomas P., RA Quan G., Kronmiller B., Arellano A., Montgomery M., Ow D., Nolan M., RA Trong S., Kobayashi A., Olsen A.O., Carrano A.V.; RT "Sequence analysis of a human P1 clone containing the XRCC9 DNA repair RT gene."; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Li J., Wang H., Liu J., Liu F.; RL Submitted (SEP-2008) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pituitary; RX PubMed=10931946; DOI=10.1073/pnas.160270997; RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J., RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., RA Chen M.-D., Chen J.-L.; RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis RT and full-length cDNA cloning."; RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 2-25. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [9] RP PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487; RP 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION RP AT ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Platelet; RA Bienvenut W.V., Claeys D.; RL Submitted (NOV-2005) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 27-41 AND 233-238, AND INTERACTION WITH CLATHRIN. RC TISSUE=Glial tumor; RX PubMed=8413590; DOI=10.1038/365459a0; RA Pleasure I.T., Black M.M., Keen J.H.; RT "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding RT protein."; RL Nature 365:459-462(1993). RN [11] RP PROTEIN SEQUENCE OF 46-53; 66-81; 96-109; 148-155; 240-251; 323-336; RP 454-502; 530-560; 600-614; 639-651; 678-693; 714-732 AND 754-766, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [12] RP PROTEIN SEQUENCE OF 314-322, IDENTIFICATION BY MASS SPECTROMETRY, RP METHYLATION AT LYS-315, MUTAGENESIS OF LYS-315, CHARACTERIZATION OF RP VARIANTS IBMPFD1 HIS-155 AND GLN-191, AND CHARACTERIZATION OF VARIANT RP FTDALS6 GLY-159. RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210; RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.; RT "A newly uncovered group of distantly related lysine methyltransferases RT preferentially interact with molecular chaperones to regulate their RT activity."; RL PLoS Genet. 9:E1003210-E1003210(2013). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 388-483. RC TISSUE=Fetal brain; RA Dmitrenko V.V., Garifulin O.M., Kavsan V.M.; RT "Characterization of different mRNA types expressed in human brain."; RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases. RN [14] RP INTERACTION WITH NGLY1. RX PubMed=15362974; DOI=10.1042/bj20041498; RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.; RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is RT a substrate for SAPKs."; RL Biochem. J. 384:391-400(2004). RN [15] RP FUNCTION, INTERACTION WITH RNF19A, IDENTIFICATION BY MASS SPECTROMETRY, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-524. RX PubMed=15456787; DOI=10.1074/jbc.m406683200; RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S., RA Kakizuka A., Tanaka K., Sobue G.; RT "Physical and functional interaction between dorfin and valosin-containing RT protein that are colocalized in ubiquitylated inclusions in RT neurodegenerative disorders."; RL J. Biol. Chem. 279:51376-51385(2004). RN [16] RP INTERACTION WITH SELENOS, AND SUBCELLULAR LOCATION. RX PubMed=15215856; DOI=10.1038/nature02656; RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.; RT "A membrane protein complex mediates retro-translocation from the ER lumen RT into the cytosol."; RL Nature 429:841-847(2004). RN [17] RP ISGYLATION. RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132; RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J., RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.; RT "Proteomic identification of proteins conjugated to ISG15 in mouse and RT human cells."; RL Biochem. Biophys. Res. Commun. 336:496-506(2005). RN [18] RP INTERACTION WITH SYVN1 AND DERL1. RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020; RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S., Wiertz E., RA Koning F., Kloetzel P.-M., Seeger M.; RT "The ubiquitin-domain protein HERP forms a complex with components of the RT endoplasmic reticulum associated degradation pathway."; RL J. Mol. Biol. 354:1021-1027(2005). RN [19] RP INTERACTION WITH AMFR, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP LYS-251 AND LYS-524. RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009; RA Song B.L., Sever N., DeBose-Boyd R.A.; RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and RT couples sterol-regulated ubiquitination to degradation of HMG CoA RT reductase."; RL Mol. Cell 19:829-840(2005). RN [20] RP FUNCTION, AND INTERACTION WITH DERL1; AMFR; SYVN1 AND SELENOS. RX PubMed=16186510; DOI=10.1073/pnas.0505006102; RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E., Rapoport T.A.; RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of RT retrotranslocation at the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005). RN [21] RP INTERACTION WITH DERL1 AND DERL2. RX PubMed=16186509; DOI=10.1073/pnas.0505014102; RA Lilley B.N., Ploegh H.L.; RT "Multiprotein complexes that link dislocation, ubiquitination, and RT extraction of misfolded proteins from the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005). RN [22] RP INTERACTION WITH CASR AND RNF19A. RX PubMed=16513638; DOI=10.1074/jbc.m513552200; RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.; RT "Calcium-sensing receptor ubiquitination and degradation mediated by the E3 RT ubiquitin ligase dorfin."; RL J. Biol. Chem. 281:11610-11617(2006). RN [23] RP INTERACTION WITH DERL1; DERL2 AND DERL3. RX PubMed=16449189; DOI=10.1083/jcb.200507057; RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.; RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein RT response and are required for ER-associated degradation."; RL J. Cell Biol. 172:383-393(2006). RN [24] RP INTERACTION WITH UBXN4. RX PubMed=16968747; DOI=10.1242/jcs.03163; RA Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A., RA Monteiro M.J.; RT "Characterization of erasin (UBXD2): a new ER protein that promotes ER- RT associated protein degradation."; RL J. Cell Sci. 119:4011-4024(2006). RN [25] RP INTERACTION WITH SVIP AND DERL1. RX PubMed=17872946; DOI=10.1074/jbc.m704446200; RA Ballar P., Zhong Y., Nagahama M., Tagaya M., Shen Y., Fang S.; RT "Identification of SVIP as an endogenous inhibitor of endoplasmic RT reticulum-associated degradation."; RL J. Biol. Chem. 282:33908-33914(2007). RN [26] RP INTERACTION WITH TRIM13. RX PubMed=17314412; DOI=10.1091/mbc.e06-03-0248; RA Lerner M., Corcoran M., Cepeda D., Nielsen M.L., Zubarev R., Ponten F., RA Uhlen M., Hober S., Grander D., Sangfelt O.; RT "The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin RT ligase involved in ERAD."; RL Mol. Biol. Cell 18:1670-1682(2007). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [28] RP INTERACTION WITH RNF103. RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126; RA Maruyama Y., Yamada M., Takahashi K., Yamada M.; RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-associated RT degradation pathway."; RL Biochem. Biophys. Res. Commun. 374:737-741(2008). RN [29] RP INTERACTION WITH UBXN6. RX PubMed=18656546; DOI=10.1016/j.biocel.2008.06.008; RA Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M., RA Hartmann-Petersen R.; RT "Ubxd1 is a novel co-factor of the human p97 ATPase."; RL Int. J. Biochem. Cell Biol. 40:2927-2942(2008). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-436 AND SER-787, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [31] RP INTERACTION WITH TRIM21. RX PubMed=18022694; DOI=10.1016/j.molimm.2007.10.023; RA Takahata M., Bohgaki M., Tsukiyama T., Kondo T., Asaka M., Hatakeyama S.; RT "Ro52 functionally interacts with IgG1 and regulates its quality control RT via the ERAD system."; RL Mol. Immunol. 45:2045-2054(2008). RN [32] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [33] RP INTERACTION WITH UBXN6. RX PubMed=19174149; DOI=10.1016/j.bbrc.2009.01.076; RA Kern M., Fernandez-Saiz V., Schaefer Z., Buchberger A.; RT "UBXD1 binds p97 through two independent binding sites."; RL Biochem. Biophys. Res. Commun. 380:303-307(2009). RN [34] RP INTERACTION WITH UBXN6. RX PubMed=19275885; DOI=10.1016/j.bbrc.2009.03.012; RA Nagahama M., Ohnishi M., Kawate Y., Matsui T., Miyake H., Yuasa K., RA Tani K., Tagaya M., Tsuji A.; RT "UBXD1 is a VCP-interacting protein that is involved in ER-associated RT degradation."; RL Biochem. Biophys. Res. Commun. 382:303-308(2009). RN [35] RP INTERACTION WITH UBXN4, AND IDENTIFICATION IN A COMPLEX WITH UBQLN1 AND RP UBXN4. RX PubMed=19822669; DOI=10.1083/jcb.200903024; RA Lim P.J., Danner R., Liang J., Doong H., Harman C., Srinivasan D., RA Rothenberg C., Wang H., Ye Y., Fang S., Monteiro M.J.; RT "Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD."; RL J. Cell Biol. 187:201-217(2009). RN [36] RP INTERACTION WITH YOD1. RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016; RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.; RT "The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to RT facilitate protein dislocation from the ER."; RL Mol. Cell 36:28-38(2009). RN [37] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3 AND SER-37, CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-775, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [39] RP INTERACTION WITH WASHC5. RX PubMed=20833645; DOI=10.1093/brain/awq222; RA Clemen C.S., Tangavelou K., Strucksberg K.H., Just S., Gaertner L., RA Regus-Leidig H., Stumpf M., Reimann J., Coras R., Morgan R.O., RA Fernandez M.P., Hofmann A., Muller S., Schoser B., Hanisch F.G., RA Rottbauer W., Blumcke I., von Horsten S., Eichinger L., Schroder R.; RT "Strumpellin is a novel valosin-containing protein binding partner linking RT hereditary spastic paraplegia to protein aggregation diseases."; RL Brain 133:2920-2941(2010). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [41] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [42] RP FUNCTION IN OMM PROTEIN TURNOVER. RX PubMed=21118995; DOI=10.1091/mbc.e10-09-0748; RA Xu S., Peng G., Wang Y., Fang S., Karbowski M.; RT "The AAA-ATPase p97 is essential for outer mitochondrial membrane protein RT turnover."; RL Mol. Biol. Cell 22:291-300(2011). RN [43] RP INTERACTION WITH BAG6. RX PubMed=21636303; DOI=10.1016/j.molcel.2011.05.010; RA Wang Q., Liu Y., Soetandyo N., Baek K., Hegde R., Ye Y.; RT "A ubiquitin ligase-associated chaperone holdase maintains polypeptides in RT soluble states for proteasome degradation."; RL Mol. Cell 42:758-770(2011). RN [44] RP FUNCTION, INTERACTION WITH CAV1 AND UBXN6, CHARACTERIZATION OF VARIANTS RP IBMPFD1 GLY-95; HIS-155 AND GLU-232, AND MUTAGENESIS OF GLU-578. RX PubMed=21822278; DOI=10.1038/ncb2301; RA Ritz D., Vuk M., Kirchner P., Bug M., Schuetz S., Hayer A., Bremer S., RA Lusk C., Baloh R.H., Lee H., Glatter T., Gstaiger M., Aebersold R., RA Weihl C.C., Meyer H.; RT "Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and RT UBXD1 and impaired by VCP disease mutations."; RL Nat. Cell Biol. 13:1116-1123(2011). RN [45] RP FUNCTION. RX PubMed=22020440; DOI=10.1038/ncb2367; RA Meerang M., Ritz D., Paliwal S., Garajova Z., Bosshard M., Mailand N., RA Janscak P., Hubscher U., Meyer H., Ramadan K.; RT "The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA RT double-strand breaks."; RL Nat. Cell Biol. 13:1376-1382(2011). RN [46] RP FUNCTION, INTERACTION WITH L3MBTL1, AND SUBCELLULAR LOCATION. RX PubMed=22120668; DOI=10.1038/nsmb.2188; RA Acs K., Luijsterburg M.S., Ackermann L., Salomons F.A., Hoppe T., RA Dantuma N.P.; RT "The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from RT DNA double-strand breaks."; RL Nat. Struct. Mol. Biol. 18:1345-1350(2011). RN [47] RP INTERACTION WITH UBXN8. RX PubMed=21949850; DOI=10.1371/journal.pone.0025061; RA Madsen L., Kriegenburg F., Vala A., Best D., Prag S., Hofmann K., RA Seeger M., Adams I.R., Hartmann-Petersen R.; RT "The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum RT membrane for degradation of misfolded proteins."; RL PLoS ONE 6:E25061-E25061(2011). RN [48] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3, CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE RP ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [49] RP INTERACTION WITH UBXN7. RX PubMed=22537386; DOI=10.1186/1741-7007-10-36; RA Bandau S., Knebel A., Gage Z.O., Wood N.T., Alexandru G.; RT "UBXN7 docks on neddylated cullin complexes using its UIM motif and causes RT HIF1alpha accumulation."; RL BMC Biol. 10:36-36(2012). RN [50] RP INTERACTION WITH RHBDD1, MUTAGENESIS OF LYS-251; LYS-524 AND GLU-578, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22795130; DOI=10.1016/j.molcel.2012.06.008; RA Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L., Lemberg M.K.; RT "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of RT membrane proteins."; RL Mol. Cell 47:558-569(2012). RN [51] RP INTERACTION WITH SPRTN. RX PubMed=22902628; DOI=10.1074/jbc.m112.400135; RA Ghosal G., Leung J.W., Nair B.C., Fong K.W., Chen J.; RT "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a RT regulator of translesion synthesis."; RL J. Biol. Chem. 287:34225-34233(2012). RN [52] RP FUNCTION IN ERAD PATHWAY. RX PubMed=22607976; DOI=10.1016/j.molcel.2012.04.015; RA Sato T., Sako Y., Sho M., Momohara M., Suico M.A., Shuto T., Nishitoh H., RA Okiyoneda T., Kokame K., Kaneko M., Taura M., Miyata M., Chosa K., Koga T., RA Morino-Koga S., Wada I., Kai H.; RT "STT3B-dependent posttranslational N-glycosylation as a surveillance system RT for secretory protein."; RL Mol. Cell 47:99-110(2012). RN [53] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [54] RP METHYLATION AT LYS-315, AND MUTAGENESIS OF LYS-312; ARG-313; GLU-314; RP LYS-315; THR-316; HIS-317 AND GLY-318. RX PubMed=22948820; DOI=10.1038/ncomms2041; RA Kernstock S., Davydova E., Jakobsson M., Moen A., Pettersen S., RA Maelandsmo G.M., Egge-Jacobsen W., Falnes P.O.; RT "Lysine methylation of VCP by a member of a novel human protein RT methyltransferase family."; RL Nat. Commun. 3:1038-1038(2012). RN [55] RP FUNCTION, AND INTERACTION WITH SPRTN. RX PubMed=23042607; DOI=10.1038/nsmb.2394; RA Davis E.J., Lachaud C., Appleton P., Macartney T.J., Nathke I., Rouse J.; RT "DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA RT damage."; RL Nat. Struct. Mol. Biol. 19:1093-1100(2012). RN [56] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SPRTN. RX PubMed=23042605; DOI=10.1038/nsmb.2395; RA Mosbech A., Gibbs-Seymour I., Kagias K., Thorslund T., Beli P., Povlsen L., RA Nielsen S.V., Smedegaard S., Sedgwick G., Lukas C., Hartmann-Petersen R., RA Lukas J., Choudhary C., Pocock R., Bekker-Jensen S., Mailand N.; RT "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes RT ubiquitin-dependent responses to replication blocks."; RL Nat. Struct. Mol. Biol. 19:1084-1092(2012). RN [57] RP FUNCTION. RX PubMed=23335559; DOI=10.1074/jbc.m112.429076; RA Kirchner P., Bug M., Meyer H.; RT "Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal RT sorting by the VCP/p97 AAA-ATPase."; RL J. Biol. Chem. 288:7363-7372(2013). RN [58] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-7; SER-13; SER-462 AND RP SER-702, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [59] RP INTERACTION WITH ZFAND2B. RX PubMed=24160817; DOI=10.1042/bj20130710; RA Glinka T., Alter J., Braunstein I., Tzach L., Wei Sheng C., Geifman S., RA Edelmann M.J., Kessler B.M., Stanhill A.; RT "Signal-peptide-mediated translocation is regulated by a p97-AIRAPL RT complex."; RL Biochem. J. 457:253-261(2014). RN [60] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [61] RP INTERACTION WITH RNF31. RX PubMed=24726327; DOI=10.1016/j.molcel.2014.03.016; RA Schaeffer V., Akutsu M., Olma M.H., Gomes L.C., Kawasaki M., Dikic I.; RT "Binding of OTULIN to the PUB domain of HOIP controls NF-kappaB RT signaling."; RL Mol. Cell 54:349-361(2014). RN [62] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH STUB1; UBXN2A AND CHRNA3, AND RP INTERACTION WITH UBXN2A. RX PubMed=26265139; DOI=10.1016/j.bcp.2015.08.084; RA Teng Y., Rezvani K., De Biasi M.; RT "UBXN2A regulates nicotinic receptor degradation by modulating the E3 RT ligase activity of CHIP."; RL Biochem. Pharmacol. 97:518-530(2015). RN [63] RP FUNCTION. RX PubMed=26565908; DOI=10.1016/j.celrep.2015.09.047; RA Kadowaki H., Nagai A., Maruyama T., Takami Y., Satrimafitrah P., Kato H., RA Honda A., Hatta T., Natsume T., Sato T., Kai H., Ichijo H., Nishitoh H.; RT "Pre-emptive quality control protects the ER from protein overload via the RT proximity of ERAD components and SRP."; RL Cell Rep. 13:944-956(2015). RN [64] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH RIGI AND RNF125, AND RP MUTAGENESIS OF 52-PHE--ASP-55; TYR-110; GLU-305 AND GLU-578. RX PubMed=26471729; DOI=10.15252/embj.201591888; RA Hao Q., Jiao S., Shi Z., Li C., Meng X., Zhang Z., Wang Y., Song X., RA Wang W., Zhang R., Zhao Y., Wong C.C., Zhou Z.; RT "A non-canonical role of the p97 complex in RIG-I antiviral signaling."; RL EMBO J. 34:2903-2920(2015). RN [65] RP INTERACTION WITH ZFAND2B. RX PubMed=26337389; DOI=10.1091/mbc.e15-02-0085; RA Braunstein I., Zach L., Allan S., Kalies K.U., Stanhill A.; RT "Proteasomal degradation of preemptive quality control (pQC) substrates is RT mediated by an AIRAPL-p97 complex."; RL Mol. Biol. Cell 26:3719-3727(2015). RN [66] RP INTERACTION WITH UBXN10. RX PubMed=26389662; DOI=10.1038/ncb3238; RA Raman M., Sergeev M., Garnaas M., Lydeard J.R., Huttlin E.L., Goessling W., RA Shah J.V., Harper J.W.; RT "Systematic proteomics of the VCP-UBXD adaptor network identifies a role RT for UBXN10 in regulating ciliogenesis."; RL Nat. Cell Biol. 17:1356-1369(2015). RN [67] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [68] RP INTERACTION WITH FAF1, AND SUBCELLULAR LOCATION. RX PubMed=26842564; DOI=10.1038/ncomms10612; RA Franz A., Pirson P.A., Pilger D., Halder S., Achuthankutty D., Kashkar H., RA Ramadan K., Hoppe T.; RT "Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard RT DNA replication fork progression."; RL Nat. Commun. 7:10612-10612(2016). RN [69] RP FUNCTION. RX PubMed=26692333; DOI=10.1038/nm.4013; RA Osorio F.G., Soria-Valles C., Santiago-Fernandez O., Bernal T., RA Mittelbrunn M., Colado E., Rodriguez F., Bonzon-Kulichenko E., Vazquez J., RA Porta-de-la-Riva M., Ceron J., Fueyo A., Li J., Green A.R., Freije J.M., RA Lopez-Otin C.; RT "Loss of the proteostasis factor AIRAPL causes myeloid transformation by RT deregulating IGF-1 signaling."; RL Nat. Med. 22:91-96(2016). RN [70] RP INTERACTION WITH ANKZF1. RX PubMed=28302725; DOI=10.1074/jbc.m116.772038; RA van Haaften-Visser D.Y., Harakalova M., Mocholi E., van Montfrans J.M., RA Elkadri A., Rieter E., Fiedler K., van Hasselt P.M., Triffaux E.M.M., RA van Haelst M.M., Nijman I.J., Kloosterman W.P., Nieuwenhuis E.E.S., RA Muise A.M., Cuppen E., Houwen R.H.J., Coffer P.J.; RT "Ankyrin repeat and zinc-finger domain-containing 1 mutations are RT associated with infantile-onset inflammatory bowel disease."; RL J. Biol. Chem. 292:7904-7920(2017). RN [71] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-8 AND LYS-18, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [72] RP INTERACTION WITH ATXN3. RX PubMed=30455355; DOI=10.1074/jbc.ra118.005801; RA Weishaeupl D., Schneider J., Peixoto Pinheiro B., Ruess C., Dold S.M., RA von Zweydorf F., Gloeckner C.J., Schmidt J., Riess O., Schmidt T.; RT "Physiological and pathophysiological characteristics of ataxin-3 RT isoforms."; RL J. Biol. Chem. 294:644-661(2019). RN [73] RP INTERACTION WITH LMBR1L. RX PubMed=31073040; DOI=10.1126/science.aau0812; RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J., RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M., RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y., RA Beutler B.; RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling."; RL Science 364:0-0(2019). RN [74] RP FUNCTION, AND INTERACTION WITH TEX264. RX PubMed=32152270; DOI=10.1038/s41467-020-15000-w; RA Fielden J., Wiseman K., Torrecilla I., Li S., Hume S., Chiang S.C., RA Ruggiano A., Narayan Singh A., Freire R., Hassanieh S., Domingo E., RA Vendrell I., Fischer R., Kessler B.M., Maughan T.S., El-Khamisy S.F., RA Ramadan K.; RT "TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1- RT DNA adducts."; RL Nat. Commun. 11:1274-1274(2020). RN [75] RP FUNCTION. RX PubMed=34739333; DOI=10.1126/science.abf6548; RA Gwon Y., Maxwell B.A., Kolaitis R.M., Zhang P., Kim H.J., Taylor J.P.; RT "Ubiquitination of G3BP1 mediates stress granule disassembly in a context- RT specific manner."; RL Science 372:eabf6548-eabf6548(2021). RN [76] RP FUNCTION. RX PubMed=35013556; DOI=10.1038/s41556-021-00807-6; RA Krastev D.B., Li S., Sun Y., Wicks A.J., Hoslett G., Weekes D., RA Badder L.M., Knight E.G., Marlow R., Pardo M.C., Yu L., Talele T.T., RA Bartek J., Choudhary J.S., Pommier Y., Pettitt S.J., Tutt A.N.J., RA Ramadan K., Lord C.J.; RT "The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from RT chromatin."; RL Nat. Cell Biol. 24:62-73(2022). RN [77] RP FUNCTION, UFMYLATION AT LYS-109, INTERACTION WITH NPLOC4, AND MUTAGENESIS RP OF LYS-109 AND TYR-110. RX PubMed=38762759; DOI=10.1080/15548627.2024.2356488; RA Wang Z., Xiong S., Wu Z., Wang X., Gong Y., Zhu W.G., Xu X.; RT "VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of RT autophagy."; RL Autophagy 20:2041-2054(2024). RN [78] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP ANALOG, RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155, MUTAGENESIS OF RP ARG-53 AND ARG-86, AND SUBUNIT. RX PubMed=20512113; DOI=10.1038/emboj.2010.104; RA Tang W.K., Li D., Li C.C., Esser L., Dai R., Guo L., Xia D.; RT "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by RT crystal structures of disease-related mutants."; RL EMBO J. 29:2217-2229(2010). RN [79] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 797-806 IN COMPLEX WITH PLAA. RX PubMed=19887378; DOI=10.1074/jbc.m109.044685; RA Qiu L., Pashkova N., Walker J.R., Winistorfer S., Allali-Hassani A., RA Akutsu M., Piper R., Dhe-Paganon S.; RT "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex."; RL J. Biol. Chem. 285:365-372(2010). RN [80] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-187 IN COMPLEX WITH AMFR. RX PubMed=21914798; DOI=10.1074/jbc.m111.274506; RA Hanzelmann P., Schindelin H.; RT "The structural and functional basis of the p97/valosin-containing protein RT (VCP)-interacting motif (VIM): mutually exclusive binding of cofactors to RT the N-terminal domain of p97."; RL J. Biol. Chem. 286:38679-38690(2011). RN [81] {ECO:0007744|PDB:5GLF} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 21-199 IN COMPLEX WITH DERL1, RP INTERACTION WITH DERL1, AND MUTAGENESIS OF 113-ARG--HIS-115; PHE-131; RP LEU-140; ASP-179 AND HIS-183. RX PubMed=27714797; DOI=10.1002/1873-3468.12447; RA Lim J.J., Lee Y., Yoon S.Y., Ly T.T., Kang J.Y., Youn H.S., An J.Y., RA Lee J.G., Park K.R., Kim T.G., Yang J.K., Jun Y., Eom S.H.; RT "Structural insights into the interaction of human p97 N-terminal domain RT and SHP motif in Derlin-1 rhomboid pseudoprotease."; RL FEBS Lett. 590:4402-4413(2016). RN [82] RP VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND GLU-232. RX PubMed=15034582; DOI=10.1038/ng1332; RA Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D., RA Pestronk A., Whyte M.P., Kimonis V.E.; RT "Inclusion body myopathy associated with Paget disease of bone and RT frontotemporal dementia is caused by mutant valosin-containing protein."; RL Nat. Genet. 36:377-381(2004). RN [83] RP VARIANT IBMPFD1 CYS-155. RX PubMed=15732117; DOI=10.1002/ana.20407; RA Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P., RA Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R.; RT "Mutant valosin-containing protein causes a novel type of frontotemporal RT dementia."; RL Ann. Neurol. 57:457-461(2005). RN [84] RP VARIANT IBMPFD1 HIS-159. RX PubMed=16247064; DOI=10.1212/01.wnl.0000180407.15369.92; RA Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F., Mannhalter C., RA Wagner L., Mineva I., Vass K., Auff E., Zimprich A.; RT "Inclusion body myopathy and Paget disease is linked to a novel mutation in RT the VCP gene."; RL Neurology 65:1304-1305(2005). RN [85] RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155. RX PubMed=16321991; DOI=10.1093/hmg/ddi426; RA Weihl C.C., Dalal S., Pestronk A., Hanson P.I.; RT "Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic RT reticulum-associated degradation."; RL Hum. Mol. Genet. 15:189-199(2006). RN [86] RP VARIANTS IBMPFD1 TRP-198 AND HIS-387. RX PubMed=17935506; DOI=10.1111/j.1399-0004.2007.00887.x; RA Watts G.D., Thomasova D., Ramdeen S.K., Fulchiero E.C., Mehta S.G., RA Drachman D.A., Weihl C.C., Jamrozik Z., Kwiecinski H., Kaminska A., RA Kimonis V.E.; RT "Novel VCP mutations in inclusion body myopathy associated with Paget RT disease of bone and frontotemporal dementia."; RL Clin. Genet. 72:420-426(2007). RN [87] RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; SER-155 AND GLU-232, RP MUTAGENESIS OF GLU-305 AND GLU-578, AND FUNCTION. RX PubMed=20104022; DOI=10.4161/auto.6.2.11014; RA Tresse E., Salomons F.A., Vesa J., Bott L.C., Kimonis V., Yao T.P., RA Dantuma N.P., Taylor J.P.; RT "VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes RT and this function is impaired by mutations that cause IBMPFD."; RL Autophagy 6:217-227(2010). RN [88] RP FUNCTION, INTERACTION WITH ZFAND1, MUTAGENESIS OF GLU-578, AND RP CHARACTERIZATION OF VARIANT IBMPFD1 HIS-155. RX PubMed=29804830; DOI=10.1016/j.molcel.2018.04.021; RA Turakhiya A., Meyer S.R., Marincola G., Boehm S., Vanselow J.T., RA Schlosser A., Hofmann K., Buchberger A.; RT "ZFAND1 recruits p97 and the 26S proteasome to promote the clearance of RT arsenite-induced stress granules."; RL Mol. Cell 70:906-919(2018). RN [89] RP INTERACTION WITH FBXL4. RX PubMed=36896912; DOI=10.15252/embj.2022113033; RA Cao Y., Zheng J., Wan H., Sun Y., Fu S., Liu S., He B., Cai G., Cao Y., RA Huang H., Li Q., Ma Y., Chen S., Wang F., Jiang H.; RT "A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and RT NIX to restrain mitophagy and prevent mitochondrial disease."; RL EMBO J. 42:e113033-e113033(2023). RN [90] RP VARIANTS IBMPFD1 LEU-155 AND TRP-198. RX PubMed=20335036; DOI=10.1016/j.nmd.2010.03.002; RA Kumar K.R., Needham M., Mina K., Davis M., Brewer J., Staples C., Ng K., RA Sue C.M., Mastaglia F.L.; RT "Two Australian families with inclusion-body myopathy, Paget's disease of RT bone and frontotemporal dementia: novel clinical and genetic findings."; RL Neuromuscul. Disord. 