ID PRKN_DROME Reviewed; 482 AA. AC Q7KTX7; Q86CZ3; Q86LE7; Q95TI4; DT 07-APR-2021, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 02-SEP-2026, entry version 190. DE RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000303|PubMed:12642658}; DE EC=2.3.2.31 {ECO:0000269|PubMed:17456438, ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:24901221}; GN Name=park {ECO:0000303|PubMed:17123504, GN ECO:0000312|FlyBase:FBgn0041100}; GN Synonyms=parkin {ECO:0000303|PubMed:12642658}; GN ORFNames=CG10523 {ECO:0000312|FlyBase:FBgn0041100}; OS Drosophila melanogaster (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Altocrustacea; Allotriocarida; OC Hexapoda; Insecta; Pterygota; Neoptera; Eumetabola; Endopterygota; OC Aparaglossata; Panorpida; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7227 {ECO:0000312|Proteomes:UP000000803}; RN [1] {ECO:0000312|Proteomes:UP000000803} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Berkeley {ECO:0000312|Proteomes:UP000000803}; RX PubMed=10731132; DOI=10.1126/science.287.5461.2185; RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C., RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D., RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R., RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., RA Venter J.C.; RT "The genome sequence of Drosophila melanogaster."; RL Science 287:2185-2195(2000). RN [2] {ECO:0000312|Proteomes:UP000000803} RP GENOME REANNOTATION. RC STRAIN=Berkeley {ECO:0000312|Proteomes:UP000000803}; RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083; RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A., RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M., RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic RT review."; RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002). RN [3] {ECO:0000312|EMBL:AAL13983.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=Berkeley {ECO:0000312|EMBL:AAL13983.1}; RC TISSUE=Embryo {ECO:0000312|EMBL:AAL13983.1}; RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080; RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A., RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M., RA Celniker S.E.; RT "A Drosophila full-length cDNA resource."; RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002). RN [4] {ECO:0000312|EMBL:ACH95278.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=Berkeley {ECO:0000312|EMBL:ACH95278.1}; RA Carlson J., Booth B., Frise E., Park S., Wan K., Yu C., Celniker S.; RL Submitted (SEP-2008) to the EMBL/GenBank/DDBJ databases. RN [5] {ECO:0000312|EMBL:AAM18800.2, ECO:0000312|EMBL:AAO48768.1, ECO:0000312|EMBL:AAP20871.1} RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=14646593; DOI=10.1038/emm.2003.52; RA Bae Y.J., Park K.S., Kang S.J.; RT "Genomic organization and expression of parkin in Drosophila RT melanogaster."; RL Exp. Mol. Med. 35:393-402(2003). RN [6] {ECO:0000305} RP FUNCTION, AND DEVELOPMENTAL STAGE. RX PubMed=12642658; DOI=10.1073/pnas.0737556100; RA Greene J.C., Whitworth A.J., Kuo I., Andrews L.A., Feany M.B., RA Pallanck L.J.; RT "Mitochondrial pathology and apoptotic muscle degeneration in Drosophila RT parkin mutants."; RL Proc. Natl. Acad. Sci. U.S.A. 100:4078-4083(2003). RN [7] {ECO:0000305} RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=15073152; DOI=10.1242/dev.01095; RA Pesah Y., Pham T., Burgess H., Middlebrooks B., Verstreken P., Zhou Y., RA Harding M., Bellen H., Mardon G.; RT "Drosophila parkin mutants have decreased mass and cell size and increased RT sensitivity to oxygen radical stress."; RL Development 131:2183-2194(2004). RN [8] {ECO:0000305} RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, RP AND MUTAGENESIS OF LYS-71. RX PubMed=16002472; DOI=10.1073/pnas.0500346102; RA Cha G.H., Kim S., Park J., Lee E., Kim M., Lee S.B., Kim J.M., Chung J., RA Cho K.S.; RT "Parkin negatively regulates JNK pathway in the dopaminergic neurons of RT Drosophila."; RL Proc. Natl. Acad. Sci. U.S.A. 102:10345-10350(2005). RN [9] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=16672980; DOI=10.1038/nature04788; RA Park J., Lee S.B., Lee S., Kim Y., Song S., Kim S., Bae E., Kim J., RA Shong M., Kim J.M., Chung J.; RT "Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by RT parkin."; RL Nature 441:1157-1161(2006). RN [10] {ECO:0000305} RP FUNCTION. RX PubMed=16672981; DOI=10.1038/nature04779; RA Clark I.E., Dodson M.W., Jiang C., Cao J.H., Huh J.R., Seol J.H., Yoo S.J., RA Hay B.A., Guo M.; RT "Drosophila pink1 is required for mitochondrial function and interacts RT genetically with parkin."; RL Nature 441:1162-1166(2006). RN [11] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=17123504; DOI=10.1016/j.ydbio.2006.10.038; RA Riparbelli M.G., Callaini G.; RT "The Drosophila parkin homologue is required for normal mitochondrial RT dynamics during spermiogenesis."; RL Dev. Biol. 303:108-120(2007). RN [12] {ECO:0000305} RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SEPTIN1 AND PNUT, DOMAIN, RP UBIQUITINATION, AND MUTAGENESIS OF 1-MET--GLU-227; LYS-71; ARG-296; RP CYS-310; 328-LEU--GLU-482 AND 433-THR--GLU-482. RX PubMed=17456438; DOI=10.1016/j.ibmb.2007.01.007; RA Bae Y.J., Kang S.J., Park K.S.; RT "Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 RT ubiquitin-protein ligase."; RL Insect Biochem. Mol. Biol. 37:430-439(2007). RN [13] {ECO:0000305} RP FUNCTION, ACTIVITY REGULATION, PATHWAY, SUBCELLULAR LOCATION, DISRUPTION RP PHENOTYPE, PHOSPHORYLATION AT SER-94 AND THR-187, AND MUTAGENESIS OF RP THR-187. 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 [14] {ECO:0000305} RP INTERACTION WITH PINK1. RX PubMed=19048081; DOI=10.1242/dmm.000109; RA Whitworth A.J., Lee J.R., Ho V.M., Flick R., Chowdhury R., McQuibban G.A.; RT "Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's RT disease factors Pink1 and Parkin."; RL Dis. Model. Mech. 1:168-174(2008). RN [15] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=18799731; DOI=10.1073/pnas.0803998105; RA Deng H., Dodson M.W., Huang H., Guo M.; RT "The Parkinson's disease genes pink1 and parkin promote mitochondrial RT fission and/or inhibit fusion in Drosophila."; RL Proc. Natl. Acad. Sci. U.S.A. 105:14503-14508(2008). RN [16] {ECO:0000305} RP FUNCTION. RX PubMed=18230723; DOI=10.1073/pnas.0709336105; RA Poole A.C., Thomas R.E., Andrews L.A., McBride H.M., Whitworth A.J., RA Pallanck L.J.; RT "The PINK1/Parkin pathway regulates mitochondrial morphology."; RL Proc. Natl. Acad. Sci. U.S.A. 105:1638-1643(2008). RN [17] {ECO:0000305} RP FUNCTION. RX PubMed=18443288; DOI=10.1073/pnas.0711845105; RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RT "Pink1 regulates mitochondrial dynamics through interaction with the RT fission/fusion machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 105:7070-7075(2008). RN [18] {ECO:0000305} RP ERRATUM OF PUBMED:18443288. RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RL Proc. Natl. Acad. Sci. U.S.A. 105:17585-17585(2008). RN [19] {ECO:0000305} RP FUNCTION. RX PubMed=20496123; DOI=10.1007/s10059-010-0068-1; RA Hwang S., Kim D., Choi G., An S.W., Hong Y.K., Suh Y.S., Lee M.J., RA Cho K.S.; RT "Parkin suppresses c-Jun N-terminal kinase-induced cell death via RT transcriptional regulation in Drosophila."; RL Mol. Cells 29:575-580(2010). RN [20] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=20483372; DOI=10.1016/j.nbd.2010.05.011; RA Saini N., Oelhafen S., Hua H., Georgiev O., Schaffner W., Bueeler H.; RT "Extended lifespan of Drosophila parkin mutants through sequestration of RT redox-active metals and enhancement of anti-oxidative pathways."; RL Neurobiol. Dis. 40:82-92(2010). RN [21] {ECO:0000305} RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, INTERACTION RP WITH MARF, AND SUBCELLULAR LOCATION. RX PubMed=20194754; DOI=10.1073/pnas.0913485107; RA Ziviani E., Tao R.N., Whitworth A.J.; RT "Drosophila parkin requires PINK1 for mitochondrial translocation and RT ubiquitinates mitofusin."; RL Proc. Natl. Acad. Sci. U.S.A. 107:5018-5023(2010). RN [22] {ECO:0000305} RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=20869429; DOI=10.1016/j.gene.2010.09.003; RA Ottone C., Galasso A., Gemei M., Pisa V., Gigliotti S., Piccioni F., RA Graziani F., Verrotti di Pianella A.; RT "Diminution of eIF4E activity suppresses parkin mutant phenotypes."; RL Gene 470:12-19(2011). RN [23] {ECO:0000305} RP FUNCTION. 