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 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 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 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 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 //