20:330-334(2010). RN [91] RP VARIANTS FTDALS6 HIS-155; GLY-159; GLN-191 AND ASN-592. RX PubMed=21145000; DOI=10.1016/j.neuron.2010.11.036; RA Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M., RA Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J., Ding J., RA McCluskey L., Martinez-Lage M., Falcone D., Hernandez D.G., Arepalli S., RA Chong S., Schymick J.C., Rothstein J., Landi F., Wang Y.D., Calvo A., RA Mora G., Sabatelli M., Monsurro M.R., Battistini S., Salvi F., Spataro R., RA Sola P., Borghero G., Galassi G., Scholz S.W., Taylor J.P., Restagno G., RA Chio A., Traynor B.J.; RT "Exome sequencing reveals VCP mutations as a cause of familial ALS."; RL Neuron 68:857-864(2010). RN [92] RP VARIANT CMT2Y LYS-185, CHARACTERIZATION OF VARIANT CMT2Y LYS-185, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155 AND GLU-232. RX PubMed=25125609; DOI=10.1093/brain/awu224; RA Gonzalez M.A., Feely S.M., Speziani F., Strickland A.V., Danzi M., RA Bacon C., Lee Y., Chou T.F., Blanton S.H., Weihl C.C., Zuchner S., RA Shy M.E.; RT "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."; RL Brain 137:2897-2902(2014). RN [93] RP VARIANT CMT2Y GLU-97, CHARACTERIZATION OF VARIANT CMT2Y GLU-97, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232. RX PubMed=25878907; DOI=10.1155/2015/239167; RA Jerath N.U., Crockett C.D., Moore S.A., Shy M.E., Weihl C.C., Chou T.F., RA Grider T., Gonzalez M.A., Zuchner S., Swenson A.; RT "Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation."; RL Case Rep. Genet. 2015:239167-239167(2015). RN [94] RP VARIANT IBMPFD1 PHE-126. RX PubMed=27209344; DOI=10.1016/j.nmd.2016.05.001; RA Matsubara S., Shimizu T., Komori T., Mori-Yoshimura M., Minami N., RA Hayashi Y.K.; RT "Nuclear inclusions mimicking poly(A)-binding protein nuclear 1 inclusions RT in a case of inclusion body myopathy associated with Paget disease of bone RT and frontotemporal dementia with a novel mutation in the valosin-containing RT protein gene."; RL Neuromuscul. Disord. 26:436-440(2016). RN [95] RP FUNCTION, INTERACTION WITH PLAA; UBXN6 AND YOD1, SUBCELLULAR LOCATION, RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232, AND RP MUTAGENESIS OF GLU-578. RX PubMed=27753622; DOI=10.15252/embj.201695148; RA Papadopoulos C., Kirchner P., Bug M., Grum D., Koerver L., Schulze N., RA Poehler R., Dressler A., Fengler S., Arhzaouy K., Lux V., Ehrmann M., RA Weihl C.C., Meyer H.; RT "VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of RT ruptured lysosomes by autophagy."; RL EMBO J. 36:135-150(2017). RN [96] RP VARIANTS IBMPFD1 THR-160; PHE-254 AND THR-369. RX PubMed=36980948; DOI=10.3390/genes14030676; RA Columbres R.C.A., Chin Y., Pratti S., Quinn C., Gonzalez-Cuyar L.F., RA Weiss M., Quintero-Rivera F., Kimonis V.; RT "Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1."; RL Genes (Basel) 14:0-0(2023). CC -!- FUNCTION: Necessary for the fragmentation of Golgi stacks during CC mitosis and for their reassembly after mitosis. Involved in the CC formation of the transitional endoplasmic reticulum (tER). The transfer CC of membranes from the endoplasmic reticulum to the Golgi apparatus CC occurs via 50-70 nm transition vesicles which derive from part-rough, CC part-smooth transitional elements of the endoplasmic reticulum (tER). CC Vesicle budding from the tER is an ATP-dependent process. The ternary CC complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins CC and is necessary for the export of misfolded proteins from the ER to CC the cytoplasm, where they are degraded by the proteasome. The NPLOC4- CC UFD1-VCP complex regulates spindle disassembly at the end of mitosis CC and is necessary for the formation of a closed nuclear envelope. CC Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of CC the VCP/p97-AMFR/gp78 complex that participates in the final step of CC the sterol-mediated ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum- CC associated degradation of CHRNA3 in cortical neurons as part of the CC STUB1-VCP-UBXN2A complex (PubMed:26265139). Involved in endoplasmic CC reticulum stress-induced pre-emptive quality control, a mechanism that CC selectively attenuates the translocation of newly synthesized proteins CC into the endoplasmic reticulum and reroutes them to the cytosol for CC proteasomal degradation (PubMed:26565908). Involved in clearance CC process by mediating G3BP1 extraction from stress granules CC (PubMed:29804830, PubMed:34739333). Also involved in DNA damage CC response: recruited to double-strand breaks (DSBs) sites in a RNF8- and CC RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA CC damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled CC replication forks by SPRTN: may act by mediating extraction of DNA CC polymerase eta (POLH) to prevent excessive translesion DNA synthesis CC and limit the incidence of mutations induced by DNA damage CC (PubMed:23042605, PubMed:23042607). Together with SPRTN CC metalloprotease, involved in the repair of covalent DNA-protein cross- CC links (DPCs) during DNA synthesis (PubMed:32152270). Involved in CC interstrand cross-link repair in response to replication stress by CC mediating unloading of the ubiquitinated CMG helicase complex (By CC similarity). Mediates extraction of PARP1 trapped to chromatin: CC recognizes and binds ubiquitinated PARP1 and promotes its removal CC (PubMed:35013556). Required for cytoplasmic retrotranslocation of CC stressed/damaged mitochondrial outer-membrane proteins and their CC subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). CC Essential for the maturation of ubiquitin-containing autophagosomes and CC the clearance of ubiquitinated protein by autophagy (PubMed:20104022, CC PubMed:27753622, PubMed:38762759). Acts as a negative regulator of type CC I interferon production by interacting with RIGI: interaction takes CC place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CC CARD domains, leading to recruit RNF125 and promote ubiquitination and CC degradation of RIGI (PubMed:26471729). May play a role in the CC ubiquitin-dependent sorting of membrane proteins to lysosomes where CC they undergo degradation (PubMed:21822278). May more particularly play CC a role in caveolins sorting in cells (PubMed:21822278, CC PubMed:23335559). By controlling the steady-state expression of the CC IGF1R receptor, indirectly regulates the insulin-like growth factor CC receptor signaling pathway (PubMed:26692333). CC {ECO:0000250|UniProtKB:P23787, ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21118995, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22020440, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:23335559, ECO:0000269|PubMed:26265139, CC ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:26565908, CC ECO:0000269|PubMed:26692333, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:32152270, CC ECO:0000269|PubMed:34739333, ECO:0000269|PubMed:35013556, CC ECO:0000269|PubMed:38762759}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.6; CC Evidence={ECO:0000269|PubMed:26471729}; CC -!- SUBUNIT: Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, CC that displays 6-fold radial symmetry. Part of a ternary complex CC containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds CC to one end of a VCP homohexamer. The complex binds to membranes CC enriched in phosphatidylethanolamine-containing lipids and promotes CC Golgi membrane fusion. Binds to a heterodimer of NPLOC4 and UFD1, CC binding to this heterodimer inhibits Golgi-membrane fusion CC (PubMed:26471729, PubMed:38762759). Interaction with VCIP135 leads to CC dissociation of the complex via ATP hydrolysis by VCP. Part of a CC ternary complex containing NPLOC4, UFD1 and VCP. Interacts with NSFL1C- CC like protein p37; the complex has membrane fusion activity and is CC required for Golgi and endoplasmic reticulum biogenesis. Interacts with CC SELENOS and SYVN1, as well as with DERL1 (via SHP-box motif), DERL2 and CC DERL3; which probably transfer misfolded proteins from the ER to VCP CC (PubMed:15215856, PubMed:16186509, PubMed:16186510, PubMed:16289116, CC PubMed:16449189, PubMed:27714797). Interacts with SVIP and forms a CC complex with SVIP and DERL1 (PubMed:17872946). Component of a complex CC required to couple retrotranslocation, ubiquitination and CC deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Part of CC a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that CC modulates the ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of CHRNA3 (PubMed:26265139). Within the complex CC UBXN2A acts as a scaffold protein required for the interaction of CC CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 CC ubiquitination by STUB1/CHIP and subsequently ERAD (PubMed:26265139). CC Interacts with UBXN2A (via UBX domain); the interaction is required for CC the interaction of CHRNA3 in the STUB1-VCP-UBXN2A complex CC (PubMed:26265139). Directly interacts with UBXN4 and RNF19A. Interacts CC with CASR. Interacts with UBE4B and YOD1. Interacts with clathrin. CC Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component of a CC VCP/p97-AMFR/gp78 complex that participates in the final step of the CC endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Interacts CC directly with AMFR/gp78 (via its VIM). Interacts with RHBDD1 (via C- CC terminal domain). Interacts with SPRTN; leading to recruitment to CC stalled replication forks (PubMed:23042605, PubMed:23042607). Interacts CC with WASHC5. Interacts with UBOX5. Interacts (via N-terminus) with CC UBXN7, UBXN8, and probably several other UBX domain-containing proteins CC (via UBX domains); the interactions are mutually exclusive with VIM- CC dependent interactions such as those with AMFR and SELENOS. Forms a CC complex with UBQLN1 and UBXN4. Interacts (via the PIM motif) with RNF31 CC (via the PUB domain) (PubMed:24726327). Interacts with RIGI and RNF125; CC interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked CC ubiquitin on its CARD domains, leading to recruit RNF125 and promote CC ubiquitination and degradation of RIGI (PubMed:26471729). Interacts CC with BAG6 (PubMed:21636303). Interacts with UBXN10 (PubMed:26389662). CC Interacts with UBXN6; the interaction with UBXN6 is direct and CC competitive with UFD1 (PubMed:19174149, PubMed:19275885). Forms a CC ternary complex with CAV1 and UBXN6 (PubMed:18656546, PubMed:19174149, CC PubMed:21822278). Interacts with PLAA, UBXN6 and YOD1; may form a CC complex involved in macroautophagy (PubMed:27753622). Interacts with CC ANKZF1 (PubMed:28302725). Interacts with ubiquitin-binding protein FAF1 CC (PubMed:26842564). Interacts with ZFAND2B (via VIM motif); the CC interaction is direct (PubMed:24160817, PubMed:26337389). Interacts CC with ZFAND1 (via its ubiquitin-like region); this interaction occurs in CC an arsenite-dependent manner (PubMed:29804830). Interacts with CCDC47 CC (By similarity). Interacts with UBAC2 (By similarity). Interacts with CC LMBR1L (PubMed:31073040). Interacts with ATXN3 (PubMed:30455355). CC Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links CC (DPCs) (PubMed:32152270). Interacts with FBXL4 (PubMed:36896912). CC {ECO:0000250|UniProtKB:P46462, ECO:0000250|UniProtKB:Q01853, CC ECO:0000269|PubMed:15215856, ECO:0000269|PubMed:15362974, CC ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, CC ECO:0000269|PubMed:16186509, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:16289116, ECO:0000269|PubMed:16449189, CC ECO:0000269|PubMed:16513638, ECO:0000269|PubMed:16968747, CC ECO:0000269|PubMed:17314412, ECO:0000269|PubMed:17872946, CC ECO:0000269|PubMed:18022694, ECO:0000269|PubMed:18656546, CC ECO:0000269|PubMed:18675248, ECO:0000269|PubMed:19174149, CC ECO:0000269|PubMed:19275885, ECO:0000269|PubMed:19818707, CC ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:19887378, CC ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:20833645, CC ECO:0000269|PubMed:21636303, ECO:0000269|PubMed:21822278, CC ECO:0000269|PubMed:21914798, ECO:0000269|PubMed:21949850, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22537386, CC ECO:0000269|PubMed:22795130, ECO:0000269|PubMed:22902628, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:24160817, ECO:0000269|PubMed:24726327, CC ECO:0000269|PubMed:26265139, ECO:0000269|PubMed:26337389, CC ECO:0000269|PubMed:26389662, ECO:0000269|PubMed:26471729, CC ECO:0000269|PubMed:26842564, ECO:0000269|PubMed:27714797, CC ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:28302725, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:30455355, CC ECO:0000269|PubMed:32152270, ECO:0000269|PubMed:36896912, CC ECO:0000269|PubMed:38762759, ECO:0000269|PubMed:8413590, CC ECO:0000305|PubMed:31073040}. CC -!- INTERACTION: CC P55072; Q9UKV5: AMFR; NbExp=12; IntAct=EBI-355164, EBI-1046367; CC P55072; Q9BZE9: ASPSCR1; NbExp=36; IntAct=EBI-355164, EBI-1993677; CC P55072; A9UGY9: ATG5; NbExp=3; IntAct=EBI-355164, EBI-10175276; CC P55072; P54253: ATXN1; NbExp=3; IntAct=EBI-355164, EBI-930964; CC P55072; P54252: ATXN3; NbExp=4; IntAct=EBI-355164, EBI-946046; CC P55072; P54252-1: ATXN3; NbExp=18; IntAct=EBI-355164, EBI-946068; CC P55072; Q96LK0: CEP19; NbExp=6; IntAct=EBI-355164, EBI-741885; CC P55072; O96017: CHEK2; NbExp=2; IntAct=EBI-355164, EBI-1180783; CC P55072; O75175: CNOT3; NbExp=3; IntAct=EBI-355164, EBI-743073; CC P55072; Q13619: CUL4A; NbExp=2; IntAct=EBI-355164, EBI-456106; CC P55072; O60941: DTNB; NbExp=4; IntAct=EBI-355164, EBI-740402; CC P55072; O60941-5: DTNB; NbExp=3; IntAct=EBI-355164, EBI-11984733; CC P55072; P26378-2: ELAVL4; NbExp=3; IntAct=EBI-355164, EBI-21603100; CC P55072; Q96J88-3: EPSTI1; NbExp=3; IntAct=EBI-355164, EBI-25885343; CC P55072; Q9UNN5: FAF1; NbExp=3; IntAct=EBI-355164, EBI-718246; CC P55072; Q9UNN5-1: FAF1; NbExp=4; IntAct=EBI-355164, EBI-15930546; CC P55072; Q96CS3: FAF2; NbExp=16; IntAct=EBI-355164, EBI-1055805; CC P55072; O94868: FCHSD2; NbExp=2; IntAct=EBI-355164, EBI-1215612; CC P55072; P09471: GNAO1; NbExp=5; IntAct=EBI-355164, EBI-715087; CC P55072; P62993: GRB2; NbExp=5; IntAct=EBI-355164, EBI-401755; CC P55072; P04792: HSPB1; NbExp=3; IntAct=EBI-355164, EBI-352682; CC P55072; P42858: HTT; NbExp=10; IntAct=EBI-355164, EBI-466029; CC P55072; Q8TBB1: LNX1; NbExp=7; IntAct=EBI-355164, EBI-739832; CC P55072; Q8WZA0: LZIC; NbExp=3; IntAct=EBI-355164, EBI-5774346; CC P55072; Q9H7H0-2: METTL17; NbExp=3; IntAct=EBI-355164, EBI-11098807; CC P55072; Q9HC29: NOD2; NbExp=5; IntAct=EBI-355164, EBI-7445625; CC P55072; Q8TAT6: NPLOC4; NbExp=17; IntAct=EBI-355164, EBI-1994109; CC P55072; Q9UNZ2: NSFL1C; NbExp=28; IntAct=EBI-355164, EBI-721577; CC P55072; Q96HA8: NTAQ1; NbExp=6; IntAct=EBI-355164, EBI-741158; CC P55072; Q9Y263: PLAA; NbExp=9; IntAct=EBI-355164, EBI-1994037; CC P55072; Q07869: PPARA; NbExp=3; IntAct=EBI-355164, EBI-78615; CC P55072; P62136: PPP1CA; NbExp=3; IntAct=EBI-355164, EBI-357253; CC P55072; P07602-1: PSAP; NbExp=3; IntAct=EBI-355164, EBI-10635648; CC P55072; P25786: PSMA1; NbExp=8; IntAct=EBI-355164, EBI-359352; CC P55072; P62191: PSMC1; NbExp=5; IntAct=EBI-355164, EBI-357598; CC P55072; P26045: PTPN3; NbExp=2; IntAct=EBI-355164, EBI-1047946; CC P55072; Q9Y4L5: RNF115; NbExp=3; IntAct=EBI-355164, EBI-2129242; CC P55072; Q96EQ8: RNF125; NbExp=3; IntAct=EBI-355164, EBI-2339208; CC P55072; O76064: RNF8; NbExp=3; IntAct=EBI-355164, EBI-373337; CC P55072; P32969: RPL9P9; NbExp=7; IntAct=EBI-355164, EBI-358122; CC P55072; Q9H0K1: SIK2; NbExp=4; IntAct=EBI-355164, EBI-1181664; CC P55072; Q8NBI5: SLC43A3; NbExp=3; IntAct=EBI-355164, EBI-2855542; CC P55072; Q16560-2: SNRNP35; NbExp=3; IntAct=EBI-355164, EBI-12938570; CC P55072; P46977: STT3A; NbExp=3; IntAct=EBI-355164, EBI-719212; CC P55072; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-355164, EBI-359276; CC P55072; P51668: UBE2D1; NbExp=3; IntAct=EBI-355164, EBI-743540; CC P55072; B1AQ61: UBE4B; NbExp=4; IntAct=EBI-355164, EBI-7931266; CC P55072; O94941: UBOX5; NbExp=6; IntAct=EBI-355164, EBI-751901; CC P55072; Q04323: UBXN1; NbExp=9; IntAct=EBI-355164, EBI-1058647; CC P55072; Q96LJ8: UBXN10; NbExp=7; IntAct=EBI-355164, EBI-1993941; CC P55072; Q5T124-6: UBXN11; NbExp=7; IntAct=EBI-355164, EBI-11524408; CC P55072; P68543: UBXN2A; NbExp=20; IntAct=EBI-355164, EBI-1993668; CC P55072; Q14CS0: UBXN2B; NbExp=16; IntAct=EBI-355164, EBI-1993619; CC P55072; Q92575: UBXN4; NbExp=12; IntAct=EBI-355164, EBI-723441; CC P55072; Q9BZV1: UBXN6; NbExp=26; IntAct=EBI-355164, EBI-1993899; CC P55072; Q9BZV1-2: UBXN6; NbExp=3; IntAct=EBI-355164, EBI-21851820; CC P55072; O94888: UBXN7; NbExp=19; IntAct=EBI-355164, EBI-1993627; CC P55072; O00124: UBXN8; NbExp=9; IntAct=EBI-355164, EBI-1993850; CC P55072; Q92890: UFD1; NbExp=10; IntAct=EBI-355164, EBI-1994090; CC P55072; P63027: VAMP2; NbExp=5; IntAct=EBI-355164, EBI-520113; CC P55072; Q969W3: VCF1; NbExp=10; IntAct=EBI-355164, EBI-10281506; CC P55072; P55072: VCP; NbExp=8; IntAct=EBI-355164, EBI-355164; CC P55072; Q6GPH4: XAF1; NbExp=3; IntAct=EBI-355164, EBI-2815120; CC P55072; Q5VVQ6: YOD1; NbExp=3; IntAct=EBI-355164, EBI-2510804; CC P55072; P63104: YWHAZ; NbExp=4; IntAct=EBI-355164, EBI-347088; CC P55072; P24278: ZBTB25; NbExp=3; IntAct=EBI-355164, EBI-739899; CC P55072; Q9WTX6: Cul1; Xeno; NbExp=2; IntAct=EBI-355164, EBI-1551052; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15456787}. CC Endoplasmic reticulum {ECO:0000269|PubMed:15215856}. Nucleus CC {ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:26842564}. Cytoplasm, CC Stress granule {ECO:0000269|PubMed:29804830}. Note=Present in the CC neuronal hyaline inclusion bodies specifically found in motor neurons CC from amyotrophic lateral sclerosis patients (PubMed:15456787). Present CC in the Lewy bodies specifically found in neurons from Parkinson disease CC patients (PubMed:15456787). Recruited to the cytoplasmic surface of the CC endoplasmic reticulum via interaction with AMFR/gp78 (PubMed:16168377). CC Following DNA double-strand breaks, recruited to the sites of damage CC (PubMed:22120668). Recruited to stalled replication forks via CC interaction with SPRTN (PubMed:23042605). Recruited to damaged CC lysosomes decorated with K48-linked ubiquitin chains (PubMed:27753622). CC Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules CC (SGs) in response to arsenite-induced stress treatment CC (PubMed:29804830). {ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22120668, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830}. CC -!- DOMAIN: The PIM (PUB-interaction motif) motif mediates interaction with CC the PUB domain of RNF31. {ECO:0000269|PubMed:24726327}. CC -!- PTM: Phosphorylated by tyrosine kinases in response to T-cell antigen CC receptor activation. Phosphorylated in mitotic cells. CC {ECO:0000250|UniProtKB:P46462}. CC -!- PTM: ISGylated. {ECO:0000269|PubMed:16139798}. CC -!- PTM: Methylation at Lys-315 catalyzed by VCPKMT is increased in the CC presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity. CC {ECO:0000269|PubMed:22948820, ECO:0000269|PubMed:23349634}. CC -!- PTM: UFMylated al Lys-109; UFMylation enhances the interactions between CC BECN1 and other components of the PtdIns3K complex and thereby promotes CC cellular autophagy initiation. {ECO:0000269|PubMed:38762759}. CC -!- DISEASE: Inclusion body myopathy with early-onset Paget disease with or CC without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal CC dominant disease characterized by disabling muscle weakness clinically CC resembling to limb girdle muscular dystrophy, osteolytic bone lesions CC consistent with Paget disease, and premature frontotemporal dementia. CC Clinical features show incomplete penetrance. CC {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, CC ECO:0000269|PubMed:16247064, ECO:0000269|PubMed:16321991, CC ECO:0000269|PubMed:17935506, ECO:0000269|PubMed:20104022, CC ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:20512113, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, CC ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, CC ECO:0000269|PubMed:27209344, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:36980948}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 CC (FTDALS6) [MIM:613954]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia (FTD) is characterized by frontal and temporal CC lobe atrophy associated with neuronal loss, gliosis, and dementia. CC Patients exhibit progressive changes in social, behavioral, and/or CC language function. Amyotrophic lateral sclerosis (ALS) is characterized CC by the death of motor neurons in the brain, brainstem, and spinal cord, CC resulting in fatal paralysis. FTDALS6 is an autosomal dominant form CC characterized by onset of ALS or FTD in adulthood. Some patients with CC the disorder may have features of both diseases. CC {ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Charcot-Marie-Tooth disease, axonal, type 2Y (CMT2Y) CC [MIM:616687]: An autosomal dominant, axonal form of Charcot-Marie-Tooth CC disease, a disorder of the peripheral nervous system, characterized by CC progressive weakness and atrophy, initially of the peroneal muscles and CC later of the distal muscles of the arms. Charcot-Marie-Tooth disease is CC classified in two main groups on the basis of electrophysiologic CC properties and histopathology: primary peripheral demyelinating CC neuropathies (designated CMT1 when they are dominantly inherited) and CC primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 CC group are characterized by signs of axonal degeneration in the absence CC of obvious myelin alterations, normal or slightly reduced nerve CC conduction velocities, and progressive distal muscle weakness and CC atrophy. {ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the AAA ATPase family. {ECO:0000305}. CC -!- CAUTION: It is unclear how it participates in the recruitment of CC TP53BP1 at DNA damage sites. According to a first report, participates CC in the recruitment of TP53BP1 by promoting ubiquitination and removal CC of L3MBTL1 from DNA damage sites (PubMed:22120668). According to a CC second report, it acts by removing 'Lys-48'-linked ubiquitination from CC sites of DNA damage (PubMed:22020440). {ECO:0000305|PubMed:22020440, CC ECO:0000305|PubMed:22120668}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AC004472; AAC07984.1; -; Genomic_DNA. DR EMBL; FJ224344; ACI46036.1; -; mRNA. DR EMBL; FJ224352; ACI46044.1; -; mRNA. DR EMBL; AF100752; AAD43016.1; -; mRNA. DR EMBL; AK312310; BAG35235.1; -; mRNA. DR EMBL; AL353795; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471071; EAW58404.1; -; Genomic_DNA. DR EMBL; BC110913; AAI10914.1; -; mRNA. DR EMBL; BC121794; AAI21795.1; -; mRNA. DR EMBL; Z70768; CAA94809.1; -; mRNA. DR CCDS; CCDS6573.1; -. DR PIR; T02243; T02243. DR RefSeq; NP_009057.1; NM_007126.5. DR PDB; 3EBB; X-ray; 1.90 A; E/F/G/H=797-806. DR PDB; 3HU1; X-ray; 2.81 A; A/B/C/D/E/F=1-481. DR PDB; 3HU2; X-ray; 2.85 A; A/B/C/D/E/F=1-481. DR PDB; 3HU3; X-ray; 2.20 A; A/B=1-481. DR PDB; 3QC8; X-ray; 2.20 A; A=21-196. DR PDB; 3QQ7; X-ray; 2.65 A; A=2-187. DR PDB; 3QQ8; X-ray; 2.00 A; A=2-187. DR PDB; 3QWZ; X-ray; 2.00 A; A=1-208. DR PDB; 3TIW; X-ray; 1.80 A; A/B=1-187. DR PDB; 4KDI; X-ray; 1.86 A; A/B=21-196. DR PDB; 4KDL; X-ray; 1.81 A; A=21-196. DR PDB; 4KLN; X-ray; 2.62 A; A/B/C/D/E/F=1-481. DR PDB; 4KO8; X-ray; 1.98 A; A/B=1-481. DR PDB; 4KOD; X-ray; 2.96 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 4P0A; X-ray; 2.30 A; B/D=797-806. DR PDB; 5B6C; X-ray; 1.55 A; A=21-191. DR PDB; 5C18; X-ray; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 5C19; X-ray; 4.20 A; A/B/C/D/E/F=2-806. DR PDB; 5C1A; X-ray; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 5C1B; X-ray; 3.08 A; A/B/C/D/E/F=2-806. DR PDB; 5DYG; X-ray; 2.20 A; A=1-460. DR PDB; 5DYI; X-ray; 3.71 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 5EPP; X-ray; 1.88 A; A=21-199. DR PDB; 5FTJ; EM; 2.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTK; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 5FTL; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTM; EM; 3.20 A; A/B/C/D/E/F=1-806. DR PDB; 5FTN; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5GLF; X-ray; 2.25 A; A/C/E/G=21-199. DR PDB; 5IFS; X-ray; 2.46 A; B/D=1-481. DR PDB; 5IFW; X-ray; 3.40 A; B=2-806. DR PDB; 5KIW; X-ray; 3.41 A; A/B=1-460. DR PDB; 5KIY; X-ray; 2.79 A; A=1-460. DR PDB; 5X4L; X-ray; 2.40 A; A/B=23-196. DR PDB; 6G2V; X-ray; 1.90 A; A=462-764. DR PDB; 6G2W; X-ray; 2.68 A; A=462-764. DR PDB; 6G2X; X-ray; 2.08 A; A=462-764. DR PDB; 6G2Y; X-ray; 2.15 A; A=462-764. DR PDB; 6G2Z; X-ray; 1.92 A; A=462-764. DR PDB; 6G30; X-ray; 2.42 A; A=462-764. DR PDB; 6HD0; X-ray; 3.73 A; A/B/C/T/U/V=1-481. DR PDB; 6MCK; X-ray; 3.77 A; A/B/C/D/E/F/G/H/I/J/K/L=210-806. DR PDB; 7BP8; EM; 3.90 A; A/B/C/D/E/F=1-806. DR PDB; 7BP9; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 7BPA; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 7BPB; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7JY5; EM; 2.89 A; A/B/C/D/E/F=1-806. DR PDB; 7K56; EM; 3.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K57; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K59; EM; 4.20 A; A/B/C/D/E/F=1-806. DR PDB; 7L5W; EM; 3.34 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7L5X; EM; 6.10 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7LMY; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LMZ; EM; 3.06 A; A/B/C/D/E/F=1-806. DR PDB; 7LN0; EM; 2.98 A; A/B/C/D/E/F=1-806. DR PDB; 7LN1; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LN2; EM; 3.63 A; A/B/C/D/E/F=1-806. DR PDB; 7LN3; EM; 3.45 A; A/B/C/D/E/F=1-806. DR PDB; 7LN4; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7LN5; EM; 3.09 A; A/B/C/D/E/F=1-806. DR PDB; 7LN6; EM; 3.58 A; A/B/C/D/E/F=1-806. DR PDB; 7MDM; EM; 4.86 A; A/B/C/D/E/F=1-806. DR PDB; 7MDO; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 7MHS; EM; 3.60 A; A/B/C/D/E=1-806. DR PDB; 7OAT; X-ray; 3.00 A; B=2-480. DR PDB; 7PUX; X-ray; 1.73 A; A=1-460. DR PDB; 7R7S; EM; 4.23 A; A/B/C/D/E/F=1-806. DR PDB; 7R7T; EM; 4.50 A; A/B/C/D/E/F=1-806. DR PDB; 7R7U; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7RL6; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RL7; EM; 3.00 A; A/B/C/D/E/F=2-806. DR PDB; 7RL9; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLA; EM; 3.10 A; A/B/C/D/E/F=2-806. DR PDB; 7RLB; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLC; EM; 3.20 A; A/B/C/D/E/F=2-806. DR PDB; 7RLD; EM; 3.40 A; A/B/C/D/E/F=2-806. DR PDB; 7RLF; EM; 3.10 A; A/B/C/D/E/F=1-806. DR PDB; 7RLG; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RLH; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7RLI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 7RLJ; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=21-775. DR PDB; 7VCS; EM; 3.32 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCT; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCU; EM; 3.15 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCV; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCX; EM; 3.24 A; A/B/C/D/E/F=1-806. DR PDB; 7Y4W; EM; 3.67 A; A/B/C/D/E/F=21-806. DR PDB; 7Y53; EM; 3.61 A; A/B/C/D/E/F=21-806. DR PDB; 7Y59; EM; 4.51 A; A/B/C/D/E/F=21-806. DR PDB; 8B5R; EM; 6.10 A; A/B/C/D/E/F=2-806. DR PDB; 8FCL; EM; 3.51 A; A/B/C/D/E/F=1-806. DR PDB; 8FCM; EM; 3.27 A; A/B/C/D/E/F=1-806. DR PDB; 8FCN; EM; 2.95 A; A/B/C/D/E/F=1-806. DR PDB; 8FCO; EM; 3.31 A; A/B/C/D/E/F=1-806. DR PDB; 8FCP; EM; 3.52 A; A/B/C/D/E/F=1-806. DR PDB; 8FCQ; EM; 3.93 A; A/B/C/D/E/F=1-806. DR PDB; 8FCR; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 8FCT; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8HL7; X-ray; 2.80 A; B=23-458. DR PDB; 8HRZ; X-ray; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8KG2; X-ray; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8OOI; EM; 2.61 A; A/B/C/D/E/F=1-806. DR PDB; 8PQX; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 8R0E; EM; 2.70 A; A/B/C/D/E/F=1-806. DR PDB; 8RS9; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSB; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSC; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UV2; EM; 3.23 A; A/B/C/D/E/F=1-806. DR PDB; 8UVO; EM; 3.22 A; A/B/C/D/E/F=1-806. DR PDB; 8UVP; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UVQ; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8VKU; EM; 3.50 A; A/B/C/D/E/F=1-806. DR PDB; 8VLS; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 8VOV; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8YKA; EM; 3.45 A; A/B/C/D/E/F=12-775. DR PDB; 9BOQ; EM; 3.33 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 9DIL; EM; 3.30 A; A/B=1-806. DR PDB; 9MQ6; EM; 3.30 A; A/B=1-806. DR PDBsum; 3EBB; -. DR PDBsum; 3HU1; -. DR PDBsum; 3HU2; -. DR PDBsum; 3HU3; -. DR PDBsum; 3QC8; -. DR PDBsum; 3QQ7; -. DR PDBsum; 3QQ8; -. DR PDBsum; 3QWZ; -. DR PDBsum; 3TIW; -. DR PDBsum; 4KDI; -. DR PDBsum; 4KDL; -. DR PDBsum; 4KLN; -. DR PDBsum; 4KO8; -. DR PDBsum; 4KOD; -. DR PDBsum; 4P0A; -. DR PDBsum; 5B6C; -. DR PDBsum; 5C18; -. DR PDBsum; 5C19; -. DR PDBsum; 5C1A; -. DR PDBsum; 5C1B; -. DR PDBsum; 5DYG; -. DR PDBsum; 5DYI; -. DR PDBsum; 5EPP; -. DR PDBsum; 5FTJ; -. DR PDBsum; 5FTK; -. DR PDBsum; 5FTL; -. DR PDBsum; 5FTM; -. DR PDBsum; 5FTN; -. DR PDBsum; 5GLF; -. DR PDBsum; 5IFS; -. DR PDBsum; 5IFW; -. DR PDBsum; 5KIW; -. DR PDBsum; 5KIY; -. DR PDBsum; 5X4L; -. DR PDBsum; 6G2V; -. DR PDBsum; 6G2W; -. DR PDBsum; 6G2X; -. DR PDBsum; 6G2Y; -. DR PDBsum; 6G2Z; -. DR PDBsum; 6G30; -. DR PDBsum; 6HD0; -. DR PDBsum; 6MCK; -. DR PDBsum; 7BP8; -. DR PDBsum; 7BP9; -. DR PDBsum; 7BPA; -. DR PDBsum; 7BPB; -. DR PDBsum; 7JY5; -. DR PDBsum; 7K56; -. DR PDBsum; 7K57; -. DR PDBsum; 7K59; -. DR PDBsum; 7L5W; -. DR PDBsum; 7L5X; -. DR PDBsum; 7LMY; -. DR PDBsum; 7LMZ; -. DR PDBsum; 7LN0; -. DR PDBsum; 7LN1; -. DR PDBsum; 7LN2; -. DR PDBsum; 7LN3; -. DR PDBsum; 7LN4; -. DR PDBsum; 7LN5; -. DR PDBsum; 7LN6; -. DR PDBsum; 7MDM; -. DR PDBsum; 7MDO; -. DR PDBsum; 7MHS; -. DR PDBsum; 7OAT; -. DR PDBsum; 7PUX; -. DR PDBsum; 7R7S; -. DR PDBsum; 7R7T; -. DR PDBsum; 7R7U; -. DR PDBsum; 7RL6; -. DR PDBsum; 7RL7; -. DR PDBsum; 7RL9; -. DR PDBsum; 7RLA; -. DR PDBsum; 7RLB; -. DR PDBsum; 7RLC; -. DR PDBsum; 7RLD; -. DR PDBsum; 7RLF; -. DR PDBsum; 7RLG; -. DR PDBsum; 7RLH; -. DR PDBsum; 7RLI; -. DR PDBsum; 7RLJ; -. DR PDBsum; 7VCS; -. DR PDBsum; 7VCT; -. DR PDBsum; 7VCU; -. DR PDBsum; 7VCV; -. DR PDBsum; 7VCX; -. DR PDBsum; 7Y4W; -. DR PDBsum; 7Y53; -. DR PDBsum; 7Y59; -. DR PDBsum; 8B5R; -. DR PDBsum; 8FCL; -. DR PDBsum; 8FCM; -. DR PDBsum; 8FCN; -. DR PDBsum; 8FCO; -. DR PDBsum; 8FCP; -. DR PDBsum; 8FCQ; -. DR PDBsum; 8FCR; -. DR PDBsum; 8FCT; -. DR PDBsum; 8HL7; -. DR PDBsum; 8HRZ; -. DR PDBsum; 8KG2; -. DR PDBsum; 8OOI; -. DR PDBsum; 8PQX; -. DR PDBsum; 8R0E; -. DR PDBsum; 8RS9; -. DR PDBsum; 8RSB; -. DR PDBsum; 8RSC; -. DR PDBsum; 8UV2; -. DR PDBsum; 8UVO; -. DR PDBsum; 8UVP; -. DR PDBsum; 8UVQ; -. DR PDBsum; 8VKU; -. DR PDBsum; 8VLS; -. DR PDBsum; 8VOV; -. DR PDBsum; 8YKA; -. DR PDBsum; 9BOQ; -. DR PDBsum; 9DIL; -. DR PDBsum; 9MQ6; -. DR AlphaFoldDB; P55072; -. DR EMDB; EMD-15774; -. DR EMDB; EMD-15861; -. DR EMDB; EMD-16781; -. DR EMDB; EMD-17016; -. DR EMDB; EMD-17024; -. DR EMDB; EMD-17128; -. DR EMDB; EMD-17827; -. DR EMDB; EMD-17837; -. DR EMDB; EMD-18517; -. DR EMDB; EMD-18790; -. DR EMDB; EMD-19473; -. DR EMDB; EMD-19475; -. DR EMDB; EMD-19476; -. DR EMDB; EMD-22521; -. DR EMDB; EMD-22675; -. DR EMDB; EMD-22676; -. DR EMDB; EMD-22678; -. DR EMDB; EMD-23191; -. DR EMDB; EMD-23192; -. DR EMDB; EMD-23442; -. DR EMDB; EMD-23443; -. DR EMDB; EMD-23444; -. DR EMDB; EMD-23445; -. DR EMDB; EMD-23446; -. DR EMDB; EMD-23447; -. DR EMDB; EMD-23448; -. DR EMDB; EMD-23449; -. DR EMDB; EMD-23450; -. DR EMDB; EMD-23451; -. DR EMDB; EMD-23452; -. DR EMDB; EMD-23453; -. DR EMDB; EMD-23454; -. DR EMDB; EMD-23455; -. DR EMDB; EMD-23456; -. DR EMDB; EMD-23457; -. DR EMDB; EMD-23458; -. DR EMDB; EMD-23775; -. DR EMDB; EMD-23776; -. DR EMDB; EMD-23835; -. DR EMDB; EMD-24302; -. DR EMDB; EMD-24304; -. DR EMDB; EMD-24305; -. DR EMDB; EMD-24306; -. DR EMDB; EMD-24518; -. DR EMDB; EMD-24519; -. DR EMDB; EMD-24522; -. DR EMDB; EMD-24523; -. DR EMDB; EMD-24524; -. DR EMDB; EMD-24525; -. DR EMDB; EMD-24526; -. DR EMDB; EMD-24528; -. DR EMDB; EMD-24529; -. DR EMDB; EMD-24530; -. DR EMDB; EMD-24531; -. DR EMDB; EMD-24532; -. DR EMDB; EMD-28982; -. DR EMDB; EMD-28983; -. DR EMDB; EMD-28984; -. DR EMDB; EMD-28985; -. DR EMDB; EMD-28986; -. DR EMDB; EMD-28987; -. DR EMDB; EMD-28988; -. DR EMDB; EMD-28989; -. DR EMDB; EMD-28990; -. DR EMDB; EMD-28991; -. DR EMDB; EMD-28992; -. DR EMDB; EMD-30147; -. DR EMDB; EMD-30148; -. DR EMDB; EMD-30149; -. DR EMDB; EMD-30150; -. DR EMDB; EMD-31894; -. DR EMDB; EMD-31895; -. DR EMDB; EMD-31896; -. DR EMDB; EMD-31897; -. DR EMDB; EMD-31899; -. DR EMDB; EMD-32827; -. DR EMDB; EMD-3295; -. DR EMDB; EMD-3296; -. DR EMDB; EMD-3297; -. DR EMDB; EMD-3298; -. DR EMDB; EMD-3299; -. DR EMDB; EMD-3323; -. DR EMDB; EMD-3324; -. DR EMDB; EMD-3325; -. DR EMDB; EMD-3326; -. DR EMDB; EMD-3327; -. DR EMDB; EMD-3328; -. DR EMDB; EMD-33608; -. DR EMDB; EMD-33611; -. DR EMDB; EMD-33613; -. DR EMDB; EMD-38770; -. DR EMDB; EMD-38771; -. DR EMDB; EMD-38772; -. DR EMDB; EMD-39360; -. DR EMDB; EMD-42603; -. DR EMDB; EMD-42625; -. DR EMDB; EMD-42626; -. DR EMDB; EMD-42627; -. DR EMDB; EMD-43329; -. DR EMDB; EMD-43343; -. DR EMDB; EMD-43392; -. DR EMDB; EMD-44748; -. DR EMDB; EMD-46912; -. DR EMDB; EMD-48514; -. DR SMR; P55072; -. DR BioGRID; 113258; 1454. DR ComplexPortal; CPX-137; VCP-NPL4-UFD1 AAA ATPase complex. DR ComplexPortal; CPX-262; VCP-NSFL1C AAA ATPase complex. DR ComplexPortal; CPX-8095; VCP-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8096; VCP-NPL4-UFD1-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8101; VCP-NPL4-UFD1-UBXN7 AAA ATPase complex. DR ComplexPortal; CPX-8104; VCP-NPL4-UFD1-FAF2 AAA ATPase complex. DR ComplexPortal; CPX-8105; VCP-NPL4-UFD1-UBXN1 AAA ATPase complex. DR ComplexPortal; CPX-8121; VCP-UBXN2B AAA ATPase complex. DR ComplexPortal; CPX-8124; VCP-UBXN2A AAA ATPase complex. DR ComplexPortal; CPX-8128; VCP-YOD1 AAA ATPase complex. DR ComplexPortal; CPX-8129; VCP-PLAA AAA ATPase complex. DR ComplexPortal; CPX-8132; VCP-VCPIP1 AAA ATPase complex. DR ComplexPortal; CPX-8133; VCP-UBXN6 AAA ATPase complex. DR ComplexPortal; CPX-8134; VCP-AMFR AAA ATPase complex. DR ComplexPortal; CPX-8570; VCP-DERL1 AAA ATPase complex. DR ComplexPortal; CPX-8782; VCP-DERL2 AAA ATPase complex. DR ComplexPortal; CPX-8783; VCP-DERL3 AAA ATPase complex. DR CORUM; P55072; -. DR DIP; DIP-33543N; -. DR FunCoup; P55072; 2295. DR IntAct; P55072; 915. DR MINT; P55072; -. DR STRING; 9606.ENSP00000351777; -. DR BindingDB; P55072; -. DR ChEMBL; CHEMBL1075145; -. DR DrugBank; DB16874; CB-5083. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR DrugCentral; P55072; -. DR MoonDB; P55072; Predicted. DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family. DR CarbonylDB; P55072; -. DR GlyGen; P55072; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P55072; -. DR MetOSite; P55072; -. DR PhosphoSitePlus; P55072; -. DR SwissPalm; P55072; -. DR BioMuta; VCP; -. DR DMDM; 6094447; -. DR OGP; P55072; -. DR REPRODUCTION-2DPAGE; IPI00022774; -. DR REPRODUCTION-2DPAGE; P55072; -. DR CPTAC; CPTAC-295; -. DR CPTAC; CPTAC-296; -. DR jPOST; P55072; -. DR MassIVE; P55072; -. DR PaxDb; 9606-ENSP00000351777; -. DR PeptideAtlas; P55072; -. DR PRIDE; P55072; -. DR ProteomicsDB; 56776; -. DR Pumba; P55072; -. DR TopDownProteomics; P55072; -. DR ABCD; P55072; 1 sequenced antibody. DR Antibodypedia; 2215; 680 antibodies from 44 providers. DR DNASU; 7415; -. DR Ensembl; ENST00000358901.11; ENSP00000351777.6; ENSG00000165280.19. DR GeneID; 7415; -. DR KEGG; hsa:7415; -. DR MANE-Select; ENST00000358901.11; ENSP00000351777.6; NM_007126.5; NP_009057.1. DR AGR; HGNC:12666; -. DR ClinPGx; PA37289; -. DR CTD; 7415; -. DR DisGeNET; 7415; -. DR GeneCards; VCP; -. DR GeneReviews; VCP; -. DR HGNC; HGNC:12666; VCP. DR HPA; ENSG00000165280; Low tissue specificity. DR MalaCards; VCP; -. DR MIM; 167320; phenotype. DR MIM; 601023; gene. DR MIM; 613954; phenotype. DR MIM; 616687; phenotype. DR OpenTargets; ENSG00000165280; -. DR Orphanet; 329478; Adult-onset distal myopathy due to VCP mutation. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 435387; Autosomal dominant Charcot-Marie-Tooth disease type 2Y. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR Orphanet; 52430; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 329475; Spastic paraplegia-Paget disease of bone syndrome. DR VEuPathDB; HostDB:ENSG00000165280; -. DR eggNOG; KOG0730; Eukaryota. DR GeneTree; ENSGT00900000141071; -. DR HOGENOM; CLU_000688_12_3_1; -. DR InParanoid; P55072; -. DR OMA; VWPAYPE; -. DR OrthoDB; 27435at2759; -. DR PAN-GO; P55072; 10 GO annotations based on evolutionary models. DR PhylomeDB; P55072; -. DR BRENDA; 3.6.4.6; 2681. DR PathwayCommons; P55072; -. DR Reactome; R-HSA-110320; Translesion Synthesis by POLH. DR Reactome; R-HSA-3371511; HSF1 activation. DR Reactome; R-HSA-382556; ABC-family proteins mediated transport. DR Reactome; R-HSA-532668; N-glycan trimming in the ER and Calnexin/Calreticulin cycle. DR Reactome; R-HSA-5358346; Hedgehog ligand biogenesis. DR Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD. DR Reactome; R-HSA-5678895; Defective CFTR causes cystic fibrosis. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-8866654; E3 ubiquitin ligases ubiquitinate target proteins. DR Reactome; R-HSA-8876725; Protein methylation. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9013407; RHOH GTPase cycle. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-9678110; Attachment and Entry. DR Reactome; R-HSA-9694614; Attachment and Entry. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR SignaLink; P55072; -. DR SIGNOR; P55072; -. DR Agora; ENSG00000165280; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7415; 852 hits in 1138 CRISPR screens. DR CD-CODE; 550E224B; Proteasome condensate. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; VCP; human. DR EvolutionaryTrace; P55072; -. DR GeneWiki; Valosin-containing_protein; -. DR GenomeRNAi; 7415; -. DR Pharos; P55072; Tchem. DR PRO; PR:P55072; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; P55072; protein. DR Bgee; ENSG00000165280; Expressed in stromal cell of endometrium and 210 other cell types or tissues. DR ExpressionAtlas; P55072; baseline and differential. DR GO; GO:1904949; C:ATPase complex; IEA:Ensembl. DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0097542; C:ciliary tip; IDA:HPA. DR GO; GO:0035869; C:ciliary transition zone; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0000153; C:cytoplasmic ubiquitin ligase complex; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0036513; C:Derlin-1 retrotranslocation complex; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB. DR GO; GO:0005811; C:lipid droplet; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0000502; C:proteasome complex; IDA:BHF-UCL. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0034098; C:VCP-NPL4-UFD1 AAA ATPase complex; IPI:ComplexPortal. DR GO; GO:1990730; C:VCP-NSFL1C complex; IPI:ComplexPortal. DR GO; GO:0043531; F:ADP binding; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:UniProt. DR GO; GO:1904288; F:BAT3 complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0035800; F:deubiquitinase activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0036435; F:K48-linked polyubiquitin modification-dependent protein binding; IDA:UniProt. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0042288; F:MHC class I protein binding; IEA:Ensembl. DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IEA:Ensembl. DR GO; GO:0046034; P:ATP metabolic process; IEA:Ensembl. DR GO; GO:0097352; P:autophagosome maturation; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1903843; P:cellular response to arsenite ion; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IMP:UniProtKB. DR GO; GO:0071218; P:cellular response to misfolded protein; IMP:ParkinsonsUK-UCL. DR GO; GO:0140455; P:cytoplasm protein quality control; IDA:UniProt. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; NAS:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0061857; P:endoplasmic reticulum stress-induced pre-emptive quality control; IMP:UniProtKB. DR GO; GO:0006888; P:endoplasmic reticulum to Golgi vesicle-mediated transport; IEA:Ensembl. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:UniProtKB. DR GO; GO:0032510; P:endosome to lysosome transport via multivesicular body sorting pathway; IMP:UniProtKB. DR GO; GO:0036503; P:ERAD pathway; IDA:UniProtKB. DR GO; GO:0045184; P:establishment of protein localization; TAS:UniProtKB. DR GO; GO:0072389; P:flavin adenine dinucleotide catabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036297; P:interstrand cross-link repair; ISS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IMP:UniProtKB. DR GO; GO:0051228; P:mitotic spindle disassembly; IBA:GO_Central. DR GO; GO:0019674; P:NAD+ metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0035331; P:negative regulation of hippo signaling; IGI:FlyBase. DR GO; GO:0120186; P:negative regulation of protein localization to chromatin; IDA:UniProt. DR GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:FlyBase. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:FlyBase. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:1903862; P:positive regulation of oxidative phosphorylation; IMP:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL. DR GO; GO:1903006; P:positive regulation of protein K63-linked deubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProt. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0106300; P:protein-DNA covalent cross-linking repair; IDA:UniProtKB. DR GO; GO:1903715; P:regulation of aerobic respiration; IMP:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:1905634; P:regulation of protein localization to chromatin; IDA:UniProtKB. DR GO; GO:0050807; P:regulation of synapse organization; IEA:Ensembl. DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB. DR GO; GO:0035617; P:stress granule disassembly; IDA:UniProtKB. DR GO; GO:0019985; P:translesion synthesis; IMP:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:ComplexPortal. DR GO; GO:0019079; P:viral genome replication; IMP:CACAO. DR CDD; cd19519; RecA-like_CDC48_r1-like; 1. DR CDD; cd19528; RecA-like_CDC48_r2-like; 1. DR DisProt; DP03238; -. DR FunFam; 1.10.8.60:FF:000004; Cell division control 48; 1. DR FunFam; 3.10.330.10:FF:000001; Cell division control 48; 1. DR FunFam; 2.40.40.20:FF:000003; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000012; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000048; Transitional endoplasmic reticulum ATPase; 1. DR Gene3D; 1.10.8.60; -; 1. DR Gene3D; 2.40.40.20; -; 1. DR Gene3D; 3.10.330.10; -; 1. DR Gene3D; 6.10.20.150; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR IDEAL; IID00201; -. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR005938; AAA_ATPase_CDC48. DR InterPro; IPR050168; AAA_ATPase_domain. DR InterPro; IPR041569; AAA_lid_3. DR InterPro; IPR009010; Asp_de-COase-like_dom_sf. DR InterPro; IPR003959; ATPase_AAA_core. DR InterPro; IPR003960; ATPase_AAA_CS. DR InterPro; IPR004201; Cdc48_dom2. DR InterPro; IPR029067; CDC48_domain_2-like_sf. DR InterPro; IPR003338; CDC4_N-term_subdom. DR InterPro; IPR027417; P-loop_NTPase. DR NCBIfam; TIGR01243; CDC48; 1. DR PANTHER; PTHR23077; AAA-FAMILY ATPASE; 1. DR PANTHER; PTHR23077:SF69; TRANSITIONAL ENDOPLASMIC RETICULUM ATPASE; 1. DR Pfam; PF00004; AAA; 2. DR Pfam; PF17862; AAA_lid_3; 2. DR Pfam; PF02933; CDC48_2; 1. DR Pfam; PF02359; CDC48_N; 1. DR SMART; SM00382; AAA; 2. DR SMART; SM01072; CDC48_2; 1. DR SMART; SM01073; CDC48_N; 1. DR SUPFAM; SSF50692; ADC-like; 1. DR SUPFAM; SSF54585; Cdc48 domain 2-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR PROSITE; PS00674; AAA; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; ATP-binding; KW Autophagy; Charcot-Marie-Tooth disease; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; KW Endoplasmic reticulum; Hydrolase; Isopeptide bond; Lipid-binding; KW Methylation; Neurodegeneration; Neuropathy; Nucleotide-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Transport; KW Ubl conjugation; Ubl conjugation pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.9, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:22223895, FT ECO:0007744|PubMed:25944712" FT CHAIN 2..806 FT /note="Transitional endoplasmic reticulum ATPase" FT /id="PRO_0000084572" FT REGION 708..727 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 768..806 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 797..806 FT /note="Interaction with UBXN6" FT /evidence="ECO:0000269|PubMed:18656546" FT MOTIF 802..806 FT /note="PIM motif" FT /evidence="ECO:0000269|PubMed:24726327" FT COMPBIAS 777..793 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 247..253 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 348 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 384 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 521..526 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.9, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:25944712" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 13 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 37 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 315 FT /note="N6,N6,N6-trimethyllysine; by VCPKMT" FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MOD_RES 436 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 462 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 502 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 505 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 702 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 770 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 775 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 787 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 805 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT CROSSLNK 8 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 18 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 109 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in UFM1)" FT /evidence="ECO:0000269|PubMed:38762759" FT VARIANT 95 FT /note="R -> G (in IBMPFD1; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; abolishes FT enhancement of K-315 methylation by ASPSCR1; decreased FT interaction with CAV1 and UBXN6; dbSNP:rs121909332)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20512113, FT ECO:0000269|PubMed:21822278" FT /id="VAR_033016" FT VARIANT 97 FT /note="G -> E (in CMT2Y; increased ATPase activity; FT dbSNP:rs864309502)" FT /evidence="ECO:0000269|PubMed:25878907" FT /id="VAR_076464" FT VARIANT 126 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:27209344" FT /id="VAR_076465" FT VARIANT 155 FT /note="R -> C (in IBMPFD1; also in one patient without FT evidence of Paget disease of the bone; dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:15732117" FT /id="VAR_033017" FT VARIANT 155 FT /note="R -> H (in FTDALS6 and IBMPFD1; properly assembles FT into a hexameric structure; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; shows normal ATPase FT activity according to PubMed:16321991 while according to FT PubMed:25878907 and PubMed:25125609 shows increased ATPase FT activity; no defect in ubiquitin-dependent protein FT degradation by the proteasome; impaired autophagic FT function; defective maturation of ubiquitin-containing FT autophagosomes; decreased interaction with CAV1 and UBXN6; FT decreased endosome to lysosome transport via multivesicular FT body sorting pathway of CAV1; decreases the arsenite- FT induced stress granules (SGs) clearance process; FT dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:29804830" FT /id="VAR_033018" FT VARIANT 155 FT /note="R -> L (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:20335036" FT /id="VAR_078910" FT VARIANT 155 FT /note="R -> P (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582" FT /id="VAR_033019" FT VARIANT 155 FT /note="R -> S (in IBMPFD1; impaired autophagic function; FT dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:20104022" FT /id="VAR_076466" FT VARIANT 159 FT /note="R -> G (in FTDALS6; dbSNP:rs387906789)" FT /evidence="ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:23349634" FT /id="VAR_065910" FT VARIANT 159 FT /note="R -> H (in IBMPFD1; without frontotemporal dementia; FT abolishes enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909335)" FT /evidence="ECO:0000269|PubMed:16247064" FT /id="VAR_033020" FT VARIANT 160 FT /note="A -> T (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088265" FT VARIANT 185 FT /note="E -> K (in CMT2Y; normal ATPase activity; impaired FT autophagic function; dbSNP:rs864309501)" FT /evidence="ECO:0000269|PubMed:25125609" FT /id="VAR_076467" FT VARIANT 191 FT /note="R -> Q (in FTDALS6 and IBMPFD1; abolishes FT enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909334)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634" FT /id="VAR_033021" FT VARIANT 198 FT /note="L -> W (in IBMPFD1; increased ATPase activity; FT impaired autophagic function; dbSNP:rs748447593)" FT /evidence="ECO:0000269|PubMed:17935506, FT ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_076468" FT VARIANT 232 FT /note="A -> E (in IBMPFD1; increased ATPase activity; no FT defect in ubiquitin-dependent protein degradation by the FT proteasome; impaired autophagic function; defect in FT maturation of ubiquitin-containing autophagosomes; FT decreased interaction with CAV1 and UBXN6; FT dbSNP:rs121909331)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21822278, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_033022" FT VARIANT 254 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088266" FT VARIANT 369 FT /note="I -> T (in IBMPFD1; uncertain significance; FT dbSNP:rs1828723406)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088267" FT VARIANT 387 FT /note="N -> H (in IBMPFD1; uncertain significance; FT dbSNP:rs1554668420)" FT /evidence="ECO:0000269|PubMed:17935506" FT /id="VAR_078911" FT VARIANT 592 FT /note="D -> N (in FTDALS6; dbSNP:rs387906790)" FT /evidence="ECO:0000269|PubMed:21145000" FT /id="VAR_065911" FT MUTAGEN 52..55 FT /note="FRGD->ARGA: Abolishes interaction with NPLOC4; when FT associated with A-110." FT /evidence="ECO:0000269|PubMed:26471729" FT MUTAGEN 53 FT /note="R->A: Minor effect on affinity for ATP and ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 86 FT /note="R->A: Strongly increased affinity for ATP. Strongly FT reduced affinity for ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 109 FT /note="K->R: Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:38762759" FT MUTAGEN 110 FT /note="Y->A: Abolishes interaction with NPLOC4; when FT associated with 52-A--A-55. Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:26471729, FT ECO:0000269|PubMed:38762759" FT MUTAGEN 113..115 FT /note="RIH->TIT: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 131 FT /note="F->R: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 140 FT /note="L->D: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 179 FT /note="D->R: No effect on binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 183 FT /note="H->W: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 251 FT /note="K->Q: Impairs ERAD degradation of HMGCR and does not FT inhibit interaction with RHBDD1; when associated with Q- FT 524." FT /evidence="ECO:0000269|PubMed:16168377, FT ECO:0000269|PubMed:22795130" FT MUTAGEN 305 FT /note="E->Q: Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-578." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:26471729" FT MUTAGEN 312 FT /note="K->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 313 FT /note="R->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="E->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="Missing: Strongly impairs methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 315 FT /note="K->L,Q,R: Abolishes methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MUTAGEN 316 FT /note="T->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 317 FT /note="H->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 318 FT /note="G->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 524 FT /note="K->A: Impairs catalytic activity of RNF19A toward FT SOD1 mutant. Does not inhibit interaction with RHBDD1; when FT associated with A-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 524 FT /note="K->Q: Impairs ERAD degradation of HMGCR; when FT associated with Q-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 578 FT /note="E->Q: Does not inhibit interaction with RHBDD1. FT Increased interaction with CAV1 and UBXN6. Impaired FT autophagic function. Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-305. FT Increases interaction with ZFAND1 in an arsenite-dependent FT manner." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22795130, FT ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:29804830" FT CONFLICT 169 FT /note="D -> H (in Ref. 7; AAI21795)" FT /evidence="ECO:0000305" FT CONFLICT 312 FT /note="K -> I (in Ref. 4; BAG35235)" FT /evidence="ECO:0000305" FT HELIX 15..17 FT /evidence="ECO:0007829|PDB:7LMY" FT TURN 21..23 FT /evidence="ECO:0007829|PDB:7BPA" FT STRAND 25..29 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 38..41 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 43..48 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 56..60 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 62..64 FT /evidence="ECO:0007829|PDB:3QQ8" FT STRAND 66..73 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 86..92 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 94..97 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 99..104 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 112..119 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 120..123 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 126..128 FT /evidence="ECO:0007829|PDB:5IFS" FT HELIX 130..133 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 135..139 FT /evidence="ECO:0007829|PDB:5B6C" FT TURN 140..142 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 144..147 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 151..154 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:4KDI" FT STRAND 161..176 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 191..193 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 203..205 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 210..225 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 229..232 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 240..244 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4KLN" FT HELIX 251..262 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 278..280 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 281..295 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 298..304 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 306..308 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 313..315 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 319..334 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 335..337 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 338..340 FT /evidence="ECO:0007829|PDB:8HRZ" FT STRAND 341..348 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 350..352 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 355..358 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 360..362 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 365..368 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 374..384 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 385..387 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:5DYG" FT HELIX 392..394 FT /evidence="ECO:0007829|PDB:8PQX" FT HELIX 396..402 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 408..427 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 428..430 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 432..436 FT /evidence="ECO:0007829|PDB:3HU1" FT HELIX 439..444 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 449..456 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 458..461 FT /evidence="ECO:0007829|PDB:4KO8" FT TURN 462..468 FT /evidence="ECO:0007829|PDB:4KO8" FT HELIX 476..478 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 483..498 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 500..505 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 513..519 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 520..523 FT /evidence="ECO:0007829|PDB:8UV2" FT HELIX 524..534 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 538..543 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 544..547 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 550..553 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 557..568 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 571..577 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 579..581 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 584..586 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 588..590 FT /evidence="ECO:0007829|PDB:5FTJ" FT STRAND 592..594 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 597..609 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 617..624 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 626..628 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 631..634 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 635..639 FT /evidence="ECO:0007829|PDB:5FTK" FT STRAND 641..644 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 650..661 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 662..664 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 672..677 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 678..681 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 684..711 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 718..721 FT /evidence="ECO:0007829|PDB:7VCU" FT STRAND 722..724 FT /evidence="ECO:0007829|PDB:5IFW" FT STRAND 729..731 FT /evidence="ECO:0007829|PDB:7LMY" FT HELIX 733..739 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 740..742 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 749..761 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 763..765 FT /evidence="ECO:0007829|PDB:7JY5" FT STRAND 767..770 FT /evidence="ECO:0007829|PDB:7RLI" SQ SEQUENCE 806 AA; 89322 MW; 501B721D3A77BA8A CRC64; MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG AGPSQGSGGG TGGSVYTEDN DDDLYG // ID TM175_HUMAN Reviewed; 504 AA. AC Q9BSA9; D3DVN4; Q8ND13; DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 148. DE RecName: Full=Endosomal/lysosomal proton channel TMEM175 {ECO:0000305}; DE AltName: Full=Potassium channel TMEM175 {ECO:0000305}; DE AltName: Full=Transmembrane protein 175 {ECO:0000303|PubMed:26317472}; DE Short=hTMEM175 {ECO:0000303|PubMed:26317472, ECO:0000303|PubMed:28723891, ECO:0000303|PubMed:32228865}; GN Name=TMEM175 {ECO:0000303|PubMed:26317472, ECO:0000312|HGNC:HGNC:28709}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-6, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [5] RP FUNCTION, TRANSPORTER ACTIVITY, DOMAIN, SUBCELLULAR LOCATION, TOPOLOGY, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF ARG-35; PHE-39; SER-40 AND ASP-41. RX PubMed=26317472; DOI=10.1016/j.cell.2015.08.002; RA Cang C., Aranda K., Seo Y.J., Gasnier B., Ren D.; RT "TMEM175 is an organelle K(+) channel regulating lysosomal function."; RL Cell 162:1101-1112(2015). RN [6] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ILE-46; RP VAL-50; LEU-53; ILE-271; LEU-275 AND LEU-278. RX PubMed=28723891; DOI=10.1038/nature23269; RA Lee C., Guo J., Zeng W., Kim S., She J., Cang C., Ren D., Jiang Y.; RT "The lysosomal potassium channel TMEM175 adopts a novel tetrameric RT architecture."; RL Nature 547:472-475(2017). RN [7] RP POSSIBLE INVOLVEMENT IN PARK. RX PubMed=28193887; DOI=10.1073/pnas.1616332114; RA Jinn S., Drolet R.E., Cramer P.E., Wong A.H., Toolan D.M., Gretzula C.A., RA Voleti B., Vassileva G., Disa J., Tadin-Strapps M., Stone D.J.; RT "TMEM175 deficiency impairs lysosomal and mitochondrial function and RT increases alpha-synuclein aggregation."; RL Proc. Natl. Acad. Sci. U.S.A. 114:2389-2394(2017). RN [8] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANTS PRO-65 AND THR-393, AND RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393. RX PubMed=31658403; DOI=10.1002/ana.25629; RA Krohn L., Oeztuerk T.N., Vanderperre B., Ouled Amar Bencheikh B., RA Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., RA Hu M.T.M., Dauvilliers Y., Hoegl B., Stefani A., Monaca C.C., Plazzi G., RA Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., RA Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., RA Liong C., Gagnon J.F., Desautels A., Hassin-Baer S., Montplaisir J.Y., RA Dupre N., Rouleau G.A., Fon E.A., Trempe J.F., Lamoureux G., Alcalay R.N., RA Gan-Or Z.; RT "Genetic, structural, and functional evidence link TMEM175 to RT synucleinopathies."; RL Ann. Neurol. 87:139-153(2020). RN [9] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANT THR-393, AND RP CHARACTERIZATION OF VARIANT THR-393. RX PubMed=31261387; DOI=10.1093/hmg/ddz136; RA Jinn S., Blauwendraat C., Toolan D., Gretzula C.A., Drolet R.E., Smith S., RA Nalls M.A., Marcus J., Singleton A.B., Stone D.J.; RT "Functionalization of the TMEM175 p.M393T variant as a risk factor for RT Parkinson disease."; RL Hum. Mol. Genet. 28:3244-3254(2019). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF 45-SER--THR-49; THR-49 RP AND THR-274. RX PubMed=32267231; DOI=10.7554/elife.53683; RA Brunner J.D., Jakob R.P., Schulze T., Neldner Y., Moroni A., Thiel G., RA Maier T., Schenck S.; RT "Structural basis for ion selectivity in TMEM175 K+ channels."; RL Elife 9:0-0(2020). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH AKT1, RP IDENTIFICATION IN THE LYSOK(GF) COMPLEX, INVOLVEMENT IN PARK, RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393, AND MUTAGENESIS OF RP SER-241; THR-338 AND MET-393. RX PubMed=33505021; DOI=10.1038/s41586-021-03185-z; RA Wie J., Liu Z., Song H., Tropea T.F., Yang L., Wang H., Liang Y., Cang C., RA Aranda K., Lohmann J., Yang J., Lu B., Chen-Plotkin A.S., Luk K.C., Ren D.; RT "A growth-factor-activated lysosomal K+ channel regulates Parkinson's RT pathology."; RL Nature 591:431-437(2021). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF RP ASP-41 AND SER-45. RX PubMed=35750034; DOI=10.1016/j.cell.2022.05.021; RA Hu M., Li P., Wang C., Feng X., Geng Q., Chen W., Marthi M., Zhang W., RA Gao C., Reid W., Swanson J., Du W., Hume R.I., Xu H.; RT "Parkinson's disease-risk protein TMEM175 is a proton-activated proton RT channel in lysosomes."; RL Cell 185:2292-2308(2022). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF SER-38; SER-45; ILE-46; RP THR-49; ILE-271; THR-274; ASP-279; ASP-283; ARG-309; HIS-327; HIS-328; RP ASN-345; GLN-360 AND HIS-449. RX PubMed=35333573; DOI=10.1126/sciadv.abm1568; RA Zheng W., Shen C., Wang L., Rawson S., Xie W.J., Nist-Lund C., Wu J., RA Shen Z., Xia S., Holt J.R., Wu H., Fu T.M.; RT "pH regulates potassium conductance and drives a constitutive proton RT current in human TMEM175."; RL Sci. Adv. 8:eabm1568-eabm1568(2022). RN [14] {ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS), FUNCTION, TRANSPORTER RP ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF SER-45 RP AND THR-274. RX PubMed=32228865; DOI=10.7554/elife.53430; RA Oh S., Paknejad N., Hite R.K.; RT "Gating and selectivity mechanisms for the lysosomal K+ channel TMEM175."; RL Elife 9:0-0(2020). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.45 ANGSTROMS), FUNCTION, SUBUNIT, AND RP MUTAGENESIS OF ILE-46 AND ILE-271. RX PubMed=35608336; DOI=10.7554/elife.75122; RA Oh S., Marinelli F., Zhou W., Lee J., Choi H.J., Kim M., RA Faraldo-Gomez J.D., Hite R.K.; RT "Differential ion dehydration energetics explains selectivity in the non- RT canonical lysosomal K+ channel TMEM175."; RL Elife 11:0-0(2022). RN [16] {ECO:0007744|PDB:8FY5} RP STRUCTURE BY ELECTRON MICROSCOPY (3.4 ANGSTROMS) IN COMPLEX WITH LAMP1, RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH LAMP1 RP AND LAMP2, AND MUTAGENESIS OF THR-395. RX PubMed=37390818; DOI=10.1016/j.molcel.2023.06.004; RA Zhang J., Zeng W., Han Y., Lee W.R., Liou J., Jiang Y.; RT "Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the RT TMEM175 channel."; RL Mol. Cell 83:2524-2539(2023). CC -!- FUNCTION: Proton-activated proton channel that catalyzes proton efflux CC from endosomes and lysosomes to maintain a steady-state pH CC (PubMed:35333573, PubMed:35750034, PubMed:37390818). Activated at low CC pH (under pH 4.6) by luminal side protons: selectively mediates CC lysosomal proton release from lysosomes, eliciting a proton leak that CC balances V-ATPase activity to maintain pH homeostasis CC (PubMed:35750034). Regulation of lumenal pH stability is required for CC autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). Also CC acts as a potassium channel at higher pH, regulating potassium CC conductance in endosomes and lysosomes (PubMed:26317472, CC PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). CC Constitutes the pore-forming subunit of the lysoK(GF) complex, a CC complex activated by extracellular growth factors (PubMed:33505021). CC The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or CC AKT3), a major target of growth factor receptors: in the complex, CC TMEM175 channel is opened by conformational changes by AKT, leading to CC its activation (PubMed:33505021). The lysoK(GF) complex is required to CC protect neurons against stress-induced damage (PubMed:33505021). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35333573, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}; CC -!- CATALYTIC ACTIVITY: CC Reaction=K(+)(in) = K(+)(out); Xref=Rhea:RHEA:29463, ChEBI:CHEBI:29103; CC Evidence={ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021}; CC -!- ACTIVITY REGULATION: Active at low pH (under pH 4.6): proton channel CC activity is activated by luminal side protons (PubMed:35750034). CC Polyunsaturated fatty acids, such as arachidonic acid, also activate CC the channel activity (PubMed:35750034). Proton channel activity is CC directly inhibited by LAMP1 or LAMP2, facilitating lysosomal CC acidification (PubMed:37390818). Channel activity is activated CC following interaction with AKT (AKT1, AKT2 or AKT3): interaction CC promotes activation from closed to an open state (PubMed:33505021). CC Activation by AKT is independent of AKT serine/threonine-protein kinase CC activity (PubMed:33505021). {ECO:0000269|PubMed:33505021, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- SUBUNIT: Homodimer (PubMed:28723891, PubMed:32228865, PubMed:35608336). CC Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the CC lysoK(GF) complex, which activates the channel (PubMed:33505021). CC Interacts with LAMP1; inhibiting the proton channel activity of TMEM175 CC (PubMed:37390818). Interacts with LAMP2; inhibiting the proton channel CC activity of TMEM175 (PubMed:37390818). {ECO:0000269|PubMed:32228865, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35608336, CC ECO:0000269|PubMed:37390818, ECO:0000305|PubMed:28723891}. CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:26317472, CC ECO:0000269|PubMed:32228865}; Multi-pass membrane protein CC {ECO:0000269|PubMed:32228865}. Lysosome membrane CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:31261387, CC ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:32228865}; Multi-pass CC membrane protein {ECO:0000269|PubMed:32228865}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9BSA9-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BSA9-2; Sequence=VSP_024213; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:26317472}. CC -!- DOMAIN: Composed of two modules of six transmembranes, forming a CC homodimer with a tetrameric architecture (PubMed:28723891, CC PubMed:32228865). The six transmembrane regions of each module are CC tightly packed within each subunit without undergoing domain swapping CC (PubMed:32228865). Forms a central ion-conduction pore lined by the CC side chains of the pore-lining helices (PubMed:32228865). Conserved CC isoleucine residues (Ile-46 in the first module and Ile-271 in the CC second module) in the center of the pore serve as the gate in the CC closed conformation (PubMed:32228865). In the widened channel in the CC open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 CC and Ile-271 in the second module), establish a constriction essential CC for potassium selectivity (PubMed:32228865). CC {ECO:0000269|PubMed:28723891, ECO:0000269|PubMed:32228865}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:28193887, CC ECO:0000269|PubMed:31261387, ECO:0000269|PubMed:31658403, CC ECO:0000269|PubMed:33505021}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC TMEM175 defects result in unstable lysosomal pH, leading to decreased CC lysosomal catalytic activity, decreased glucocerebrosidase activity, CC impaired autophagosome clearance by the lysosome and decreased CC mitochondrial respiration (PubMed:28193887). CC {ECO:0000269|PubMed:28193887}. CC -!- SIMILARITY: Belongs to the TMEM175 family. {ECO:0000305}. CC -!- CAUTION: A publication claims that potassium transport was initially CC measured with a luminal side pH above 7.0, which is non-physiological CC for lysosomal channels (PubMed:35750034). This statement is however CC incorrect as potassium transport was tested at lumenal pH of 5.5, which CC is considered physiological (PubMed:26317472). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:35750034}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL834199; CAD38888.1; -; mRNA. DR EMBL; CH471131; EAW82633.1; -; Genomic_DNA. DR EMBL; CH471131; EAW82638.1; -; Genomic_DNA. DR EMBL; BC005158; AAH05158.1; -; mRNA. DR CCDS; CCDS3341.1; -. [Q9BSA9-1] DR CCDS; CCDS75088.1; -. [Q9BSA9-2] DR RefSeq; NP_001284355.1; NM_001297426.2. [Q9BSA9-2] DR RefSeq; NP_001284356.1; NM_001297427.2. [Q9BSA9-2] DR RefSeq; NP_001284357.1; NM_001297428.2. [Q9BSA9-2] DR RefSeq; NP_115702.1; NM_032326.4. [Q9BSA9-1] DR RefSeq; XP_016864190.1; XM_017008701.2. [Q9BSA9-1] DR RefSeq; XP_054207016.1; XM_054351041.1. [Q9BSA9-1] DR PDB; 6W8N; EM; 3.20 A; A/B=1-504. DR PDB; 6W8O; EM; 3.40 A; A/B=1-504. DR PDB; 6W8P; EM; 3.60 A; A/B=1-504. DR PDB; 6WC9; EM; 2.64 A; A/B=1-504. DR PDB; 6WCA; EM; 3.03 A; A/B=1-504. DR PDB; 6WCB; EM; 3.17 A; A/B=1-504. DR PDB; 6WCC; EM; 3.24 A; A/B=1-504. DR PDB; 7LF6; EM; 3.50 A; A/B=1-504. DR PDB; 7UNL; EM; 2.45 A; A/B=1-504. DR PDB; 7UNM; EM; 2.61 A; A/B=1-504. DR PDB; 8DHM; EM; 2.73 A; A/B=1-504. DR PDB; 8FY5; EM; 3.40 A; A/B=1-504. DR PDB; 8FYF; EM; 3.40 A; A/B=1-504. DR PDB; 8VIC; EM; 3.48 A; A/B=1-504. DR PDB; 8VIE; EM; 3.52 A; A/B=1-504. DR PDBsum; 6W8N; -. DR PDBsum; 6W8O; -. DR PDBsum; 6W8P; -. DR PDBsum; 6WC9; -. DR PDBsum; 6WCA; -. DR PDBsum; 6WCB; -. DR PDBsum; 6WCC; -. DR PDBsum; 7LF6; -. DR PDBsum; 7UNL; -. DR PDBsum; 7UNM; -. DR PDBsum; 8DHM; -. DR PDBsum; 8FY5; -. DR PDBsum; 8FYF; -. DR PDBsum; 8VIC; -. DR PDBsum; 8VIE; -. DR AlphaFoldDB; Q9BSA9; -. DR EMDB; EMD-21575; -. DR EMDB; EMD-21576; -. DR EMDB; EMD-21577; -. DR EMDB; EMD-21603; -. DR EMDB; EMD-21604; -. DR EMDB; EMD-21605; -. DR EMDB; EMD-21606; -. DR EMDB; EMD-23300; -. DR EMDB; EMD-26626; -. DR EMDB; EMD-26627; -. DR EMDB; EMD-27436; -. DR EMDB; EMD-29553; -. DR EMDB; EMD-29572; -. DR EMDB; EMD-43257; -. DR EMDB; EMD-43259; -. DR SMR; Q9BSA9; -. DR BioGRID; 124013; 9. DR FunCoup; Q9BSA9; 1264. DR IntAct; Q9BSA9; 9. DR MINT; Q9BSA9; -. DR STRING; 9606.ENSP00000264771; -. DR TCDB; 1.A.78.1.1; the k+-selective channel in endosomes and lysosomes (kel) family. DR iPTMnet; Q9BSA9; -. DR PhosphoSitePlus; Q9BSA9; -. DR SwissPalm; Q9BSA9; -. DR BioMuta; TMEM175; -. DR DMDM; 74732981; -. DR jPOST; Q9BSA9; -. DR MassIVE; Q9BSA9; -. DR PaxDb; 9606-ENSP00000264771; -. DR PeptideAtlas; Q9BSA9; -. DR ProteomicsDB; 78871; -. [Q9BSA9-1] DR ProteomicsDB; 78872; -. [Q9BSA9-2] DR Antibodypedia; 8167; 61 antibodies from 20 providers. DR DNASU; 84286; -. DR Ensembl; ENST00000264771.9; ENSP00000264771.4; ENSG00000127419.18. [Q9BSA9-1] DR Ensembl; ENST00000515740.5; ENSP00000427039.1; ENSG00000127419.18. [Q9BSA9-2] DR Ensembl; ENST00000622959.3; ENSP00000485461.1; ENSG00000127419.18. [Q9BSA9-2] DR GeneID; 84286; -. DR KEGG; hsa:84286; -. DR MANE-Select; ENST00000264771.9; ENSP00000264771.4; NM_032326.4; NP_115702.1. DR UCSC; uc003gbq.4; human. [Q9BSA9-1] DR AGR; HGNC:28709; -. DR ClinPGx; PA162405946; -. DR CTD; 84286; -. DR DisGeNET; 84286; -. DR GeneCards; TMEM175; -. DR HGNC; HGNC:28709; TMEM175. DR HPA; ENSG00000127419; Low tissue specificity. DR MIM; 168600; phenotype. DR MIM; 616660; gene. DR OpenTargets; ENSG00000127419; -. DR VEuPathDB; HostDB:ENSG00000127419; -. DR eggNOG; ENOG502QR5C; Eukaryota. DR GeneTree; ENSGT00390000015667; -. DR InParanoid; Q9BSA9; -. DR OMA; FFFPVSY; -. DR OrthoDB; 203835at2759; -. DR PAN-GO; Q9BSA9; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9BSA9; -. DR PathwayCommons; Q9BSA9; -. DR SignaLink; Q9BSA9; -. DR Agora; ENSG00000127419; -. DR BioGRID-ORCS; 84286; 16 hits in 1152 CRISPR screens. DR ChiTaRS; TMEM175; human. DR GenomeRNAi; 84286; -. DR Pharos; Q9BSA9; Tbio. DR PRO; PR:Q9BSA9; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q9BSA9; protein. DR Bgee; ENSG00000127419; Expressed in right hemisphere of cerebellum and 157 other cell types or tissues. DR ExpressionAtlas; Q9BSA9; baseline and differential. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0050544; F:arachidonate binding; IDA:UniProtKB. DR GO; GO:0005267; F:potassium channel activity; IDA:UniProtKB. DR GO; GO:0022841; F:potassium ion leak channel activity; IDA:UniProtKB. DR GO; GO:0015252; F:proton channel activity; IDA:UniProtKB. DR GO; GO:0035752; P:lysosomal lumen pH elevation; IDA:UniProtKB. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:UniProtKB. DR GO; GO:0090385; P:phagosome-lysosome fusion; IEA:Ensembl. DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:1902600; P:proton transmembrane transport; IDA:UniProtKB. DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IDA:UniProt. DR InterPro; IPR010617; TMEM175-like. DR PANTHER; PTHR31462; ENDOSOMAL/LYSOSOMAL POTASSIUM CHANNEL TMEM175; 1. DR PANTHER; PTHR31462:SF5; ENDOSOMAL_LYSOSOMAL PROTON CHANNEL TMEM175; 1. DR Pfam; PF06736; TMEM175; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Endosome; Hydrogen ion transport; KW Ion channel; Ion transport; Lysosome; Membrane; Neurodegeneration; KW Parkinson disease; Parkinsonism; Phosphoprotein; Potassium; KW Potassium channel; Potassium transport; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..504 FT /note="Endosomal/lysosomal proton channel TMEM175" FT /id="PRO_0000282588" FT TOPO_DOM 1..33 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT TRANSMEM 34..56 FT /note="Helical; Name=TM1-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 57..77 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 78..100 FT /note="Helical; Name=TM2-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 101..106 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 107..128 FT /note="Helical; Name=TM3-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 129..138 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 139..160 FT /note="Helical; Name=TM4-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 161..184 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 185..205 FT /note="Helical; Name=TM5-1" FT /evidence="ECO:0000255" FT TOPO_DOM 206..210 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 211..230 FT /note="Helical; Name=TM6-1" FT /evidence="ECO:0000255" FT TOPO_DOM 231..257 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 258..282 FT /note="Helical; Name=TM1-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 283..309 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 310..332 FT /note="Helical; Name=TM2-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 333..338 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 339..360 FT /note="Helical; Name=TM3-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 361..375 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 376..396 FT /note="Helical; Name=TM4-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 397..416 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 417..440 FT /note="Helical; Name=TM5-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 441..442 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 443..469 FT /note="Helical; Name=TM6-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 470..504 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT REGION 1..27 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 58..63 FT /note="Short helix H1-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 65..71 FT /note="Short helix H2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 288..296 FT /note="Short helix H1-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 298..304 FT /note="Short helix H2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 483..504 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 35..41 FT /note="RxxxFSD motif 1" FT /evidence="ECO:0000269|PubMed:26317472" FT MOTIF 260..266 FT /note="RxxxFSD motif 2" FT /evidence="ECO:0000305|PubMed:26317472" FT COMPBIAS 493..504 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 46 FT /note="Hydrophobic filter residue 1-1" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 50 FT /note="Hydrophobic filter residue 2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 53 FT /note="Hydrophobic filter residue 3-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 271 FT /note="Hydrophobic filter residue 1-2" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 275 FT /note="Hydrophobic filter residue 2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 278 FT /note="Hydrophobic filter residue 3-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT MOD_RES 6 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT VAR_SEQ 1..116 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_024213" FT VARIANT 65 FT /note="Q -> P (associated with decreased risk for Parkinson FT disease; gain-of-function variant; does not affect FT lysosomal localization; dbSNP:rs34884217)" FT /evidence="ECO:0000269|PubMed:31658403, FT ECO:0000269|PubMed:33505021" FT /id="VAR_053873" FT VARIANT 393 FT /note="M -> T (associated with increased risk for Parkinson FT disease; reduced potassium channel activity; does not FT affect lysosomal localization; dbSNP:rs34311866)" FT /evidence="ECO:0000269|PubMed:31261387, FT ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:33505021" FT /id="VAR_053874" FT MUTAGEN 35 FT /note="R->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 38 FT /note="S->A: Does not affect proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 39 FT /note="F->V: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 40 FT /note="S->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 41 FT /note="D->A: Abolished proton permeability without altering FT potassium permeability." FT /evidence="ECO:0000269|PubMed:35750034" FT MUTAGEN 41 FT /note="D->E,N: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 45..49 FT /note="SIIAT->AIIAA: Decreased selectivity for potassium FT ion; when associated with A-274." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 45 FT /note="S->A: Reduced potassium channel activity without FT altering proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573, FT ECO:0000269|PubMed:35750034" FT MUTAGEN 45 FT /note="S->T: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 46 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 46 FT /note="I->M: Abolished proton and potassium channel FT activity; when associated with M-271." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 46 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-271." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 49 FT /note="T->A: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 49 FT /note="T->V: Abolished potassium channel activity and FT decreased proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 50 FT /note="V->A: Does not affect selectivity; when associated FT with A-275." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 53 FT /note="L->A: Does not affect selectivity; when associated FT with A-278." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 241 FT /note="S->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with A- FT 338." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 271 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 271 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-46." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 271 FT /note="I->W: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->A: Decreased selectivity for potassium ion. FT Abolished proton and potassium channel activity. Decreased FT selectivity for potassium ion; when associated with 45-A-- FT A-49." FT /evidence="ECO:0000269|PubMed:32267231, FT ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 275 FT /note="L->A: Does not affect selectivity; when associated FT with A-50." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 278 FT /note="L->A: Does not affect selectivity; when associated FT with A-53." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 279 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 279 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 309 FT /note="R->A,Q: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 327 FT /note="H->A: Reduced potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 328 FT /note="H->A: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 338 FT /note="T->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with A- FT 241." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 345 FT /note="N->L: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 360 FT /note="Q->L: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 393 FT /note="M->I: Does not affect potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 393 FT /note="M->W: Reduced potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 395 FT /note="T->W: Abolished interaction with LAMP1 and FT subsequent inhibition." FT /evidence="ECO:0000269|PubMed:37390818" FT MUTAGEN 449 FT /note="H->A: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT HELIX 34..48 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 49..52 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 53..56 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 67..101 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 107..120 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 123..132 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:8DHM" FT HELIX 138..163 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 165..167 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 170..172 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 181..204 FT /evidence="ECO:0007829|PDB:6W8N" FT TURN 208..211 FT /evidence="ECO:0007829|PDB:7LF6" FT HELIX 212..223 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:6W8O" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:8FYF" FT HELIX 258..283 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 290..293 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 294..297 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 299..304 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 307..331 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 333..335 FT /evidence="ECO:0007829|PDB:6WC9" FT HELIX 339..352 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 355..361 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 364..367 FT /evidence="ECO:0007829|PDB:7UNM" FT HELIX 369..398 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 401..404 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 416..439 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 441..460 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 462..475 FT /evidence="ECO:0007829|PDB:7UNL" SQ SEQUENCE 504 AA; 55615 MW; 7FEE4C22CA248094 CRC64; MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVTV AWAAHTRLFQ VVGKTDDTLA LLNLACMMTI TFLPYTFSLM VTFPDVPLGI FLFCVCVIAI GVVQALIVGY AFHFPHLLSP QIQRSAHRAL YRRHVLGIVL QGPALCFAAA IFSLFFVPLS YLLMVTVILL PYVSKVTGWC RDRLLGHREP SAHPVEVFSF DLHEPLSKER VEAFSDGVYA IVATLLILDI CEDNVPDPKD VKERFSGSLV AALSATGPRF LAYFGSFATV GLLWFAHHSL FLHVRKATRA MGLLNTLSLA FVGGLPLAYQ QTSAFARQPR DELERVRVSC TIIFLASIFQ LAMWTTALLH QAETLQPSVW FGGREHVLMF AKLALYPCAS LLAFASTCLL SRFSVGIFHL MQIAVPCAFL LLRLLVGLAL ATLRVLRGLA RPEHPPPAPT GQDDPQSQLL PAPC // ID TM230_HUMAN Reviewed; 120 AA. AC Q96A57; B2RDM8; D3DVZ9; Q0VGC8; Q5TDS5; Q96ES2; Q9P0A7; DT 02-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 171. DE RecName: Full=Transmembrane protein 230; GN Name=TMEM230; Synonyms=C20orf30; ORFNames=HSPC274, UNQ2432/PRO4992; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Umbilical cord blood; RA Ye M., Zhang Q.-H., Zhou J., Shen Y., Wu X.-Y., Guan Z.Q., Wang L., RA Fan H.-Y., Mao Y.-F., Dai M., Huang Q.-H., Chen S.-J., Chen Z.; RT "Human partial CDS from CD34+ stem cells."; RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skeletal muscle; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Bone marrow, Brain, Duodenum, Gall bladder, Lung, Ovary, and RC Prostate; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15 AND SER-24, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, POSSIBLE INVOLVEMENT IN PARK, VARIANTS PARK RP CYS-29 AND LEU-78, VARIANT CYS-108, VARIANT THR-64 (ISOFORM 1), AND RP CHARACTERIZATION OF VARIANTS PARK CYS-29 AND LEU-78. RX PubMed=27270108; DOI=10.1038/ng.3589; RA Deng H.X., Shi Y., Yang Y., Ahmeti K.B., Miller N., Huang C., Cheng L., RA Zhai H., Deng S., Nuytemans K., Corbett N.J., Kim M.J., Deng H., Tang B., RA Yang Z., Xu Y., Chan P., Huang B., Gao X.P., Song Z., Liu Z., Fecto F., RA Siddique N., Foroud T., Jankovic J., Ghetti B., Nicholson D.A., Krainc D., RA Melen O., Vance J.M., Pericak-Vance M.A., Ma Y.C., Rajput A.H., RA Siddique T.; RT "Identification of TMEM230 mutations in familial Parkinson's disease."; RL Nat. Genet. 48:733-739(2016). CC -!- FUNCTION: Involved in trafficking and recycling of synaptic vesicles. CC {ECO:0000269|PubMed:27270108}. CC -!- INTERACTION: CC Q96A57-2; O43765: SGTA; NbExp=3; IntAct=EBI-17546822, EBI-347996; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane CC protein {ECO:0000305}. Golgi apparatus, trans-Golgi network CC {ECO:0000269|PubMed:27270108}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle {ECO:0000269|PubMed:27270108}. Early endosome CC {ECO:0000269|PubMed:27270108}. Recycling endosome CC {ECO:0000269|PubMed:27270108}. Late endosome CC {ECO:0000269|PubMed:27270108}. Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:27270108}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=2; CC IsoId=Q96A57-1; Sequence=Displayed; CC Name=1; CC IsoId=Q96A57-2; Sequence=VSP_018155; CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:27270108}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC Genetic variants in TMEM230 and DNAJC13 have been found in the same CC large multigenerational family with adult-onset Parkinson disease. The CC pathological role of each gene and therefore the exact molecular basis CC of the disease is unclear. {ECO:0000305|PubMed:27270108}. CC -!- SIMILARITY: Belongs to the TMEM134/TMEM230 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: [Isoform 1]: CC Sequence=AAF28952.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF161392; AAF28952.1; ALT_FRAME; mRNA. DR EMBL; AY359115; AAQ89473.1; -; mRNA. DR EMBL; AK315606; BAG37975.1; -; mRNA. DR EMBL; AL121890; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL121924; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471133; EAX10431.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10432.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10433.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10434.1; -; Genomic_DNA. DR EMBL; CH471133; EAX10437.1; -; Genomic_DNA. DR EMBL; BC070212; AAH70212.1; -; mRNA. DR EMBL; BC009768; AAH09768.1; -; mRNA. DR EMBL; BC009769; AAH09769.1; -; mRNA. DR EMBL; BC009770; AAH09770.1; -; mRNA. DR EMBL; BC011990; AAH11990.1; -; mRNA. DR EMBL; BC015113; AAH15113.1; -; mRNA. DR EMBL; BC110408; AAI10409.2; -; mRNA. DR CCDS; CCDS13086.1; -. [Q96A57-1] DR RefSeq; NP_001009924.1; NM_001009924.2. [Q96A57-1] DR RefSeq; NP_001009925.1; NM_001009925.2. [Q96A57-1] DR RefSeq; NP_001317913.1; NM_001330984.2. [Q96A57-1] DR RefSeq; NP_001317914.1; NM_001330985.2. [Q96A57-1] DR RefSeq; NP_001317915.1; NM_001330986.2. [Q96A57-1] DR RefSeq; NP_001410909.1; NM_001423980.1. [Q96A57-1] DR RefSeq; NP_054864.3; NM_014145.4. [Q96A57-1] DR AlphaFoldDB; Q96A57; -. DR BioGRID; 118834; 60. DR FunCoup; Q96A57; 1851. DR IntAct; Q96A57; 28. DR MINT; Q96A57; -. DR STRING; 9606.ENSP00000341364; -. DR TCDB; 9.B.232.1.1; the parkinson's disease tmem230 (tmem230) family. DR iPTMnet; Q96A57; -. DR PhosphoSitePlus; Q96A57; -. DR BioMuta; TMEM230; -. DR DMDM; 74751737; -. DR CPTAC; CPTAC-960; -. DR jPOST; Q96A57; -. DR MassIVE; Q96A57; -. DR PaxDb; 9606-ENSP00000341364; -. DR PeptideAtlas; Q96A57; -. DR ProteomicsDB; 75916; -. [Q96A57-1] DR ProteomicsDB; 75917; -. [Q96A57-2] DR Pumba; Q96A57; -. DR TopDownProteomics; Q96A57-1; -. [Q96A57-1] DR TopDownProteomics; Q96A57-2; -. [Q96A57-2] DR Antibodypedia; 2275; 190 antibodies from 23 providers. DR DNASU; 29058; -. DR Ensembl; ENST00000202834.12; ENSP00000202834.7; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000342308.11; ENSP00000341364.6; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379277.7; ENSP00000368579.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379279.6; ENSP00000368581.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379283.6; ENSP00000368585.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379286.6; ENSP00000368588.2; ENSG00000089063.17. [Q96A57-1] DR Ensembl; ENST00000379299.6; ENSP00000368601.2; ENSG00000089063.17. [Q96A57-1] DR GeneID; 29058; -. DR KEGG; hsa:29058; -. DR MANE-Select; ENST00000202834.12; ENSP00000202834.7; NM_001009925.2; NP_001009925.1. DR UCSC; uc002wlk.4; human. [Q96A57-1] DR AGR; HGNC:15876; -. DR ClinPGx; PA25746; -. DR CTD; 29058; -. DR DisGeNET; 29058; -. DR GeneCards; TMEM230; -. DR HGNC; HGNC:15876; TMEM230. DR HPA; ENSG00000089063; Low tissue specificity. DR MalaCards; TMEM230; -. DR MIM; 168600; phenotype. DR MIM; 617019; gene. DR OpenTargets; ENSG00000089063; -. DR VEuPathDB; HostDB:ENSG00000089063; -. DR eggNOG; KOG4753; Eukaryota. DR GeneTree; ENSGT00390000008694; -. DR HOGENOM; CLU_126638_1_0_1; -. DR InParanoid; Q96A57; -. DR OMA; AYYAYYK; -. DR OrthoDB; 5597044at2759; -. DR PAN-GO; Q96A57; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q96A57; -. DR PathwayCommons; Q96A57; -. DR SignaLink; Q96A57; -. DR Agora; ENSG00000089063; -. DR BioGRID-ORCS; 29058; 77 hits in 1128 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; TMEM230; human. DR GenomeRNAi; 29058; -. DR Pharos; Q96A57; Tbio. DR PRO; PR:Q96A57; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; Q96A57; protein. DR Bgee; ENSG00000089063; Expressed in gall bladder and 104 other cell types or tissues. DR ExpressionAtlas; Q96A57; baseline and differential. DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell. DR GO; GO:0030424; C:axon; IEA:GOC. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0012505; C:endomembrane system; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0098930; P:axonal transport; IDA:SynGO. DR GO; GO:0048489; P:synaptic vesicle transport; IMP:UniProtKB. DR InterPro; IPR044234; TMEM230. DR InterPro; IPR008590; TMEM_230/134. DR PANTHER; PTHR15664; C20ORF30 PROTEIN; 1. DR PANTHER; PTHR15664:SF6; TRANSMEMBRANE PROTEIN 230; 1. DR Pfam; PF05915; TMEM_230_134; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasmic vesicle; Disease variant; Endosome; KW Golgi apparatus; Membrane; Neurodegeneration; Parkinson disease; KW Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Synapse; Transmembrane; Transmembrane helix. FT CHAIN 1..120 FT /note="Transmembrane protein 230" FT /id="PRO_0000233892" FT TRANSMEM 46..66 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 79..99 FT /note="Helical" FT /evidence="ECO:0000255" FT MOD_RES 15 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 23 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 1 FT /note="M -> MQPWALPTVGELWVCGRPGAALRWSLVLSPRLEPSGVISAHCNLHLL FT ASSDSSASASRLCQRVM (in isoform 1)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_018155" FT VARIANT 29 FT /note="Y -> C (in PARK; uncertain significance; sporadic FT case; results in decreased synaptic vesicle trafficking; FT dbSNP:rs1056737920)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076713" FT VARIANT 78 FT /note="R -> L (in PARK; uncertain significance; results in FT decreased synaptic vesicle trafficking; dbSNP:rs764786986)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076714" FT VARIANT 108 FT /note="R -> C (in dbSNP:rs143571424)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_076715" FT CONFLICT 59..61 FT /note="LII -> SY (in Ref. 1; AAF28952)" FT /evidence="ECO:0000305" FT CONFLICT 109 FT /note="G -> A (in Ref. 6; AAH11990)" FT /evidence="ECO:0000305" FT VARIANT Q96A57-2:64 FT /note="M -> T (in dbSNP:rs141394228)" FT /evidence="ECO:0000269|PubMed:27270108" FT /id="VAR_082923" SQ SEQUENCE 120 AA; 13188 MW; 18A4A556330D77CE CRC64; MMPSRTNLAT GIPSSKVKYS RLSSTDDGYI DLQFKKTPPK IPYKAIALAT VLFLIGAFLI IIGSLLLSGY ISKGGADRAV PVLIIGILVF LPGFYHLRIA YYASKGYRGY SYDDIPDFDD // ID TRIM9_HUMAN Reviewed; 710 AA. AC Q9C026; D3DSB7; D3DSB8; Q92557; Q96D24; Q96NI4; Q9C025; Q9C027; DT 04-AUG-2003, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 216. DE RecName: Full=E3 ubiquitin-protein ligase TRIM9; DE EC=2.3.2.27 {ECO:0000269|PubMed:20085810}; DE AltName: Full=RING finger protein 91; DE AltName: Full=RING-type E3 ubiquitin transferase TRIM9 {ECO:0000305}; DE AltName: Full=Tripartite motif-containing protein 9; GN Name=TRIM9; Synonyms=KIAA0282, RNF91; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT PHE-653. RX PubMed=11331580; DOI=10.1093/emboj/20.9.2140; RA Reymond A., Meroni G., Fantozzi A., Merla G., Cairo S., Luzi L., RA Riganelli D., Zanaria E., Messali S., Cainarca S., Guffanti A., Minucci S., RA Pelicci P.G., Ballabio A.; RT "The tripartite motif family identifies cell compartments."; RL EMBO J. 20:2140-2151(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PHE-653. RC TISSUE=Brain; RX PubMed=9179496; DOI=10.1093/dnares/4.1.53; RA Ohara O., Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., RA Nomura N.; RT "Construction and characterization of human brain cDNA libraries suitable RT for analysis of cDNA clones encoding relatively large proteins."; RL DNA Res. 4:53-59(1997). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Fetal brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5), AND VARIANT RP PHE-653. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCALIZATION, TISSUE RP SPECIFICITY, AND AUTOUBIQUITINATION. RX PubMed=20085810; DOI=10.1016/j.nbd.2010.01.007; RA Tanji K., Kamitani T., Mori F., Kakita A., Takahashi H., Wakabayashi K.; RT "TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the RT brain of Parkinson's disease and dementia with Lewy bodies."; RL Neurobiol. Dis. 38:210-218(2010). RN [8] RP STRUCTURE BY NMR OF 437-534. RG RIKEN structural genomics initiative (RSGI); RT "Solution structures of the FN3 domain of human tripartite motif protein RT 9."; RL Submitted (JUN-2006) to the PDB data bank. CC -!- FUNCTION: E3 ubiquitin-protein ligase which ubiquitinates itself in CC cooperation with an E2 enzyme UBE2D2/UBC4 and serves as a targeting CC signal for proteasomal degradation. May play a role in regulation of CC neuronal functions and may also participate in the formation or CC breakdown of abnormal inclusions in neurodegenerative disorders. May CC act as a regulator of synaptic vesicle exocytosis by controlling the CC availability of SNAP25 for the SNARE complex formation. CC {ECO:0000269|PubMed:20085810}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:20085810}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:20085810}. CC -!- SUBUNIT: Interacts with SNAP25. {ECO:0000250|UniProtKB:Q91ZY8}. CC -!- INTERACTION: CC Q9C026; Q9Y2T2: AP3M1; NbExp=3; IntAct=EBI-720828, EBI-2371151; CC Q9C026; P05067: APP; NbExp=3; IntAct=EBI-720828, EBI-77613; CC Q9C026; P54253: ATXN1; NbExp=6; IntAct=EBI-720828, EBI-930964; CC Q9C026; B7Z3H4: BTRC; NbExp=3; IntAct=EBI-720828, EBI-16429269; CC Q9C026; Q9Y297: BTRC; NbExp=8; IntAct=EBI-720828, EBI-307461; CC Q9C026; P48730: CSNK1D; NbExp=3; IntAct=EBI-720828, EBI-751621; CC Q9C026; Q2TBE0: CWF19L2; NbExp=6; IntAct=EBI-720828, EBI-5453285; CC Q9C026; Q9UI08: EVL; NbExp=3; IntAct=EBI-720828, EBI-346653; CC Q9C026; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-720828, EBI-6448852; CC Q9C026; Q9H5Z6-2: FAM124B; NbExp=3; IntAct=EBI-720828, EBI-11986315; CC Q9C026; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-720828, EBI-6658203; CC Q9C026; Q969S9: GFM2; NbExp=3; IntAct=EBI-720828, EBI-2371750; CC Q9C026; O60333-2: KIF1B; NbExp=3; IntAct=EBI-720828, EBI-10975473; CC Q9C026; Q969V5: MUL1; NbExp=3; IntAct=EBI-720828, EBI-744120; CC Q9C026; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-720828, EBI-10271199; CC Q9C026; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-720828, EBI-741158; CC Q9C026; Q9NZD8: SPG21; NbExp=6; IntAct=EBI-720828, EBI-742688; CC Q9C026; Q13148: TARDBP; NbExp=6; IntAct=EBI-720828, EBI-372899; CC Q9C026; Q96PN8: TSSK3; NbExp=3; IntAct=EBI-720828, EBI-3918381; CC Q9C026; Q68CQ4: UTP25; NbExp=3; IntAct=EBI-720828, EBI-747711; CC Q9C026; P50552: VASP; NbExp=4; IntAct=EBI-720828, EBI-748201; CC Q9C026; P62258: YWHAE; NbExp=2; IntAct=EBI-720828, EBI-356498; CC Q9C026-5; A0A0S2Z507: BTRC; NbExp=3; IntAct=EBI-16437499, EBI-16429247; CC Q9C026-5; B7Z3H4: BTRC; NbExp=3; IntAct=EBI-16437499, EBI-16429269; CC Q9C026-5; Q9Y297: BTRC; NbExp=4; IntAct=EBI-16437499, EBI-307461; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20085810}. Cell CC projection, dendrite {ECO:0000269|PubMed:20085810}. Cytoplasmic CC vesicle, secretory vesicle, synaptic vesicle CC {ECO:0000250|UniProtKB:Q91ZY8}. Synapse {ECO:0000250|UniProtKB:Q91ZY8}. CC Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q91ZY8}. Note=Enriched CC at synaptic terminals where it exists in a soluble form and a synaptic CC vesicle-associated form. Associated with the cytoskeleton (By CC similarity). Found in proximal dendrites of pyramidal neurons in the CC cerebral cortex and hippocampus, and Purkinje cells in the cerebellum CC (PubMed:20085810). {ECO:0000250|UniProtKB:Q91ZY8, CC ECO:0000269|PubMed:20085810}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Beta; CC IsoId=Q9C026-1; Sequence=Displayed; CC Name=4; CC IsoId=Q9C026-4; Sequence=VSP_007922, VSP_007923, VSP_007924; CC Name=5; CC IsoId=Q9C026-5; Sequence=VSP_007925, VSP_007926; CC -!- TISSUE SPECIFICITY: Brain. Highly expressed in the cerebral cortex (at CC protein level). Severely decreased in the affected brain areas in CC Parkinson disease and dementia with Lewy bodies. CC {ECO:0000269|PubMed:20085810}. CC -!- DOMAIN: The coiled coil domain mediates the interaction with the N- CC terminal t-SNARE domain of SNAP25. {ECO:0000250|UniProtKB:Q91ZY8}. CC -!- PTM: Auto-ubiquitinated. Poly-ubiquitinated in cultured cells, whereas CC it is monoubiquitinated in vitro. {ECO:0000269|PubMed:20085810}. CC -!- MISCELLANEOUS: [Isoform 4]: May be due to a competing donor splice CC site, to exon inclusion and to intron retention. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be due to intron retention. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the TRIM/RBCC family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG53490.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAG53492.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA13398.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA13398.2; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF220036; AAG53490.1; ALT_FRAME; mRNA. DR EMBL; AF220037; AAG53491.1; -; mRNA. DR EMBL; AF220038; AAG53492.1; ALT_FRAME; mRNA. DR EMBL; D87458; BAA13398.2; ALT_SEQ; mRNA. DR EMBL; AK055388; BAB70913.1; -; mRNA. DR EMBL; CH471078; EAW65680.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65681.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65682.1; -; Genomic_DNA. DR EMBL; CH471078; EAW65684.1; -; Genomic_DNA. DR EMBL; BC013414; AAH13414.1; -; mRNA. DR EMBL; BC063872; AAH63872.1; -; mRNA. DR CCDS; CCDS45105.1; -. [Q9C026-5] DR CCDS; CCDS9703.1; -. [Q9C026-1] DR RefSeq; NP_055978.4; NM_015163.5. [Q9C026-1] DR RefSeq; NP_443210.1; NM_052978.5. [Q9C026-5] DR RefSeq; XP_011534691.1; XM_011536389.3. [Q9C026-4] DR RefSeq; XP_054231290.1; XM_054375315.1. [Q9C026-4] DR RefSeq; XP_054231294.1; XM_054375319.1. [Q9C026-1] DR RefSeq; XP_054231300.1; XM_054375325.1. [Q9C026-5] DR PDB; 2DB8; NMR; -; A=439-534. DR PDB; 7B2S; X-ray; 1.50 A; A=535-710. DR PDBsum; 2DB8; -. DR PDBsum; 7B2S; -. DR AlphaFoldDB; Q9C026; -. DR BMRB; Q9C026; -. DR SMR; Q9C026; -. DR BioGRID; 125280; 412. DR FunCoup; Q9C026; 729. DR IntAct; Q9C026; 65. DR MINT; Q9C026; -. DR STRING; 9606.ENSP00000298355; -. DR iPTMnet; Q9C026; -. DR PhosphoSitePlus; Q9C026; -. DR BioMuta; TRIM9; -. DR DMDM; 33516964; -. DR REPRODUCTION-2DPAGE; Q9C026; -. DR jPOST; Q9C026; -. DR MassIVE; Q9C026; -. DR PaxDb; 9606-ENSP00000298355; -. DR PeptideAtlas; Q9C026; -. DR ProteomicsDB; 79943; -. [Q9C026-1] DR ProteomicsDB; 79944; -. [Q9C026-4] DR ProteomicsDB; 79945; -. [Q9C026-5] DR Pumba; Q9C026; -. DR Antibodypedia; 10667; 507 antibodies from 25 providers. DR DNASU; 114088; -. DR Ensembl; ENST00000298355.7; ENSP00000298355.3; ENSG00000100505.15. [Q9C026-1] DR Ensembl; ENST00000338969.9; ENSP00000342970.5; ENSG00000100505.15. [Q9C026-4] DR Ensembl; ENST00000360392.4; ENSP00000353561.4; ENSG00000100505.15. [Q9C026-5] DR GeneID; 114088; -. DR KEGG; hsa:114088; -. DR UCSC; uc001wyx.5; human. [Q9C026-1] DR AGR; HGNC:16288; -. DR ClinPGx; PA38116; -. DR CTD; 114088; -. DR DisGeNET; 114088; -. DR GeneCards; TRIM9; -. DR HGNC; HGNC:16288; TRIM9. DR HPA; ENSG00000100505; Tissue enriched (brain). DR MIM; 606555; gene. DR OpenTargets; ENSG00000100505; -. DR VEuPathDB; HostDB:ENSG00000100505; -. DR eggNOG; KOG4367; Eukaryota. DR GeneTree; ENSGT00940000154071; -. DR HOGENOM; CLU_013137_19_2_1; -. DR InParanoid; Q9C026; -. DR OMA; PDTICTI; -. DR OrthoDB; 295536at2759; -. DR PAN-GO; Q9C026; 1 GO annotation based on evolutionary models. DR PhylomeDB; Q9C026; -. DR PathwayCommons; Q9C026; -. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9C026; -. DR SIGNOR; Q9C026; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000100505; -. DR BioGRID-ORCS; 114088; 32 hits in 1186 CRISPR screens. DR ChiTaRS; TRIM9; human. DR EvolutionaryTrace; Q9C026; -. DR GeneWiki; TRIM9; -. DR GenomeRNAi; 114088; -. DR Pharos; Q9C026; Tbio. DR PRO; PR:Q9C026; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9C026; protein. DR Bgee; ENSG00000100505; Expressed in right hemisphere of cerebellum and 145 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR CDD; cd19843; Bbox1_TRIM9_C-I; 1. DR CDD; cd19826; Bbox2_TRIM9_C-I; 1. DR CDD; cd00063; FN3; 1. DR CDD; cd16755; RING-HC_TRIM9; 1. DR CDD; cd12889; SPRY_PRY_TRIM67_9; 1. DR FunFam; 2.60.120.920:FF:000009; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 2.60.40.10:FF:000178; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 3.30.40.10:FF:000168; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 4.10.830.40:FF:000001; E3 ubiquitin-protein ligase TRIM9 isoform X1; 1. DR FunFam; 3.30.160.60:FF:000329; E3 ubiquitin-protein ligase TRIM9 isoform X2; 1. DR FunFam; 1.20.5.170:FF:000017; Putative E3 ubiquitin-protein ligase TRIM9; 1. DR Gene3D; 1.20.5.170; -; 1. DR Gene3D; 2.60.120.920; -; 1. DR Gene3D; 4.10.830.40; -; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR001870; B30.2/SPRY. DR InterPro; IPR043136; B30.2/SPRY_sf. DR InterPro; IPR003649; Bbox_C. DR InterPro; IPR013320; ConA-like_dom_sf. DR InterPro; IPR017903; COS_domain. DR InterPro; IPR050617; E3_ligase_FN3/SPRY. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR003877; SPRY_dom. DR InterPro; IPR049582; TRIM9_Bbox1. DR InterPro; IPR000315; Znf_B-box. DR InterPro; IPR018957; Znf_C3HC4_RING-type. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR PANTHER; PTHR24099; E3 UBIQUITIN-PROTEIN LIGASE TRIM36-RELATED; 1. DR PANTHER; PTHR24099:SF13; E3 UBIQUITIN-PROTEIN LIGASE TRIM9; 1. DR Pfam; PF22586; ANCHR-like_BBOX; 1. DR Pfam; PF00041; fn3; 1. DR Pfam; PF00622; SPRY; 1. DR Pfam; PF00643; zf-B_box; 1. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00502; BBC; 1. DR SMART; SM00336; BBOX; 2. DR SMART; SM00060; FN3; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00449; SPRY; 1. DR SUPFAM; SSF57845; B-box zinc-binding domain; 1. DR SUPFAM; SSF49899; Concanavalin A-like lectins/glucanases; 1. DR SUPFAM; SSF49265; Fibronectin type III; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR PROSITE; PS50188; B302_SPRY; 1. DR PROSITE; PS51262; COS; 1. DR PROSITE; PS50853; FN3; 1. DR PROSITE; PS50119; ZF_BBOX; 2. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell projection; Coiled coil; KW Cytoplasm; Cytoplasmic vesicle; Cytoskeleton; Metal-binding; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW Synapse; Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; KW Zinc-finger. FT CHAIN 1..710 FT /note="E3 ubiquitin-protein ligase TRIM9" FT /id="PRO_0000056208" FT DOMAIN 374..432 FT /note="COS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00586" FT DOMAIN 440..535 FT /note="Fibronectin type-III" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 533..702 FT /note="B30.2/SPRY" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00548" FT ZN_FING 10..50 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT ZN_FING 163..212 FT /note="B box-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT ZN_FING 224..266 FT /note="B box-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT COILED 273..340 FT /evidence="ECO:0000255" FT BINDING 168 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 171 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 193 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 198 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 229 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 232 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 252 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT BINDING 258 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024" FT MOD_RES 41 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 44 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 46 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT MOD_RES 49 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8C7M3" FT VAR_SEQ 436..439 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007922" FT VAR_SEQ 534 FT /note="E -> EDTDSEEQTLPFPVPSERLPLRRMSPFSSTLNLQPSFPGRSYFDFRS FT SPHQLSLHSSLQSLNAPGCNFETQSAPYSQLVDIKKLLA (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007923" FT VAR_SEQ 535..550 FT /note="VAWFAFDPGSAHSDII -> GKALQQYPSERELRGI (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_007925" FT VAR_SEQ 551..710 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_007926" FT VAR_SEQ 692..710 FT /note="TLHTGLPVPDFYSSRASIA -> STLPLRLNSCCWLPVQRLPRAVQSNRREG FT S (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_007924" FT VARIANT 653 FT /note="L -> F (in dbSNP:rs2275462)" FT /evidence="ECO:0000269|PubMed:11331580, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9179496" FT /id="VAR_016202" FT CONFLICT 314 FT /note="A -> V (in Ref. 2; BAB70913)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="Q -> R (in Ref. 2; BAB70913)" FT /evidence="ECO:0000305" FT STRAND 454..460 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 473..479 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 482..485 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 488..494 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 498..501 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 505..507 FT /evidence="ECO:0007829|PDB:2DB8" FT STRAND 510..516 FT /evidence="ECO:0007829|PDB:2DB8" FT HELIX 542..544 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 549..552 FT /evidence="ECO:0007829|PDB:7B2S" FT TURN 553..556 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 557..564 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 566..571 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 576..588 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 595..599 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 605..607 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 615..620 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 622..629 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 632..638 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 646..652 FT /evidence="ECO:0007829|PDB:7B2S" FT TURN 653..656 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 657..662 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 679..685 FT /evidence="ECO:0007829|PDB:7B2S" FT STRAND 689..694 FT /evidence="ECO:0007829|PDB:7B2S" SQ SEQUENCE 710 AA; 79177 MW; AEAB24807C89D0E2 CRC64; MEEMEEELKC PVCGSFYREP IILPCSHNLC QACARNILVQ TPESESPQSH RAAGSGVSDY DYLDLDKMSL YSEADSGYGS YGGFASAPTT PCQKSPNGVR VFPPAMPPPA THLSPALAPV PRNSCITCPQ CHRSLILDDR GLRGFPKNRV LEGVIDRYQQ SKAAALKCQL CEKAPKEATV MCEQCDVFYC DPCRLRCHPP RGPLAKHRLV PPAQGRVSRR LSPRKVSTCT DHELENHSMY CVQCKMPVCY QCLEEGKHSS HEVKALGAMW KLHKSQLSQA LNGLSDRAKE AKEFLVQLRN MVQQIQENSV EFEACLVAQC DALIDALNRR KAQLLARVNK EHEHKLKVVR DQISHCTVKL RQTTGLMEYC LEVIKENDPS GFLQISDALI RRVHLTEDQW GKGTLTPRMT TDFDLSLDNS PLLQSIHQLD FVQVKASSPV PATPILQLEE CCTHNNSATL SWKQPPLSTV PADGYILELD DGNGGQFREV YVGKETMCTV DGLHFNSTYN ARVKAFNKTG VSPYSKTLVL QTSEVAWFAF DPGSAHSDII LSNDNLTVTC SSYDDRVVLG KTGFSKGIHY WELTVDRYDN HPDPAFGVAR MDVMKDVMLG KDDKAWAMYV DNNRSWFMHN NSHTNRTEGG ITKGATIGVL LDLNRKNLTF FINDEQQGPI AFDNVEGLFF PAVSLNRNVQ VTLHTGLPVP DFYSSRASIA // ID UCHL1_HUMAN Reviewed; 223 AA. AC P09936; Q4W5K6; Q71UM0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 2. DT 28-JAN-2026, entry version 248. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1; DE Short=UCH-L1; DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; DE AltName: Full=Neuron cytoplasmic protein 9.5; DE AltName: Full=PGP 9.5; DE Short=PGP9.5; DE AltName: Full=Ubiquitin thioesterase L1; DE Flags: Precursor; GN Name=UCHL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15. RX PubMed=2163617; DOI=10.1042/bj2680521; RA Day I.N.M., Hinks L.J., Thompson R.J.; RT "The structure of the human gene encoding protein gene product 9.5 RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase."; RL Biochem. J. 268:521-524(1990). RN [5] RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=14722078; DOI=10.1074/jbc.m314124200; RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., RA Li L.; RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's RT diseases."; RL J. Biol. Chem. 279:13256-13264(2004). RN [6] RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3; RA Day I.N.M., Thompson R.J.; RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel RT cytoplasmic marker for neurones and neuroendocrine cells."; RL FEBS Lett. 210:157-160(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION RP OF VARIANT PARK5 MET-93. RX PubMed=9774100; DOI=10.1038/26652; RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.; RT "The ubiquitin pathway in Parkinson's disease."; RL Nature 395:451-452(1998). RN [9] RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151. RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r; RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.; RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in RT their SV40 transformed counterparts."; RL FEBS Lett. 280:235-240(1991). RN [10] RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151. RX PubMed=1286667; DOI=10.1002/elps.11501301199; RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., RA Vandekerckhove J.; RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein RT database of normal human epidermal keratinocytes."; RL Electrophoresis 13:960-969(1992). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8639624; DOI=10.1021/bi960099f; RA Larsen C.N., Price J.S., Wilkinson K.D.; RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: RT identification of two active site residues."; RL Biochemistry 35:6735-6744(1996). RN [12] RP TISSUE SPECIFICITY. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND RP CHARACTERIZATION OF VARIANT TYR-18. RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7; RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.; RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect RT alpha-synuclein degradation and Parkinson's disease susceptibility."; RL Cell 111:209-218(2002). RN [14] RP INTERACTION WITH COPS5. RX PubMed=12082530; DOI=10.1038/sj.onc.1205390; RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., RA Yochem R., Ratovitski E., Sidransky D., Jen J.; RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)."; RL Oncogene 21:3003-3010(2002). RN [15] RP CATALYTIC ACTIVITY, AND ACTIVE SITE. RX PubMed=16475834; DOI=10.1021/bi052135t; RA Case A., Stein R.L.; RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1."; RL Biochemistry 45:2443-2452(2006). RN [16] RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220. RX PubMed=19261853; DOI=10.1073/pnas.0806474106; RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R., RA Liu Y., Logan T., Lansbury P.T. Jr.; RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein RT neurotoxicity and is a therapeutic target for Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP FUNCTION. RX PubMed=22212137; DOI=10.1111/j.1471-4159.2011.07644.x; RA Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.; RT "Control of BACE1 degradation and APP processing by ubiquitin carboxyl- RT terminal hydrolase L1."; RL J. Neurochem. 120:1129-1138(2012). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93, RP CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90. RX PubMed=23359680; DOI=10.1073/pnas.1222732110; RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M., RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C., RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A., RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.; RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads RT to early-onset progressive neurodegeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT RP MET-1 (ISOFORMS 1; 2 AND 3). RX PubMed=37316325; DOI=10.26508/lsa.202301972; RA Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M., RA Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.; RT "N-terminal proteoforms may engage in different protein complexes."; RL Life. Sci Alliance 6:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT. RX PubMed=16537382; DOI=10.1073/pnas.0510403103; RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S., RA Lansbury P.T., Ringe D., Petsko G.A.; RT "Structural basis for conformational plasticity of the Parkinson's disease- RT associated ubiquitin hydrolase UCH-L1."; RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF RP CYS-90 AND PHE-204. RX PubMed=20439756; DOI=10.1073/pnas.0910870107; RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.; RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of RT the ubiquitin hydrolase UCHL1 into productive conformation."; RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010). RN [25] RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2; RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.; RT "Alterations of structure and hydrolase activity of parkinsonism-associated RT human ubiquitin carboxyl-terminal hydrolase L1 variants."; RL Biochem. Biophys. Res. Commun. 304:176-183(2003). RN [26] RP VARIANT MET-93. RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6; RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.; RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene RT is not observed in European cases with familial Parkinson's disease."; RL Neurosci. Lett. 270:1-4(1999). RN [27] RP VARIANT TYR-18. RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040; RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., RA Lynch T., Hardy J., Farrer M.; RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal RT hydrolase gene in familial Parkinson's disease."; RL NeuroReport 10:427-429(1999). RN [28] RP VARIANT TYR-18. RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x; RA Mellick G.D., Silburn P.A.; RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does RT not confer protection against idiopathic Parkinson's disease."; RL Neurosci. Lett. 293:127-130(2000). RN [29] RP VARIANT TYR-18. RX PubMed=15048890; DOI=10.1002/ana.20017; RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RT "UCHL1 is a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 55:512-521(2004). RN [30] RP ERRATUM OF PUBMED:15048890. RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RL Ann. Neurol. 55:899-899(2004). RN [31] RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON RP DISEASE. RX PubMed=16450370; DOI=10.1002/ana.20757; RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T., RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P., RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.; RT "UCHL-1 is not a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 59:627-633(2006). RN [32] RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL RP CELLS. RX PubMed=18411255; DOI=10.1093/hmg/ddn115; RA Kyratzi E., Pavlaki M., Stefanis L.; RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to RT neuronal cells."; RL Hum. Mol. Genet. 17:2160-2171(2008). RN [33] RP VARIANT TYR-18. RX PubMed=21268678; DOI=10.3109/13816810.2010.544360; RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N., RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.; RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in RT patients with cataracts."; RL Ophthalmic Genet. 32:75-79(2011). RN [34] RP VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS RP SPG79B GLN-178 AND ASP-216. RX PubMed=28007905; DOI=10.1093/hmg/ddw391; RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y., RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M., RA Tallaksen C.M., Selmer K.K.; RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing."; RL Hum. Mol. Genet. 26:1031-1040(2017). RN [35] RP VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS; RP 178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A. RX PubMed=35986737; DOI=10.1016/j.gim.2022.07.006; RG Genomics England Research Consortium; RA Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J., RA Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L., RA Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A., RA Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y., RA Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N., RA Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K., RA Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B., RA Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O., RA Schoels L., Houlden H., Haack T.B., Hengel H.; RT "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative RT disorder with spasticity, ataxia, neuropathy, and optic atrophy."; RL Genet. Med. 24:2079-2090(2022). CC -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several CC processes such as maintenance of synaptic function, cardiac function, CC inflammatory response or osteoclastogenesis (PubMed:22212137, CC PubMed:23359680). Abrogates the ubiquitination of multiple proteins CC including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor CC protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In CC addition, recognizes and hydrolyzes a peptide bond at the C-terminal CC glycine of ubiquitin to maintain a stable pool of monoubiquitin that is CC a key requirement for the ubiquitin-proteasome and the autophagy- CC lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100). CC Regulates amyloid precursor protein/APP processing by promoting BACE1 CC degradation resulting in decreased amyloid beta production CC (PubMed:22212137). Plays a role in the immune response by regulating CC the ability of MHC I molecules to reach cross-presentation compartments CC competent for generating Ag-MHC I complexes (By similarity). Mediates CC the 'Lys-48'-linked deubiquitination of the transcriptional coactivator CC WWTR1/TAZ leading to its stabilization and inhibition of CC osteoclastogenesis (By similarity). Deubiquitinates and stabilizes CC epidermal growth factor receptor EGFR to prevent its degradation and to CC activate its downstream mediators (By similarity). Modulates oxidative CC activity in skeletal muscle by regulating key mitochondrial oxidative CC proteins (By similarity). Enhances the activity of hypoxia-inducible CC factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated CC ubiquitination and consequently inhibiting its degradation CC (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9, CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137, CC ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865, CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity). CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530, CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}. CC -!- INTERACTION: CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439; CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613; CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467; CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449; CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767; CC P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414; CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823; CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444; CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129; CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644; CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567; CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590; CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661; CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353; CC P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343; CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952; CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852; CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242; CC P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369; CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304; CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629; CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415; CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377; CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779; CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407; CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247; CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082; CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354; CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063; CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642; CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555; CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984; CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535; CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109; CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083; CC P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276; CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290; CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370; CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829; CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850; CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242; CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid- CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is CC associated with membranes in brain. Localizes near and/or within CC mitochondria to potentially interact with mitochondrial proteins. CC {ECO:0000250|UniProtKB:Q9R0P9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; CC IsoId=P09936-1; Sequence=Displayed; CC Name=2; CC IsoId=P09936-2; Sequence=VSP_062524; CC Name=3; CC IsoId=P09936-3; Sequence=VSP_062523; CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes CC throughout the neocortex (at protein level). Expressed in neurons and CC cells of the diffuse neuroendocrine system and their tumors. Weakly CC expressed in ovary. Down-regulated in brains from Parkinson disease and CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078, CC ECO:0000269|PubMed:9790970}. CC -!- PTM: O-glycosylated. {ECO:0000250}. CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex CC neurodegenerative disorder with manifestations ranging from typical CC Parkinson disease to dementia with Lewy bodies. Clinical features CC include parkinsonian symptoms (resting tremor, rigidity, postural CC instability and bradykinesia), dementia, diffuse Lewy body pathology, CC autonomic dysfunction, hallucinations and paranoia. CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia CC (SPG79A) [MIM:620221]: A form of spastic paraplegia, a CC neurodegenerative disorder characterized by a slow, gradual, CC progressive weakness and spasticity of the lower limbs. Rate of CC progression and the severity of symptoms are quite variable. Initial CC symptoms may include difficulty with balance, weakness and stiffness in CC the legs, muscle spasms, and dragging the toes when walking. In some CC forms of the disorder, bladder symptoms (such as incontinence) may CC appear, or the weakness and stiffness may spread to other parts of the CC body. SPG79A is a slowly progressive form characterized by late-onset CC spastic ataxia, neuropathy, and often optic atrophy. CC {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG79B is CC characterized by childhood onset blindness, cerebellar ataxia, CC nystagmus, dorsal column dysfunction, and spasticity with upper motor CC neuron dysfunction. {ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic CC acid have been observed in brains from Alzheimer disease (AD) and CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be CC associated with neurofibrillary tangles. In contrast to UCHL3, does not CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8. CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}. CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met CC with Parkinson disease. However, according to PubMed:16450370 this CC association is uncertain and UCHL1 is not a susceptibility gene for CC Parkinson disease. {ECO:0000305}. CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 CC and Cys-220 are subject of controversy and could be the artifactual CC results of sample handling. {ECO:0000305|PubMed:14722078}. CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase CC activity (PubMed:12408865). However, in another study, UCHL1 was shown CC to lack ubiquitin ligase activity (PubMed:23359680). CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase CC L1 entry; CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AC095043; AAY40923.1; -; Genomic_DNA. DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA. DR EMBL; BC000332; AAH00332.1; -; mRNA. DR EMBL; BC005117; AAH05117.1; -; mRNA. DR EMBL; BC006305; AAH06305.1; -; mRNA. DR EMBL; X17377; CAA35249.1; -; Genomic_DNA. DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA. DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA. DR CCDS; CCDS3462.1; -. [P09936-1] DR PIR; A25856; A25856. DR RefSeq; NP_004172.2; NM_004181.4. [P09936-1] DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223. DR PDB; 2LEN; NMR; -; A=1-223. DR PDB; 3IFW; X-ray; 2.40 A; A=1-223. DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223. DR PDB; 3KVF; X-ray; 2.80 A; A=1-223. DR PDB; 3KW5; X-ray; 2.83 A; A=1-223. DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223. DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223. DR PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8DY8; X-ray; 2.10 A; A/B=1-223. DR PDB; 8EDE; X-ray; 1.80 A; A/B=1-223. DR PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8XI7; X-ray; 1.95 A; A/B=1-223. DR PDB; 9O4M; X-ray; 2.00 A; A/B=1-223. DR PDBsum; 2ETL; -. DR PDBsum; 2LEN; -. DR PDBsum; 3IFW; -. DR PDBsum; 3IRT; -. DR PDBsum; 3KVF; -. DR PDBsum; 3KW5; -. DR PDBsum; 4DM9; -. DR PDBsum; 4JKJ; -. DR PDBsum; 7ZM0; -. DR PDBsum; 8DY8; -. DR PDBsum; 8EDE; -. DR PDBsum; 8PW1; -. DR PDBsum; 8XI7; -. DR PDBsum; 9O4M; -. DR AlphaFoldDB; P09936; -. DR BMRB; P09936; -. DR SASBDB; P09936; -. DR SMR; P09936; -. DR BioGRID; 113192; 258. DR CORUM; P09936; -. DR DIP; DIP-36620N; -. DR FunCoup; P09936; 1475. DR IntAct; P09936; 199. DR MINT; P09936; -. DR STRING; 9606.ENSP00000284440; -. DR BindingDB; P09936; -. DR ChEMBL; CHEMBL6159; -. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR GuidetoPHARMACOLOGY; 2426; -. DR MEROPS; C12.001; -. DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09936; -. DR MetOSite; P09936; -. DR PhosphoSitePlus; P09936; -. DR SwissPalm; P09936; -. DR BioMuta; UCHL1; -. DR DMDM; 136681; -. DR CPTAC; CPTAC-601; -. DR CPTAC; CPTAC-602; -. DR jPOST; P09936; -. DR MassIVE; P09936; -. DR PaxDb; 9606-ENSP00000284440; -. DR PeptideAtlas; P09936; -. DR ProteomicsDB; 52282; -. DR Pumba; P09936; -. DR Antibodypedia; 1062; 2368 antibodies from 53 providers. DR DNASU; 7345; -. DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1] DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1] DR GeneID; 7345; -. DR KEGG; hsa:7345; -. DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2. DR AGR; HGNC:12513; -. DR ClinPGx; PA37160; -. DR CTD; 7345; -. DR DisGeNET; 7345; -. DR GeneCards; UCHL1; -. DR HGNC; HGNC:12513; UCHL1. DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland). DR MalaCards; UCHL1; -. DR MIM; 191342; gene. DR MIM; 613643; phenotype. DR MIM; 615491; phenotype. DR MIM; 620221; phenotype. DR OpenTargets; ENSG00000154277; -. DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000154277; -. DR eggNOG; KOG1415; Eukaryota. DR GeneTree; ENSGT00940000157306; -. DR HOGENOM; CLU_054406_2_0_1; -. DR InParanoid; P09936; -. DR OMA; AQTYSKH; -. DR OrthoDB; 427186at2759; -. DR PAN-GO; P09936; 3 GO annotations based on evolutionary models. DR PhylomeDB; P09936; -. DR BRENDA; 3.4.19.12; 2681. DR PathwayCommons; P09936; -. DR Reactome; R-HSA-5689603; UCH proteinases. DR SABIO-RK; P09936; -. DR SignaLink; P09936; -. DR SIGNOR; P09936; -. DR Agora; ENSG00000154277; -. DR BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UCHL1; human. DR EvolutionaryTrace; P09936; -. DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -. DR GenomeRNAi; 7345; -. DR Pharos; P09936; Tchem. DR PRO; PR:P09936; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P09936; protein. DR Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues. DR ExpressionAtlas; P09936; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB. DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl. DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IBA:GO_Central. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1. DR FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1. DR Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001578; Peptidase_C12_UCH. DR InterPro; IPR036959; Peptidase_C12_UCH_sf. DR InterPro; IPR057254; UCH_AS. DR PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1. DR Pfam; PF01088; Peptidase_C12; 1. DR PRINTS; PR00707; UBCTHYDRLASE. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00140; UCH_1; 1. DR PROSITE; PS52048; UCH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Cytoplasm; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; KW Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; KW Phosphoprotein; Prenylation; Protease; Proteomics identification; KW Reference proteome; Thiol protease; Ubl conjugation pathway. FT CHAIN 1..220 FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1" FT /id="PRO_0000211055" FT PROPEP 221..223 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000414311" FT DOMAIN 2..221 FT /note="UCH catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT REGION 5..10 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT REGION 211..216 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT ACT_SITE 90 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT ACT_SITE 161 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT SITE 1 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 6 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 12 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 84 FT /note="Transition state stabilizer" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:8639624" FT SITE 124 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 176 FT /note="Important for enzyme activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT SITE 179 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 220 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES 125 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00981" FT LIPID 220 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:19261853" FT VAR_SEQ 1..11 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062523" FT VAR_SEQ 1..5 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062524" FT VARIANT 2..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087898" FT VARIANT 7 FT /note="E -> A (in SPG79B; has decreased binding to FT ubiquitin and significantly decreased hydrolase activity FT compared to wild-type; dbSNP:rs397515634)" FT /evidence="ECO:0000269|PubMed:23359680" FT /id="VAR_070875" FT VARIANT 18 FT /note="S -> Y (it confers protection from oxidative stress FT when expressed at physiological levels in neuroblastoma FT cells and primary cortical neurons; loss of dimerization FT ability; impaired ligase activity; dbSNP:rs5030732)" FT /evidence="ECO:0000269|PubMed:10203348, FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865, FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890, FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255, FT ECO:0000269|PubMed:21268678" FT /id="VAR_015677" FT VARIANT 25..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087899" FT VARIANT 52 FT /note="L -> LL (in SPG79A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087900" FT VARIANT 93 FT /note="I -> M (in PARK5; impaired enzymatic hydrolase FT activity; has about a 50% reduction in catalytic activity FT compared to wild-type protein; dbSNP:rs121917767)" FT /evidence="ECO:0000269|PubMed:10454131, FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100" FT /id="VAR_015678" FT VARIANT 178..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087901" FT VARIANT 178 FT /note="R -> Q (in SPG79B; increased hydrolase activity; FT decreased protein abundance; dbSNP:rs768996179)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078119" FT VARIANT 211..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087902" FT VARIANT 216 FT /note="A -> D (in SPG79B; decreased protein abundance; FT dbSNP:rs1057519600)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078120" FT MUTAGEN 73 FT /note="Q->R: No effect on enzymatic parameters." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 90 FT /note="C->S: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, FT ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624" FT MUTAGEN 97 FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin FT ethyl ester, slight reduction in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->D: 10000-fold decrease in enzymatic activity; no FT change in affinity for ubiquitin ethyl ester." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->K,Q,N,Y: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 176 FT /note="D->N: 6-fold decrease in affinity for ubiquitin FT ethyl ester; 97.5% decrease in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 204 FT /note="F->A: Almost complete loss of activity." FT /evidence="ECO:0000269|PubMed:20439756" FT HELIX 10..19 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 22..25 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 27..31 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 36..41 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 46..54 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 57..70 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 71..74 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:2LEN" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 101..105 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 113..120 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 121..123 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 126..135 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 137..147 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 160..168 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 183..187 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 193..207 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2LEN" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:8EDE" FT MOD_RES P09936-2:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES P09936-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" SQ SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64; MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA // ID VP13C_HUMAN Reviewed; 3753 AA. AC Q709C8; Q6ISR4; Q702P2; Q702P3; Q709C9; Q9NXN8; Q9P2C6; DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 158. DE RecName: Full=Intermembrane lipid transfer protein VPS13C {ECO:0000303|PubMed:30093493}; DE AltName: Full=Vacuolar protein sorting-associated protein 13C {ECO:0000305}; GN Name=VPS13C {ECO:0000312|EMBL:AAH69387.1}; GN Synonyms=KIAA1421 {ECO:0000312|EMBL:BAA92659.1}; 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] {ECO:0000305, ECO:0000312|EMBL:CAE75583.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), AND TISSUE RP SPECIFICITY. RC TISSUE=Lymphoblast {ECO:0000269|PubMed:15498460}; RX PubMed=15498460; DOI=10.1016/j.ygeno.2004.04.012; RA Velayos-Baeza A., Vettori A., Copley R.R., Dobson-Stone C., Monaco A.P.; RT "Analysis of the human VPS13 gene family."; RL Genomics 84:536-549(2004). RN [2] {ECO:0000305, ECO:0000312|EMBL:BAA92659.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1439 (ISOFORMS 1/2), AND RP VARIANT LYS-974. RC TISSUE=Brain {ECO:0000312|EMBL:BAA92659.1}; RX PubMed=10718198; DOI=10.1093/dnares/7.1.65; RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XVI. The RT complete sequences of 150 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 7:65-73(2000). RN [3] {ECO:0000305, ECO:0000312|EMBL:BAA90972.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3305-3753 (ISOFORMS 1/3). RC TISSUE=Colon {ECO:0000312|EMBL:BAA90972.1}; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] {ECO:0000305, ECO:0000312|EMBL:AAH69387.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3305-3753 (ISOFORMS 1/3). 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 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 [6] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-614; SER-619; THR-624 AND RP SER-737, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [7] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-3538, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [8] 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 [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-737; SER-842 AND SER-3641, RP AND IDENTIFICATION BY 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 [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2473, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [12] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-3526, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN PARK23, AND VARIANT PARK23 RP ARG-1389. RX PubMed=26942284; DOI=10.1016/j.ajhg.2016.01.014; RG French Parkinson's Disease Genetics Study (PDG); RG International Parkinson's Disease Genomics Consortium (IPDGC); RG International Parkinson's Disease Genomics Consortium IPDGC; RA Lesage S., Drouet V., Majounie E., Deramecourt V., Jacoupy M., Nicolas A., RA Cormier-Dequaire F., Hassoun S.M., Pujol C., Ciura S., Erpapazoglou Z., RA Usenko T., Maurage C.A., Sahbatou M., Liebau S., Ding J., Bilgic B., RA Emre M., Erginel-Unaltuna N., Guven G., Tison F., Tranchant C., RA Vidailhet M., Corvol J.C., Krack P., Leutenegger A.L., Nalls M.A., RA Hernandez D.G., Heutink P., Gibbs J.R., Hardy J., Wood N.W., Gasser T., RA Durr A., Deleuze J.F., Tazir M., Destee A., Lohmann E., Kabashi E., RA Singleton A., Corti O., Brice A.; RT "Loss of mitochondrial morphology, transmembrane potential, and respiration RT function in autosomal-recessive parkinsonism causes mitochondrial RT dysfunction and increases PINK1/Parkin-dependent mitophagy."; RL Am. J. Hum. Genet. 98:500-513(2016). RN [14] RP VARIANT PHE-2872. RX PubMed=25787250; DOI=10.1073/pnas.1503696112; RA Cromer M.K., Choi M., Nelson-Williams C., Fonseca A.L., Kunstman J.W., RA Korah R.M., Overton J.D., Mane S., Kenney B., Malchoff C.D., Stalberg P., RA Akerstroem G., Westin G., Hellman P., Carling T., Bjoerklund P., RA Lifton R.P.; RT "Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in RT insulin-producing adenomas."; RL Proc. Natl. Acad. Sci. U.S.A. 112:4062-4067(2015). RN [15] RP SUBCELLULAR LOCATION, DOMAIN FFAT MOTIF, AND MUTAGENESIS OF RP 878-TYR-PHE-879. RX PubMed=30093493; DOI=10.1083/jcb.201807019; RA Kumar N., Leonzino M., Hancock-Cerutti W., Horenkamp F.A., Li P., RA Lees J.A., Wheeler H., Reinisch K.M., De Camilli P.; RT "VPS13A and VPS13C are lipid transport proteins differentially localized at RT ER contact sites."; RL J. Cell Biol. 217:3625-3639(2018). CC -!- FUNCTION: Mediates the transfer of lipids between membranes at CC organelle contact sites (By similarity). Necessary for proper CC mitochondrial function and maintenance of mitochondrial transmembrane CC potential (PubMed:26942284). Involved in the regulation of PINK1/PRKN- CC mediated mitophagy in response to mitochondrial depolarization CC (PubMed:26942284). {ECO:0000250|UniProtKB:Q07878, CC ECO:0000269|PubMed:26942284}. CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000269|PubMed:26942284}. Lipid droplet CC {ECO:0000269|PubMed:30093493}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:30093493}. Lysosome membrane CC {ECO:0000269|PubMed:30093493}. Late endosome membrane CC {ECO:0000269|PubMed:30093493}. Note=May localize to endoplasmic CC reticulum-endolysosome contact sites. {ECO:0000269|PubMed:30093493}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1 {ECO:0000269|PubMed:15498460}; Synonyms=2A CC {ECO:0000269|PubMed:15498460}; CC IsoId=Q709C8-1; Sequence=Displayed; CC Name=2 {ECO:0000269|PubMed:15498460}; Synonyms=2B CC {ECO:0000269|PubMed:15498460}; CC IsoId=Q709C8-2; Sequence=VSP_052244, VSP_052245; CC Name=3 {ECO:0000269|PubMed:15498460}; Synonyms=1A CC {ECO:0000269|PubMed:15498460}; CC IsoId=Q709C8-3; Sequence=VSP_052243; CC Name=4 {ECO:0000269|PubMed:15498460}; Synonyms=1B CC {ECO:0000269|PubMed:15498460}; CC IsoId=Q709C8-4; Sequence=VSP_052243, VSP_052244, VSP_052245; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:15498460}. CC -!- DOMAIN: The FFAT motif is required for localization to the endoplasmic CC reticulum. {ECO:0000269|PubMed:30093493}. CC -!- DISEASE: Parkinson disease 23, autosomal recessive, early onset CC (PARK23) [MIM:616840]: An autosomal recessive, early-onset form of CC Parkinson disease, a complex neurodegenerative disorder characterized CC by bradykinesia, resting tremor, muscular rigidity and postural CC instability, as well as by a clinically significant response to CC treatment with levodopa. The pathology involves the loss of CC dopaminergic neurons in the substantia nigra and the presence of Lewy CC bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. CC {ECO:0000269|PubMed:26942284}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the VPS13 family. {ECO:0000255}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA90972.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA92659.1; 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; AJ608770; CAE75582.1; -; mRNA. DR EMBL; AJ608771; CAE75583.1; -; mRNA. DR EMBL; AJ626860; CAF25187.1; -; mRNA. DR EMBL; AJ626861; CAF25188.1; -; mRNA. DR EMBL; AB037842; BAA92659.1; ALT_INIT; mRNA. DR EMBL; AK000143; BAA90972.1; ALT_INIT; mRNA. DR EMBL; BC069387; AAH69387.1; -; mRNA. DR CCDS; CCDS10180.1; -. [Q709C8-3] DR CCDS; CCDS32257.1; -. [Q709C8-1] DR CCDS; CCDS45272.1; -. [Q709C8-2] DR CCDS; CCDS58367.1; -. [Q709C8-4] DR RefSeq; NP_001018098.1; NM_001018088.3. [Q709C8-2] DR RefSeq; NP_060154.3; NM_017684.4. [Q709C8-3] DR RefSeq; NP_060550.2; NM_018080.3. [Q709C8-4] DR RefSeq; NP_065872.1; NM_020821.3. [Q709C8-1] DR SMR; Q709C8; -. DR BioGRID; 120186; 137. DR ELM; Q709C8; -. DR FunCoup; Q709C8; 2695. DR IntAct; Q709C8; 72. DR MINT; Q709C8; -. DR STRING; 9606.ENSP00000493560; -. DR CarbonylDB; Q709C8; -. DR GlyGen; Q709C8; 4 sites, 3 N-linked glycans (2 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q709C8; -. DR MetOSite; Q709C8; -. DR PhosphoSitePlus; Q709C8; -. DR SwissPalm; Q709C8; -. DR BioMuta; VPS13C; -. DR DMDM; 74712594; -. DR jPOST; Q709C8; -. DR MassIVE; Q709C8; -. DR PaxDb; 9606-ENSP00000261517; -. DR PeptideAtlas; Q709C8; -. DR ProteomicsDB; 68512; -. [Q709C8-1] DR ProteomicsDB; 68513; -. [Q709C8-2] DR ProteomicsDB; 68514; -. [Q709C8-3] DR ProteomicsDB; 68515; -. [Q709C8-4] DR Pumba; Q709C8; -. DR Antibodypedia; 50681; 12 antibodies from 7 providers. DR DNASU; 54832; -. DR Ensembl; ENST00000249837.7; ENSP00000249837.3; ENSG00000129003.19. [Q709C8-3] DR Ensembl; ENST00000395898.3; ENSP00000379235.3; ENSG00000129003.19. [Q709C8-4] DR Ensembl; ENST00000644861.2; ENSP00000493560.2; ENSG00000129003.19. [Q709C8-1] DR Ensembl; ENST00000645819.1; ENSP00000496179.1; ENSG00000129003.19. [Q709C8-2] DR GeneID; 54832; -. DR KEGG; hsa:54832; -. DR MANE-Select; ENST00000644861.2; ENSP00000493560.2; NM_020821.3; NP_065872.1. DR UCSC; uc002agz.4; human. [Q709C8-1] DR AGR; HGNC:23594; -. DR ClinPGx; PA134990089; -. DR CTD; 54832; -. DR DisGeNET; 54832; -. DR GeneCards; VPS13C; -. DR HGNC; HGNC:23594; VPS13C. DR HPA; ENSG00000129003; Low tissue specificity. DR MalaCards; VPS13C; -. DR MIM; 608879; gene. DR MIM; 616840; phenotype. DR OpenTargets; ENSG00000129003; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000129003; -. DR eggNOG; KOG1809; Eukaryota. DR GeneTree; ENSGT00950000183083; -. DR HOGENOM; CLU_000135_1_1_1; -. DR InParanoid; Q709C8; -. DR OMA; SGWRPIR; -. DR OrthoDB; 428159at2759; -. DR PAN-GO; Q709C8; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q709C8; -. DR PathwayCommons; Q709C8; -. DR SignaLink; Q709C8; -. DR Agora; ENSG00000129003; -. DR BioGRID-ORCS; 54832; 8 hits in 1163 CRISPR screens. DR ChiTaRS; VPS13C; human. DR GenomeRNAi; 54832; -. DR Pharos; Q709C8; Tbio. DR PRO; PR:Q709C8; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q709C8; protein. DR Bgee; ENSG00000129003; Expressed in calcaneal tendon and 206 other cell types or tissues. DR ExpressionAtlas; Q709C8; baseline and differential. DR GO; GO:0005737; C:cytoplasm; TAS:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0032127; C:dense core granule membrane; IEA:Ensembl. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005811; C:lipid droplet; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0006895; P:Golgi to endosome transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:1905090; P:negative regulation of type 2 mitophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0045053; P:protein retention in Golgi apparatus; IBA:GO_Central. DR GO; GO:0006623; P:protein targeting to vacuole; IBA:GO_Central. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR InterPro; IPR026847; VPS13. DR InterPro; IPR056748; VPS13-like_C. DR InterPro; IPR056747; VPS13-like_M. DR InterPro; IPR026854; VPS13_N. DR InterPro; IPR009543; VPS13_VAB. DR PANTHER; PTHR16166:SF125; INTERMEMBRANE LIPID TRANSFER PROTEIN VPS13C; 1. DR PANTHER; PTHR16166; VACUOLAR PROTEIN SORTING-ASSOCIATED PROTEIN VPS13; 1. DR Pfam; PF25037; VPS13_C; 1. DR Pfam; PF25033; VPS13_M; 1. DR Pfam; PF12624; VPS13_N; 1. DR Pfam; PF25036; VPS13_VAB; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Disease variant; Endoplasmic reticulum; KW Endosome; Lipid droplet; Lipid transport; Lysosome; Membrane; Methylation; KW Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; KW Parkinson disease; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Transport. FT CHAIN 1..3753 FT /note="Intermembrane lipid transfer protein VPS13C" FT /id="PRO_0000262949" FT DOMAIN 3..116 FT /note="Chorein N-terminal" FT /evidence="ECO:0000255" FT DOMAIN 2766..3016 FT /note="SHR-BD" FT /evidence="ECO:0000255" FT REGION 150..176 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2415..3309 FT /note="Required for late endosome/lysosome localization" FT /evidence="ECO:0000269|PubMed:30093493" FT REGION 3310..3753 FT /note="Required for lipid droplet localization" FT /evidence="ECO:0000269|PubMed:30093493" FT MOTIF 877..883 FT /note="FFAT" FT /evidence="ECO:0000305" FT COMPBIAS 150..164 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 165..176 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 132 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8BX70" FT MOD_RES 614 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 619 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 624 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 737 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT MOD_RES 842 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 872 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8BX70" FT MOD_RES 874 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8BX70" FT MOD_RES 1979 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8BX70" FT MOD_RES 2473 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 3519 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q8BX70" FT MOD_RES 3526 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 3538 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 3641 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 129..171 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15498460" FT /id="VSP_052243" FT VAR_SEQ 3622..3627 FT /note="NHIKKL -> QELEIQE (in isoform 2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15498460" FT /id="VSP_052244" FT VAR_SEQ 3628..3753 FT /note="Missing (in isoform 2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15498460" FT /id="VSP_052245" FT VARIANT 153 FT /note="R -> H (in dbSNP:rs12595158)" FT /id="VAR_029548" FT VARIANT 974 FT /note="R -> K (in dbSNP:rs3784634)" FT /evidence="ECO:0000269|PubMed:10718198" FT /id="VAR_029549" FT VARIANT 1132 FT /note="I -> V (in dbSNP:rs3784635)" FT /id="VAR_029550" FT VARIANT 1302 FT /note="Y -> C (in dbSNP:rs2303405)" FT /id="VAR_029551" FT VARIANT 1389 FT /note="G -> R (in PARK23; dbSNP:rs369100678)" FT /evidence="ECO:0000269|PubMed:26942284" FT /id="VAR_076363" FT VARIANT 1485 FT /note="T -> A (in dbSNP:rs8026956)" FT /id="VAR_029552" FT VARIANT 1495 FT /note="I -> V (in dbSNP:rs11629598)" FT /id="VAR_029553" FT VARIANT 1592 FT /note="S -> Y (in dbSNP:rs11629838)" FT /id="VAR_029554" FT VARIANT 2322 FT /note="V -> M (in dbSNP:rs12907567)" FT /id="VAR_029555" FT VARIANT 2808 FT /note="K -> R (in dbSNP:rs34060567)" FT /id="VAR_053808" FT VARIANT 2872 FT /note="C -> F" FT /evidence="ECO:0000269|PubMed:25787250" FT /id="VAR_074191" FT VARIANT 2913 FT /note="S -> N (in dbSNP:rs10851704)" FT /id="VAR_029556" FT MUTAGEN 878..879 FT /note="YF->SL: Abnormal localization to the cytosol." FT /evidence="ECO:0000269|PubMed:30093493" SQ SEQUENCE 3753 AA; 422390 MW; 8B51A6778A89F639 CRC64; MVLESVVADL LNRFLGDYVE NLNKSQLKLG IWGGNVALDN LQIKENALSE LDVPFKVKAG QIDKLTLKIP WKNLYGEAVV ATLEGLYLLV VPGASIKYDA VKEEKSLQDV KQKELSRIEE ALQKAAEKGT HSGEFIYGLE NFVYKDIKPG RKRKKHKKHF KKPFKGLDRS KDKPKEAKKD TFVEKLATQV IKNVQVKITD IHIKYEDDVT DPKRPLSFGV TLGELSLLTA NEHWTPCILN EADKIIYKLI RLDSLSAYWN VNCSMSYQRS REQILDQLKN EILTSGNIPP NYQYIFQPIS ASAKLYMNPY AESELKTPKL DCNIEIQNIA IELTKPQYLS MIDLLESVDY MVRNAPYRKY KPYLPLHTNG RRWWKYAIDS VLEVHIRRYT QMWSWSNIKK HRQLLKSYKI AYKNKLTQSK VSEEIQKEIQ DLEKTLDVFN IILARQQAQV EVIRSGQKLR KKSADTGEKR GGWFSGLWGK KESKKKDEES LIPETIDDLM TPEEKDKLFT AIGYSESTHN LTLPKQYVAH IMTLKLVSTS VTIRENKNIP EILKIQIIGL GTQVSQRPGA QALKVEAKLE HWYITGLRQQ DIVPSLVASI GDTTSSLLKI KFETNPEDSP ADQTLIVQSQ PVEVIYDAKT VNAVVEFFQS NKGLDLEQIT SATLMKLEEI KERTATGLTH IIETRKVLDL RINLKPSYLV VPQTGFHHEK SDLLILDFGT FQLNSKDQGL QKTTNSSLEE IMDKAYDKFD VEIKNVQLLF ARAEETWKKC RFQHPSTMHI LQPMDIHVEL AKAMVEKDIR MARFKVSGGL PLMHVRISDQ KMKDVLYLMN SIPLPQKSSA QSPERQVSSI PIISGGTKGL LGTSLLLDTV ESESDDEYFD AEDGEPQTCK SMKGSELKKA AEVPNEELIN LLLKFEIKEV ILEFTKQQKE EDTILVFNVT QLGTEATMRT FDLTVVSYLK KISLDYHEIE GSKRKPLHLI SSSDKPGLDL LKVEYIKADK NGPSFQTAFG KTEQTVKVAF SSLNLLLQTQ ALVASINYLT TIIPSDDQSI SVAKEVQIST EKQQKNSTLP KAIVSSRDSD IIDFRLFAKL NAFCVIVCNE KNNIAEIKIQ GLDSSLSLQS RKQSLFARLE NIIVTDVDPK TVHKKAVSIM GNEVFRFNLD LYPDATEGDL YTDMSKVDGV LSLNVGCIQI VYLHKFLMSL LNFLNNFQTA KESLSAATAQ AAERAATSVK DLAQRSFRVS INIDLKAPVI VIPQSSISTN AVVVDLGLIR VHNQFSLVSD EDYLNPPVID RMDVQLTKLT LYRTVIQPGI YHPDIQLLHP INLEFLVNRN LAASWYHKVP VVEIKGHLDS MNVSLNQEDL NLLFRILTEN LCEGTEDLDK VKPRVQETGE IKEPLEISIS QDVHDSKNTL TTGVEEIRSV DIINMLLNFE IKEVVVTLMK KSEKKGRPLH ELNVLQLGME AKVKTYDMTA KAYLKKISMQ CFDFTDSKGE PLHIINSSNV TDEPLLKMLL TKADSDGPEF KTIHDSTKQR LKVSFASLDL VLHLEALLSF MDFLSSAAPF SEPSSSEKES ELKPLVGESR SIAVKAVSSN ISQKDVFDLK ITAELNAFNV FVCDQKCNIA DIKIHGMDAS ISVKPKQTDV FARLKDIIVM NVDLQSIHKK AVSILGDEVF RFQLTLYPDA TEGEAYADMS KVDGKLSFKV GCIQIVYVHK FFMSLLNFLN NFQTAKEALS TATVQAAERA ASSMKDLAQK SFRLLMDINL KAPVIIIPQS SVSPNAVIAD LGLIRVENKF SLVPMEHYSL PPVIDKMNIE LTQLKLSRTI LQASLPQNDI EILKPVNMLL SIQRNLAAAW YVQIPGMEIK GKLKPMQVAL SEDDLTVLMK ILLENLGEAS SQPSPTQSVQ ETVRVRKVDV SSVPDHLKEQ EDWTDSKLSM NQIVSLQFDF HFESLSIILY NNDINQESGV AFHNDSFQLG ELRLHLMASS GKMFKDGSMN VSVKLKTCTL DDLREGIERA TSRMIDRKND QDNNSSMIDI SYKQDKNGSQ IDAVLDKLYV CASVEFLMTV ADFFIKAVPQ SPENVAKETQ ILPRQTATGK VKIEKDDSVR PNMTLKAMIT DPEVVFVASL TKADAPALTA SFQCNLSLST SKLEQMMEAS VRDLKVLACP FLREKRGKNI TTVLQPCSLF MEKCTWASGK QNINIMVKEF IIKISPIILN TVLTIMAALS PKTKEDGSKD TSKEMENLWG IKSINDYNTW FLGVDTATEI TESFKGIEHS LIEENCGVVV ESIQVTLECG LGHRTVPLLL AESKFSGNIK NWTSLMAAVA DVTLQVHYYN EIHAVWEPLI ERVEGKRQWN LRLDVKKNPV QDKSLLPGDD FIPEPQMAIH ISSGNTMNIT ISKSCLNVFN NLAKGFSEGT ASTFDYSLKD RAPFTVKNAV GVPIKVKPNC NLRVMGFPEK SDIFDVDAGQ NLELEYASMV PSSQGNLSIL SRQESSFFTL TIVPHGYTEV ANIPVARPGR RLYNVRNPNA SHSDSVLVQI DATEGNKVIT LRSPLQIKNH FSIAFIIYKF VKNVKLLERI GIARPEEEFH VPLDSYRCQL FIQPAGILEH QYKESTTYIS WKEELHRSRE VRCMLQCPSV EVSFLPLIVN TVALPDELSY ICTHGEDWDV AYIIHLYPSL TLRNLLPYSL RYLLEGTAET HELAEGSTAD VLHSRISGEI MELVLVKYQG KNWNGHFRIR DTLPEFFPVC FSSDSTEVTT VDLSVHVRRI GSRMVLSVFS PYWLINKTTR VLQYRSEDIH VKHPADFRDI ILFSFKKKNI FTKNKVQLKI STSAWSSSFS LDTVGSYGCV KCPANNMEYL VGVSIKMSSF NLSRIVTLTP FCTIANKSSL ELEVGEIASD GSMPTNKWNY IASSECLPFW PESLSGKLCV RVVGCEGSSK PFFYNRQDNG TLLSLEDLNG GILVDVNTAE HSTVITFSDY HEGSAPALIM NHTPWDILTY KQSGSPEEMV LLPRQARLFA WADPTGTRKL TWTYAANVGE HDLLKDGCGQ FPYDANIQIH WVSFLDGRQR VLLFTDDVAL VSKALQAEEM EQADYEITLS LHSLGLSLVN NESKQEVSYI GITSSGVVWE VKPKQKWKPF SQKQIILLEQ SYQKHQISRD HGWIKLDNNF EVNFDKDPME MRLPIRSPIK RDFLSGIQIE FKQSSHQRSL RARLYWLQVD NQLPGAMFPV VFHPVAPPKS IALDSEPKPF IDVSVITRFN EYSKVLQFKY FMVLIQEMAL KIDQGFLGAI IALFTPTTDP EAERRRTKLI QQDIDALNAE LMETSMTDMS ILSFFEHFHI SPVKLHLSLS LGSGGEESDK EKQEMFAVHS VNLLLKSIGA TLTDVDDLIF KLAYYEIRYQ FYKRDQLIWS VVRHYSEQFL KQMYVLVLGL DVLGNPFGLI RGLSEGVEAL FYEPFQGAVQ GPEEFAEGLV IGVRSLFGHT VGGAAGVVSR ITGSVGKGLA AITMDKEYQQ KRREELSRQP RDFGDSLARG GKGFLRGVVG GVTGIITKPV EGAKKEGAAG FFKGIGKGLV GAVARPTGGI VDMASSTFQG IQRAAESTEE VSSLRPPRLI HEDGIIRPYD RQESEGSDLL ENHIKKLEGE TYRYHCAIPG SKKTILMVTN RRVLCIKEVE ILGLMCVDWQ CPFEDFVFPP SVSENVLKIS VKEQGLFHKK DSANQGCVRK VYLKDTATAE RACNAIEDAQ STRQQQKLMK QSSVRLLRPQ LPS // ID VPS35_HUMAN Reviewed; 796 AA. AC Q96QK1; Q561W2; Q9H016; Q9H096; Q9H4P3; Q9H8J0; Q9NRS7; Q9NVG2; Q9NX80; AC Q9NZK2; DT 25-NOV-2002, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2002, sequence version 2. DT 28-JAN-2026, entry version 217. DE RecName: Full=Vacuolar protein sorting-associated protein 35; DE Short=hVPS35; DE AltName: Full=Maternal-embryonic 3; DE AltName: Full=Vesicle protein sorting 35; GN Name=VPS35 {ECO:0000303|PubMed:28397838, ECO:0000312|HGNC:HGNC:13487}; GN Synonyms=MEM3; ORFNames=TCCCTA00141; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Lung; RX PubMed=11062004; DOI=10.1006/bbrc.2000.3727; RA Edgar A.J., Polak J.M.; RT "Human homologues of yeast vacuolar protein sorting 29 and 35."; RL Biochem. Biophys. Res. Commun. 277:622-630(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Testis; RX PubMed=11112353; DOI=10.1006/geno.2000.6380; RA Zhang P., Yu L., Gao J., Fu Q., Dai F., Zhao Y., Zheng L., Zhao S.; RT "Cloning and characterization of human VPS35 and mouse Vps35 and mapping of RT VPS35 to human chromosome 16q13-q21."; RL Genomics 70:253-257(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH VPS29; VPS26A; SNX1 AND RP SNX2. RC TISSUE=Colon; RX PubMed=11102511; DOI=10.1091/mbc.11.12.4105; RA Renfrew Haft C., de la Luz Sierra M., Bafford R., Lesniak M.A., Barr V.A., RA Taylor S.I.; RT "Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and RT 35: assembly into multimeric complexes."; RL Mol. Biol. Cell 11:4105-4116(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pheochromocytoma; RA Peng Y., Li Y., Tu Y., Xu S., Han Z., Fu G., Chen Z.; RT "A novel gene expressed in human pheochromocytoma."; RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Ileal mucosa, Placenta, and Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Testis; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Placenta, and Prostate; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 469-796. RC TISSUE=Leukemia; RA Zhou J., Yu W., Tang H., Mei G., Tsang Y.T.M., Bouck J., Gibbs R.A., RA Margolin J.F.; RT "Pediatric leukemia cDNA sequencing project."; RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases. RN [9] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH IGF2R. RX PubMed=15078903; DOI=10.1083/jcb.200312055; RA Arighi C.N., Hartnell L.M., Aguilar R.C., Haft C.R., Bonifacino J.S.; RT "Role of the mammalian retromer in sorting of the cation-independent RT mannose 6-phosphate receptor."; RL J. Cell Biol. 165:123-133(2004). RN [10] RP FUNCTION. RX PubMed=15247922; DOI=10.1038/ncb1153; RA Verges M., Luton F., Gruber C., Tiemann F., Reinders L.G., Huang L., RA Burlingame A.L., Haft C.R., Mostov K.E.; RT "The mammalian retromer regulates transcytosis of the polymeric RT immunoglobulin receptor."; RL Nat. Cell Biol. 6:763-769(2004). RN [11] RP INTERACTION WITH EHD1. RX PubMed=17868075; DOI=10.1111/j.1600-0854.2007.00652.x; RA Gokool S., Tattersall D., Seaman M.N.; RT "EHD1 interacts with retromer to stabilize SNX1 tubules and facilitate RT endosome-to-Golgi retrieval."; RL Traffic 8:1873-1886(2007). RN [12] RP INTERACTION WITH RAB7A. RX PubMed=19531583; DOI=10.1242/jcs.048686; RA Seaman M.N., Harbour M.E., Tattersall D., Read E., Bright N.; RT "Membrane recruitment of the cargo-selective retromer subcomplex is RT catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5."; RL J. Cell Sci. 122:2371-2382(2009). RN [13] RP INTERACTION WITH GOLPH3. RX PubMed=19553991; DOI=10.1038/nature08109; RA Scott K.L., Kabbarah O., Liang M.C., Ivanova E., Anagnostou V., Wu J., RA Dhakal S., Wu M., Chen S., Feinberg T., Huang J., Saci A., Widlund H.R., RA Fisher D.E., Xiao Y., Rimm D.L., Protopopov A., Wong K.K., Chin L.; RT "GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer."; RL Nature 459:1085-1090(2009). RN [14] RP FUNCTION. RX PubMed=20923837; DOI=10.1242/jcs.071472; RA Harbour M.E., Breusegem S.Y., Antrobus R., Freeman C., Reid E., RA Seaman M.N.; RT "The cargo-selective retromer complex is a recruiting hub for protein RT complexes that regulate endosomal tubule dynamics."; RL J. Cell Sci. 123:3703-3717(2010). RN [15] RP FUNCTION. RX PubMed=20164305; DOI=10.1242/jcs.060574; RA Tabuchi M., Yanatori I., Kawai Y., Kishi F.; RT "Retromer-mediated direct sorting is required for proper endosomal RT recycling of the mammalian iron transporter DMT1."; RL J. Cell Sci. 123:756-766(2010). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, 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 [17] 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 [18] RP FUNCTION OF THE SNX3-RETROMER, AND SUBUNIT. RX PubMed=21725319; DOI=10.1038/ncb2281; RA Harterink M., Port F., Lorenowicz M.J., McGough I.J., Silhankova M., RA Betist M.C., van Weering J.R., van Heesbeen R.G., Middelkoop T.C., RA Basler K., Cullen P.J., Korswagen H.C.; RT "A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt RT sorting receptor Wntless and is required for Wnt secretion."; RL Nat. Cell Biol. 13:914-923(2011). RN [19] RP FUNCTION, AND INTERACTION WITH WASHC2C; FKBP15 AND WASHC1. RX PubMed=22070227; DOI=10.1042/bj20111761; RA Harbour M.E., Breusegem S.Y., Seaman M.N.; RT "Recruitment of the endosomal WASH complex is mediated by the extended RT 'tail' of Fam21 binding to the retromer protein Vps35."; RL Biochem. J. 442:209-220(2012). RN [20] RP FUNCTION, AND INTERACTION WITH WASHC2C. RX PubMed=22513087; DOI=10.1091/mbc.e11-12-1059; RA Jia D., Gomez T.S., Billadeau D.D., Rosen M.K.; RT "Multiple repeat elements within the FAM21 tail link the WASH actin RT regulatory complex to the retromer."; RL Mol. Biol. Cell 23:2352-2361(2012). RN [21] RP INTERACTION WITH VPS29 AND VPS26, AND MUTAGENESIS OF LEU-108 AND HIS-675. RX PubMed=23331060; DOI=10.1111/boc.201200038; RA Helfer E., Harbour M.E., Henriot V., Lakisic G., Sousa-Blin C., RA Volceanov L., Seaman M.N., Gautreau A.; RT "Endosomal recruitment of the WASH complex: active sequences and mutations RT impairing interaction with the retromer."; RL Biol. Cell 105:191-207(2013). RN [22] RP INTERACTION WITH MAGEL2. RX PubMed=23452853; DOI=10.1016/j.cell.2013.01.051; RA Hao Y.H., Doyle J.M., Ramanathan S., Gomez T.S., Jia D., Xu M., Chen Z.J., RA Billadeau D.D., Rosen M.K., Potts P.R.; RT "Regulation of WASH-dependent actin polymerization and protein trafficking RT by ubiquitination."; RL Cell 152:1051-1064(2013). RN [23] RP FUNCTION OF THE SNX27-RETROMER, SUBUNIT, AND INTERACTION WITH SNX27 AND RP WASHC5. RX PubMed=23563491; DOI=10.1038/ncb2721; RA Steinberg F., Gallon M., Winfield M., Thomas E.C., Bell A.J., Heesom K.J., RA Tavare J.M., Cullen P.J.; RT "A global analysis of SNX27-retromer assembly and cargo specificity reveals RT a function in glucose and metal ion transport."; RL Nat. Cell Biol. 15:461-471(2013). RN [24] RP FUNCTION IN RETROGRADE TRANSPORT, INTERACTION WITH LRRK2, AND RP CHARACTERIZATION OF VARIANT PARK17 ASN-620. RX PubMed=23395371; DOI=10.1016/j.neuron.2012.11.033; RA MacLeod D.A., Rhinn H., Kuwahara T., Zolin A., Di Paolo G., McCabe B.D., RA MacCabe B.D., Marder K.S., Honig L.S., Clark L.N., Small S.A., RA Abeliovich A.; RT "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and RT Parkinson's disease risk."; RL Neuron 77:425-439(2013). RN [25] 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 [26] RP INTERACTION WITH SNX3 AND SLC11A2. RX PubMed=24344282; DOI=10.1073/pnas.1316482111; RA Harrison M.S., Hung C.S., Liu T.T., Christiano R., Walther T.C., Burd C.G.; RT "A mechanism for retromer endosomal coat complex assembly with cargo."; RL Proc. Natl. Acad. Sci. U.S.A. 111:267-272(2014). RN [27] RP FUNCTION, INTERACTION WITH WASHC2C, AND CHARACTERIZATION OF VARIANT PARK17 RP ASN-620. RX PubMed=24980502; DOI=10.1016/j.cub.2014.06.024; RA McGough I.J., Steinberg F., Jia D., Barbuti P.A., McMillan K.J., RA Heesom K.J., Whone A.L., Caldwell M.A., Billadeau D.D., Rosen M.K., RA Cullen P.J.; RT "Retromer binding to FAM21 and the WASH complex is perturbed by the RT Parkinson disease-linked VPS35(D620N) mutation."; RL Curr. Biol. 24:1670-1676(2014). RN [28] RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK17 ASN-620. RX PubMed=24819384; DOI=10.1038/ncomms4828; RA Zavodszky E., Seaman M.N., Moreau K., Jimenez-Sanchez M., Breusegem S.Y., RA Harbour M.E., Rubinsztein D.C.; RT "Mutation in VPS35 associated with Parkinson's disease impairs WASH complex RT association and inhibits autophagy."; RL Nat. Commun. 5:3828-3828(2014). RN [29] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [30] RP INTERACTION WITH HUMAN PAPILLOMAVIRUS 16 MINOR CAPSID PROTEIN L2 (MICROBIAL RP INFECTION), AND FUNCTION (MICROBIAL INFECTION). RX PubMed=25693203; DOI=10.1371/journal.ppat.1004699; RA Popa A., Zhang W., Harrison M.S., Goodner K., Kazakov T., Goodwin E.C., RA Lipovsky A., Burd C.G., DiMaio D.; RT "Direct binding of retromer to human papillomavirus type 16 minor capsid RT protein L2 mediates endosome exit during viral infection."; RL PLoS Pathog. 11:E1004699-E1004699(2015). RN [31] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VPS26A AND VPS29. RX PubMed=28892079; DOI=10.1038/ncb3610; RA McNally K.E., Faulkner R., Steinberg F., Gallon M., Ghai R., Pim D., RA Langton P., Pearson N., Danson C.M., Naegele H., Morris L.L., Singla A., RA Overlee B.L., Heesom K.J., Sessions R., Banks L., Collins B.M., Berger I., RA Billadeau D.D., Burstein E., Cullen P.J.; RT "Retriever is a multiprotein complex for retromer-independent endosomal RT cargo recycling."; RL Nat. Cell Biol. 19:1214-1225(2017). RN [32] RP INTERACTION WITH HUMAN PAPILLOMAVIRUS 16 MINOR CAPSID PROTEIN L2 (MICROBIAL RP INFECTION). RX PubMed=30122350; DOI=10.1016/j.cell.2018.07.031; RA Zhang P., Monteiro da Silva G., Deatherage C., Burd C., DiMaio D.; RT "Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human RT Papillomavirus L2 Protein to Trigger Retrograde Trafficking."; RL Cell 0:0-0(2018). RN [33] RP FUNCTION, INTERACTION WITH SNX3, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=30213940; DOI=10.1038/s41467-018-06114-3; RA McGough I.J., de Groot R.E.A., Jellett A.P., Betist M.C., Varandas K.C., RA Danson C.M., Heesom K.J., Korswagen H.C., Cullen P.J.; RT "SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex RT to mediate Wntless sorting and Wnt secretion."; RL Nat. Commun. 9:3737-3737(2018). RN [34] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 483-780 IN COMPLEX WITH VPS29, AND RP ELECTRON MICROSCOPY OF THE RETROMER COMPLEX CONTAINING VPS29; VPS35 AND RP VPS26. RX PubMed=17891154; DOI=10.1038/nature06216; RA Hierro A., Rojas A.L., Rojas R., Murthy N., Effantin G., Kajava A.V., RA Steven A.C., Bonifacino J.S., Hurley J.H.; RT "Functional architecture of the retromer cargo-recognition complex."; RL Nature 449:1063-1067(2007). RN [35] RP VARIANT PARK17 ASN-620, AND VARIANTS SER-316 AND VAL-737. RX PubMed=21763482; DOI=10.1016/j.ajhg.2011.06.001; RA Vilarino-Guell C., Wider C., Ross O.A., Dachsel J.C., Kachergus J.M., RA Lincoln S.J., Soto-Ortolaza A.I., Cobb S.A., Wilhoite G.J., Bacon J.A., RA Behrouz B., Melrose H.L., Hentati E., Puschmann A., Evans D.M., RA Conibear E., Wasserman W.W., Aasly J.O., Burkhard P.R., Djaldetti R., RA Ghika J., Hentati F., Krygowska-Wajs A., Lynch T., Melamed E., Rajput A., RA Rajput A.H., Solida A., Wu R.M., Uitti R.J., Wszolek Z.K., Vingerhoets F., RA Farrer M.J.; RT "VPS35 mutations in Parkinson disease."; RL Am. J. Hum. Genet. 89:162-167(2011). RN [36] RP VARIANT PARK17 ASN-620, AND VARIANTS SER-51; ILE-57; ARG-82; MET-241; RP TRP-524 AND MET-774. RX PubMed=21763483; DOI=10.1016/j.ajhg.2011.06.008; RA Zimprich A., Benet-Pages A., Struhal W., Graf E., Eck S.H., Offman M.N., RA Haubenberger D., Spielberger S., Schulte E.C., Lichtner P., Rossle S.C., RA Klopp N., Wolf E., Seppi K., Pirker W., Reinthaler E., Harutyunyan A., RA Kralovics R., Peters A., Zimprich F., Brucke T., Poewe W., Auff E., RA Trenkwalder C., Rost B., Ransmayr G., Winkelmann J., Meitinger T., RA Strom T.M.; RT "A mutation in VPS35, encoding a subunit of the retromer complex, causes RT late-onset Parkinson disease."; RL Am. J. Hum. Genet. 89:168-175(2011). RN [37] RP VARIANT PARK17 ASN-620. RX PubMed=22517097; DOI=10.1212/wnl.0b013e318253d5f2; RA Lesage S., Condroyer C., Klebe S., Honore A., Tison F., Brefel-Courbon C., RA Durr A., Brice A.; RT "Identification of VPS35 mutations replicated in French families with RT Parkinson disease."; RL Neurology 78:1449-1450(2012). RN [38] RP VARIANT PRO-469. RX PubMed=28397838; DOI=10.1038/mp.2017.60; RA Harripaul R., Vasli N., Mikhailov A., Rafiq M.A., Mittal K., RA Windpassinger C., Sheikh T.I., Noor A., Mahmood H., Downey S., Johnson M., RA Vleuten K., Bell L., Ilyas M., Khan F.S., Khan V., Moradi M., Ayaz M., RA Naeem F., Heidari A., Ahmed I., Ghadami S., Agha Z., Zeinali S., Qamar R., RA Mozhdehipanah H., John P., Mir A., Ansar M., French L., Ayub M., RA Vincent J.B.; RT "Mapping autosomal recessive intellectual disability: combined microarray RT and exome sequencing identifies 26 novel candidate genes in 192 RT consanguineous families."; RL Mol. Psychiatry 23:973-984(2018). CC -!- FUNCTION: Acts as a component of the retromer cargo-selective complex CC (CSC). The CSC is believed to be the core functional component of CC retromer or respective retromer complex variants acting to prevent CC missorting of selected transmembrane cargo proteins into the lysosomal CC degradation pathway. The recruitment of the CSC to the endosomal CC membrane involves RAB7A and SNX3. The CSC seems to associate with the CC cytoplasmic domain of cargo proteins predominantly via VPS35; however, CC these interactions seem to be of low affinity and retromer SNX proteins CC may also contribute to cargo selectivity thus questioning the classical CC function of the CSC. The SNX-BAR retromer mediates retrograde transport CC of cargo proteins from endosomes to the trans-Golgi network (TGN) and CC is involved in endosome-to-plasma membrane transport for cargo protein CC recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN CC transport of WLS distinct from the SNX-BAR retromer pathway CC (PubMed:30213940). The SNX27-retromer is believed to be involved in CC endosome-to-plasma membrane trafficking and recycling of a broad CC spectrum of cargo proteins. The CSC seems to act as recruitment hub for CC other proteins, such as the WASH complex and TBC1D5 (Probable). CC Required for retrograde transport of lysosomal enzyme receptor IGF2R CC and SLC11A2. Required to regulate transcytosis of the polymeric CC immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, CC PubMed:20164305). Required for endosomal localization of WASHC2C CC (PubMed:22070227, PubMed:28892079). Mediates the association of the CSC CC with the WASH complex via WASHC2 (PubMed:22070227, PubMed:24819384, CC PubMed:24980502). Required for the endosomal localization of TBC1D5 CC (PubMed:20923837). {ECO:0000269|PubMed:15078903, CC ECO:0000269|PubMed:15247922, ECO:0000269|PubMed:20164305, CC ECO:0000269|PubMed:20923837, ECO:0000269|PubMed:22070227, CC ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24819384, CC ECO:0000269|PubMed:24980502, ECO:0000269|PubMed:28892079, CC ECO:0000269|PubMed:30213940, ECO:0000303|PubMed:21725319, CC ECO:0000303|PubMed:22070227, ECO:0000303|PubMed:22513087, CC ECO:0000303|PubMed:23563491}. CC -!- FUNCTION: (Microbial infection) The heterotrimeric retromer cargo- CC selective complex (CSC) mediates the exit of human papillomavirus from CC the early endosome and the delivery to the Golgi apparatus. CC {ECO:0000269|PubMed:25693203, ECO:0000269|PubMed:30122350}. CC -!- SUBUNIT: Component of the heterotrimeric retromer cargo-selective CC complex (CSC), also decribed as vacuolar protein sorting subcomplex CC (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35 CC (PubMed:11102511, PubMed:28892079). The CSC has a highly elongated CC structure with VPS26 and VPS29 binding independently at opposite distal CC ends of VPS35 as central platform (By similarity). The CSC is believed CC to associate with variable sorting nexins to form functionally distinct CC retromer complex variants. The originally described retromer complex CC (also called SNX-BAR retromer) is a pentamer containing the CSC and a CC heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 CC and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC CC and SNX-BAR subcomplexes associate with low affinity. The CSC CC associates with SNX3 to form a SNX3-retromer complex. The CSC CC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to CC form the SNX27-retromer complex (Probable). Interacts with VPS26A, CC VPS26B, VPS29, SNX1, SNX2, IGF2R, SNX3, GOLPH3, LRRK2, SLC11A2, CC WASHC2A, WASHC2C, FKBP15, WASHC1, RAB7A, SNX27, WASHC5, EHD1 CC (PubMed:11102511, PubMed:15078903, PubMed:17868075, PubMed:17891154, CC PubMed:19531583, PubMed:19553991, PubMed:21725319, PubMed:22070227, CC PubMed:22513087, PubMed:23331060, PubMed:23395371, PubMed:23563491, CC PubMed:24344282, PubMed:24980502, PubMed:30213940). Interacts with CC MAGEL2; leading to recruitment of the TRIM27:MAGEL2 E3 ubiquitin ligase CC complex retromer-containing endosomes (PubMed:23452853). Interacts with CC SORCS2 (By similarity). {ECO:0000250|UniProtKB:Q9EQH3, CC ECO:0000269|PubMed:11102511, ECO:0000269|PubMed:15078903, CC ECO:0000269|PubMed:17868075, ECO:0000269|PubMed:17891154, CC ECO:0000269|PubMed:19553991, ECO:0000269|PubMed:21725319, CC ECO:0000269|PubMed:22070227, ECO:0000269|PubMed:22513087, CC ECO:0000269|PubMed:23331060, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:23452853, ECO:0000269|PubMed:23563491, CC ECO:0000269|PubMed:24344282, ECO:0000269|PubMed:24980502, CC ECO:0000269|PubMed:28892079, ECO:0000303|PubMed:21725319, CC ECO:0000303|PubMed:23563491}. CC -!- SUBUNIT: (Microbial infection) Interacts with human papillomavirus 16 CC minor capsid protein L2 (via C-terminus); this interaction mediates the CC transport of the capsid from the early endosome to the Golgi apparatus. CC {ECO:0000269|PubMed:25693203}. CC -!- INTERACTION: CC Q96QK1; P05067: APP; NbExp=3; IntAct=EBI-1054634, EBI-77613; CC Q96QK1; Q13596: SNX1; NbExp=2; IntAct=EBI-1054634, EBI-2822329; CC Q96QK1; Q92609: TBC1D5; NbExp=11; IntAct=EBI-1054634, EBI-742381; CC Q96QK1; O75436: VPS26A; NbExp=30; IntAct=EBI-1054634, EBI-1043891; CC Q96QK1; Q4G0F5: VPS26B; NbExp=12; IntAct=EBI-1054634, EBI-6151831; CC Q96QK1; Q9UBQ0: VPS29; NbExp=27; IntAct=EBI-1054634, EBI-718596; CC Q96QK1; Q9UBQ0-2: VPS29; NbExp=4; IntAct=EBI-1054634, EBI-11141397; CC Q96QK1; Q9Y4E1: WASHC2C; NbExp=8; IntAct=EBI-1054634, EBI-948957; CC Q96QK1; Q9QZ88: Vps29; Xeno; NbExp=7; IntAct=EBI-1054634, EBI-8334188; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane protein. CC Endosome {ECO:0000269|PubMed:15078903, ECO:0000269|PubMed:28892079}. CC Early endosome {ECO:0000305}. Late endosome {ECO:0000305}. CC Note=Localizes to tubular profiles adjacent to endosomes. CC {ECO:0000269|PubMed:15078903}. CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, brain, CC placenta, skeletal muscle, spleen, thymus, testis, ovary, small CC intestine, kidney and colon. CC -!- DISEASE: Parkinson disease 17 (PARK17) [MIM:614203]: An autosomal CC dominant, adult-onset form of Parkinson disease. Parkinson disease is a CC complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability, as well as CC by a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:21763482, ECO:0000269|PubMed:21763483, CC ECO:0000269|PubMed:22517097, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:24819384, ECO:0000269|PubMed:24980502}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the VPS35 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG01989.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA91137.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAB14626.1; 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; AF191298; AAF02778.2; -; mRNA. DR EMBL; AF186382; AAG40619.1; -; mRNA. DR EMBL; AF175265; AAF89953.1; -; mRNA. DR EMBL; AF183418; AAG09687.1; -; mRNA. DR EMBL; AK001614; BAA91790.1; -; mRNA. DR EMBL; AK023650; BAB14626.1; ALT_INIT; mRNA. DR EMBL; AK000395; BAA91137.1; ALT_INIT; mRNA. DR EMBL; AL136888; CAB66822.1; -; mRNA. DR EMBL; AL512769; CAC21686.1; -; mRNA. DR EMBL; BC002414; AAH02414.1; -; mRNA. DR EMBL; BC010362; AAH10362.1; -; mRNA. DR EMBL; BC093036; AAH93036.1; -; mRNA. DR EMBL; AY007112; AAG01989.1; ALT_INIT; mRNA. DR CCDS; CCDS10721.1; -. DR PIR; JC7516; JC7516. DR RefSeq; NP_060676.2; NM_018206.5. DR PDB; 2R17; X-ray; 2.80 A; C/D=483-780. DR PDB; 5F0J; X-ray; 2.70 A; A=14-470. DR PDB; 5F0K; X-ray; 3.07 A; A/B/C/D/E=14-470. DR PDB; 5F0L; X-ray; 3.20 A; A=14-470. DR PDB; 5F0M; X-ray; 3.10 A; A=14-470. DR PDB; 5F0P; X-ray; 2.78 A; A=14-470. DR PDB; 5OSH; X-ray; 4.30 A; B/E/H/K=482-780. DR PDB; 5OSI; X-ray; 2.52 A; B/E/H/K=471-781. DR PDB; 7BLN; EM; 8.90 A; A/C=1-796. DR PDB; 7BLO; EM; 9.50 A; A/C=12-363. DR PDB; 8R02; X-ray; 2.50 A; C/D=476-780. DR PDB; 8R0J; X-ray; 2.40 A; C/D=476-780. DR PDB; 8RKS; X-ray; 3.10 A; B/D/F/H=471-781. DR PDBsum; 2R17; -. DR PDBsum; 5F0J; -. DR PDBsum; 5F0K; -. DR PDBsum; 5F0L; -. DR PDBsum; 5F0M; -. DR PDBsum; 5F0P; -. DR PDBsum; 5OSH; -. DR PDBsum; 5OSI; -. DR PDBsum; 7BLN; -. DR PDBsum; 7BLO; -. DR PDBsum; 8R02; -. DR PDBsum; 8R0J; -. DR PDBsum; 8RKS; -. DR AlphaFoldDB; Q96QK1; -. DR EMDB; EMD-12220; -. DR EMDB; EMD-12221; -. DR SMR; Q96QK1; -. DR BioGRID; 120855; 343. DR ComplexPortal; CPX-7842; Retromer complex, VPS26A variant. DR ComplexPortal; CPX-7843; Retromer complex, VPS26B variant. DR CORUM; Q96QK1; -. DR DIP; DIP-29076N; -. DR FunCoup; Q96QK1; 4197. DR IntAct; Q96QK1; 209. DR MINT; Q96QK1; -. DR STRING; 9606.ENSP00000299138; -. DR BindingDB; Q96QK1; -. DR ChEMBL; CHEMBL2216744; -. DR TCDB; 9.A.3.1.1; the sorting nexin27 (snx27)-retromer assembly apparatus (retromeraa) family. DR GlyGen; Q96QK1; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96QK1; -. DR PhosphoSitePlus; Q96QK1; -. DR SwissPalm; Q96QK1; -. DR BioMuta; VPS35; -. DR DMDM; 25453321; -. DR CPTAC; CPTAC-605; -. DR jPOST; Q96QK1; -. DR MassIVE; Q96QK1; -. DR PaxDb; 9606-ENSP00000299138; -. DR PeptideAtlas; Q96QK1; -. DR ProteomicsDB; 77884; -. DR Pumba; Q96QK1; -. DR Antibodypedia; 28023; 276 antibodies from 41 providers. DR DNASU; 55737; -. DR YCharOS; Q96QK1; Tested 13 antibodies from 7 manufacturers. DR Ensembl; ENST00000299138.12; ENSP00000299138.7; ENSG00000069329.20. DR GeneID; 55737; -. DR KEGG; hsa:55737; -. DR MANE-Select; ENST00000299138.12; ENSP00000299138.7; NM_018206.6; NP_060676.2. DR UCSC; uc002eef.5; human. DR AGR; HGNC:13487; -. DR ClinPGx; PA37783; -. DR CTD; 55737; -. DR DisGeNET; 55737; -. DR GeneCards; VPS35; -. DR GeneReviews; VPS35; -. DR HGNC; HGNC:13487; VPS35. DR HPA; ENSG00000069329; Low tissue specificity. DR MalaCards; VPS35; -. DR MIM; 601501; gene. DR MIM; 614203; phenotype. DR OpenTargets; ENSG00000069329; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000069329; -. DR eggNOG; KOG1107; Eukaryota. DR GeneTree; ENSGT00390000007315; -. DR HOGENOM; CLU_005836_1_0_1; -. DR InParanoid; Q96QK1; -. DR OMA; YIRSREY; -. DR OrthoDB; 10258141at2759; -. DR PAN-GO; Q96QK1; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96QK1; -. DR PathwayCommons; Q96QK1; -. DR Reactome; R-HSA-3238698; WNT ligand biogenesis and trafficking. DR SignaLink; Q96QK1; -. DR SIGNOR; Q96QK1; -. DR Agora; ENSG00000069329; -. DR BioGRID-ORCS; 55737; 424 hits in 1189 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; VPS35; human. DR EvolutionaryTrace; Q96QK1; -. DR GeneWiki; VPS35; -. DR GenomeRNAi; 55737; -. DR Pharos; Q96QK1; Tbio. DR PRO; PR:Q96QK1; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q96QK1; protein. DR Bgee; ENSG00000069329; Expressed in ventricular zone and 113 other cell types or tissues. DR ExpressionAtlas; Q96QK1; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005770; C:late endosome; IBA:GO_Central. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:HPA. DR GO; GO:0099073; C:mitochondrion-derived vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl. DR GO; GO:0098793; C:presynapse; IEA:Ensembl. DR GO; GO:0030904; C:retromer complex; IDA:UniProtKB. DR GO; GO:0030906; C:retromer, cargo-selective complex; IDA:UniProtKB. DR GO; GO:0097422; C:tubular endosome; IDA:UniProtKB. DR GO; GO:0031748; F:D1 dopamine receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0032456; P:endocytic recycling; IMP:UniProtKB. DR GO; GO:0006886; P:intracellular protein transport; IBA:GO_Central. DR GO; GO:0007040; P:lysosome organization; IEA:Ensembl. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IMP:ParkinsonsUK-UCL. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl. DR GO; GO:0050728; P:negative regulation of inflammatory response; IGI:ParkinsonsUK-UCL. DR GO; GO:1902823; P:negative regulation of late endosome to lysosome transport; IMP:UniProtKB. DR GO; GO:1905166; P:negative regulation of lysosomal protein catabolic process; IEA:Ensembl. DR GO; GO:0032463; P:negative regulation of protein homooligomerization; IEA:Ensembl. DR GO; GO:1903828; P:negative regulation of protein localization; IEA:Ensembl. DR GO; GO:0099639; P:neurotransmitter receptor transport, endosome to plasma membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0098887; P:neurotransmitter receptor transport, endosome to postsynaptic membrane; IEA:Ensembl. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IEA:Ensembl. DR GO; GO:1903181; P:positive regulation of dopamine biosynthetic process; IEA:Ensembl. DR GO; GO:0060161; P:positive regulation of dopamine receptor signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ParkinsonsUK-UCL. DR GO; GO:0090326; P:positive regulation of locomotion involved in locomotory behavior; IEA:Ensembl. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IMP:ParkinsonsUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IMP:ParkinsonsUK-UCL. DR GO; GO:0061357; P:positive regulation of Wnt protein secretion; IEA:Ensembl. DR GO; GO:0031648; P:protein destabilization; IEA:Ensembl. DR GO; GO:0036010; P:protein localization to endosome; IMP:UniProtKB. DR GO; GO:1902950; P:regulation of dendritic spine maintenance; IMP:ParkinsonsUK-UCL. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IGI:ParkinsonsUK-UCL. DR GO; GO:0150052; P:regulation of postsynapse assembly; IEA:Ensembl. DR GO; GO:1905606; P:regulation of presynapse assembly; ISS:ParkinsonsUK-UCL. DR GO; GO:0051246; P:regulation of protein metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL. DR GO; GO:0090128; P:regulation of synapse maturation; IEA:Ensembl. DR GO; GO:2000331; P:regulation of terminal button organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IMP:UniProtKB. DR GO; GO:0045056; P:transcytosis; IDA:UniProtKB. DR GO; GO:0099003; P:vesicle-mediated transport in synapse; IEA:Ensembl. DR GO; GO:0050882; P:voluntary musculoskeletal movement; IEA:Ensembl. DR GO; GO:0016055; P:Wnt signaling pathway; NAS:ParkinsonsUK-UCL. DR FunFam; 1.25.40.660:FF:000001; Vacuolar protein sorting-associated protein 35; 1. DR Gene3D; 1.25.40.660; Vacuolar protein sorting-associated protein 35, helical subcomplex Vps35-C; 1. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR005378; Vps35. DR InterPro; IPR042491; Vps35_C. DR PANTHER; PTHR11099:SF0; VACUOLAR PROTEIN SORTING-ASSOCIATED PROTEIN 35; 1. DR PANTHER; PTHR11099; VACUOLAR SORTING PROTEIN 35; 1. DR Pfam; PF03635; Vps35; 1. DR PIRSF; PIRSF009375; Retromer_Vps35; 1. DR SUPFAM; SSF48371; ARM repeat; 1. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasm; Endosome; Host-virus interaction; Membrane; KW Neurodegeneration; Parkinson disease; Parkinsonism; Phosphoprotein; KW Protein transport; Proteomics identification; Reference proteome; KW Transport. FT CHAIN 1..796 FT /note="Vacuolar protein sorting-associated protein 35" FT /id="PRO_0000065896" FT REGION 25..44 FT /note="Interaction with SNX3" FT /evidence="ECO:0000269|PubMed:24344282" FT REGION 205..215 FT /note="Interaction with SNX3" FT /evidence="ECO:0000269|PubMed:24344282" FT REGION 438..796 FT /note="Interaction with SLC11A2" FT /evidence="ECO:0000269|PubMed:24344282" FT REGION 500..693 FT /note="Interaction with IGF2R cytoplasmic domain" FT /evidence="ECO:0000269|PubMed:15078903" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 783 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9EQH3" FT MOD_RES 791 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9EQH3" FT VARIANT 51 FT /note="G -> S (in dbSNP:rs193077277)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066653" FT VARIANT 57 FT /note="M -> I (in dbSNP:rs183554824)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066654" FT VARIANT 82 FT /note="T -> R (in dbSNP:rs188245364)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066655" FT VARIANT 241 FT /note="I -> M (found in a patient with Parkinson disease; FT dbSNP:rs192783364)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066656" FT VARIANT 316 FT /note="P -> S (found in a patient with Parkinson disease; FT dbSNP:rs770029606)" FT /evidence="ECO:0000269|PubMed:21763482" FT /id="VAR_066657" FT VARIANT 469 FT /note="Q -> P (found in a consanguineous family with FT intellectual disability; uncertain significance)" FT /evidence="ECO:0000269|PubMed:28397838" FT /id="VAR_080769" FT VARIANT 524 FT /note="R -> W (found in a patient with Parkinson disease; FT dbSNP:rs184277092)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066658" FT VARIANT 602 FT /note="V -> D (in dbSNP:rs34687100)" FT /id="VAR_054046" FT VARIANT 620 FT /note="D -> N (in PARK17; decreases interaction with FT WASHC2C, FKBP15 and the WASH complex; impairs recruitment FT of the WASH complex to endosomes; shows reduced retrograde FT transport of selective cargo between lysosomes and the FT Golgi apparatus; shows a progressive reduction in neurite FT length and branching; dbSNP:rs188286943)" FT /evidence="ECO:0000269|PubMed:21763482, FT ECO:0000269|PubMed:21763483, ECO:0000269|PubMed:22517097, FT ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24819384, FT ECO:0000269|PubMed:24980502" FT /id="VAR_066659" FT VARIANT 737 FT /note="A -> V (in dbSNP:rs749516404)" FT /evidence="ECO:0000269|PubMed:21763482" FT /id="VAR_066660" FT VARIANT 774 FT /note="L -> M (in dbSNP:rs192419029)" FT /evidence="ECO:0000269|PubMed:21763483" FT /id="VAR_066661" FT MUTAGEN 108 FT /note="L->P: Disrupts interaction with VPS26; no effect on FT interaction with VPS29." FT /evidence="ECO:0000269|PubMed:23331060" FT MUTAGEN 675 FT /note="H->R: Disrupts interaction with VPS29. Does not FT effect interaction with VPS26." FT /evidence="ECO:0000269|PubMed:23331060" FT CONFLICT 42 FT /note="A -> S (in Ref. 6; CAB66822)" FT /evidence="ECO:0000305" FT CONFLICT 160 FT /note="I -> T (in Ref. 5; BAB14626)" FT /evidence="ECO:0000305" FT CONFLICT 168 FT /note="T -> P (in Ref. 3; AAF89953)" FT /evidence="ECO:0000305" FT CONFLICT 453 FT /note="S -> F (in Ref. 7; AAH10362)" FT /evidence="ECO:0000305" FT CONFLICT 526 FT /note="R -> G (in Ref. 5; BAA91790)" FT /evidence="ECO:0000305" FT CONFLICT 694 FT /note="K -> E (in Ref. 5; BAA91790)" FT /evidence="ECO:0000305" FT CONFLICT 796 FT /note="L -> H (in Ref. 5; BAA91137)" FT /evidence="ECO:0000305" FT HELIX 14..35 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 39..50 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 51..54 FT /evidence="ECO:0007829|PDB:5F0J" FT STRAND 56..58 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 60..86 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 94..97 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 98..100 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 104..121 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 123..125 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 126..136 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 137..139 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 143..156 FT /evidence="ECO:0007829|PDB:5F0J" FT TURN 157..160 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 176..196 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 197..199 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 206..229 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 235..240 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 242..252 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 256..269 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 272..277 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 279..286 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 295..310 FT /evidence="ECO:0007829|PDB:5F0J" FT STRAND 313..315 FT /evidence="ECO:0007829|PDB:5F0J" FT STRAND 320..322 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 324..338 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 344..361 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 366..382 FT /evidence="ECO:0007829|PDB:5F0J" FT STRAND 390..392 FT /evidence="ECO:0007829|PDB:5F0P" FT HELIX 393..408 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 413..416 FT /evidence="ECO:0007829|PDB:5F0J" FT TURN 419..422 FT /evidence="ECO:0007829|PDB:5F0P" FT HELIX 423..427 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 430..446 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:5F0J" FT HELIX 485..498 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 503..518 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 521..528 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 530..545 FT /evidence="ECO:0007829|PDB:5OSI" FT TURN 546..549 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 553..573 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 578..594 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 599..617 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 621..637 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 643..657 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 663..672 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 674..678 FT /evidence="ECO:0007829|PDB:5OSI" FT STRAND 685..687 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 693..708 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 713..732 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 740..753 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 754..756 FT /evidence="ECO:0007829|PDB:5OSI" FT HELIX 761..778 FT /evidence="ECO:0007829|PDB:5OSI" SQ SEQUENCE 796 AA; 91707 MW; 28D2DD1C6B920A0A CRC64; MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML GELRTSMLSP KSYYELYMAI SDELHYLEVY LTDEFAKGRK VADLYELVQY AGNIIPRLYL LITVGVVYVK SFPQSRKDIL KDLVEMCRGV QHPLRGLFLR NYLLQCTRNI LPDEGEPTDE ETTGDISDSM DFVLLNFAEM NKLWVRMQHQ GHSRDREKRE RERQELRILV GTNLVRLSQL EGVNVERYKQ IVLTGILEQV VNCRDALAQE YLMECIIQVF PDEFHLQTLN PFLRACAELH QNVNVKNIII ALIDRLALFA HREDGPGIPA DIKLFDIFSQ QVATVIQSRQ DMPSEDVVSL QVSLINLAMK CYPDRVDYVD KVLETTVEIF NKLNLEHIAT SSAVSKELTR LLKIPVDTYN NILTVLKLKH FHPLFEYFDY ESRKSMSCYV LSNVLDYNTE IVSQDQVDSI MNLVSTLIQD QPDQPVEDPD PEDFADEQSL VGRFIHLLRS EDPDQQYLIL NTARKHFGAG GNQRIRFTLP PLVFAAYQLA FRYKENSKVD DKWEKKCQKI FSFAHQTISA LIKAELAELP LRLFLQGALA AGEIGFENHE TVAYEFMSQA FSLYEDEISD SKAQLAAITL IIGTFERMKC FSEENHEPLR TQCALAASKL LKKPDQGRAV STCAHLFWSG RNTDKNGEEL HGGKRVMECL KKALKIANQC MDPSLQVQLF IEILNRYIYF YEKENDAVTI QVLNQLIQKI REDLPNLESS EETEQINKHF HNTLEHLRLR RESPESEGPI YEGLIL //