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 [24] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=23509287; DOI=10.1073/pnas.1221132110; RA Vincow E.S., Merrihew G., Thomas R.E., Shulman N.J., Beyer R.P., RA MacCoss M.J., Pallanck L.J.; RT "The PINK1-Parkin pathway promotes both mitophagy and selective respiratory RT chain turnover in vivo."; RL Proc. Natl. Acad. Sci. U.S.A. 110:6400-6405(2013). RN [25] {ECO:0000305} RP FUNCTION. RX PubMed=23650379; DOI=10.1073/pnas.1216197110; RA Rana A., Rera M., Walker D.W.; RT "Parkin overexpression during aging reduces proteotoxicity, alters RT mitochondrial dynamics, and extends lifespan."; RL Proc. Natl. Acad. Sci. U.S.A. 110:8638-8643(2013). RN [26] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=24192653; DOI=10.1161/circresaha.114.302734; RA Bhandari P., Song M., Chen Y., Burelle Y., Dorn G.W. II; RT "Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts RT and its containment by suppressing mitofusin."; RL Circ. Res. 114:257-265(2014). RN [27] {ECO:0000305} RP INTERACTION WITH MARF. 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 [28] {ECO:0000305} RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, DISRUPTION RP PHENOTYPE, PHOSPHORYLATION AT SER-94, AND MUTAGENESIS OF SER-94. RX PubMed=24901221; DOI=10.1371/journal.pgen.1004391; RA Shiba-Fukushima K., Inoshita T., Hattori N., Imai Y.; RT "PINK1-mediated phosphorylation of Parkin boosts Parkin activity in RT Drosophila."; RL PLoS Genet. 10:E1004391-E1004391(2014). RN [29] {ECO:0000305} RP FUNCTION, ACTIVITY REGULATION, AND PHOSPHORYLATION AT SER-94. 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 [30] {ECO:0000305} RP FUNCTION. RX PubMed=25565208; DOI=10.1016/j.cmet.2014.12.007; RA Gehrke S., Wu Z., Klinkenberg M., Sun Y., Auburger G., Guo S., Lu B.; RT "PINK1 and Parkin control localized translation of respiratory chain RT component mRNAs on mitochondria outer membrane."; RL Cell Metab. 21:95-108(2015). RN [31] {ECO:0000305} RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT RP SER-94, AND MUTAGENESIS OF SER-94. RX PubMed=27906179; DOI=10.1038/cddis.2016.396; RA Zhuang N., Li L., Chen S., Wang T.; RT "PINK1-dependent phosphorylation of PINK1 and Parkin is essential for RT mitochondrial quality control."; RL Cell Death Dis. 7:e2501-e2501(2016). RN [32] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=28435104; DOI=10.1016/j.nbd.2017.04.014; RA Julienne H., Buhl E., Leslie D.S., Hodge J.J.L.; RT "Drosophila PINK1 and parkin loss-of-function mutants display a range of RT non-motor Parkinson's disease phenotypes."; RL Neurobiol. Dis. 104:15-23(2017). RN [33] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=29497364; DOI=10.3389/fncel.2018.00039; RA Cackovic J., Gutierrez-Luke S., Call G.B., Juba A., O'Brien S., Jun C.H., RA Buhlman L.M.; RT "Vulnerable Parkin Loss-of-Function Drosophila Dopaminergic Neurons Have RT Advanced Mitochondrial Aging, Mitochondrial Network Loss and Transiently RT Reduced Autophagosome Recruitment."; RL Front. Cell. Neurosci. 12:39-39(2018). RN [34] {ECO:0000305} RP FUNCTION. RX PubMed=31714929; DOI=10.1371/journal.pone.0225214; RA Si H., Ma P., Liang Q., Yin Y., Wang P., Zhang Q., Wang S., Deng H.; RT "Overexpression of pink1 or parkin in indirect flight muscles promotes RT mitochondrial proteostasis and extends lifespan in Drosophila RT melanogaster."; RL PLoS ONE 14:e0225214-e0225214(2019). RN [35] {ECO:0000305} RP FUNCTION, INTERACTION WITH PARIS, AND DISRUPTION PHENOTYPE. RX PubMed=32138754; DOI=10.1186/s13024-020-00363-x; RA Pirooznia S.K., Yuan C., Khan M.R., Karuppagounder S.S., Wang L., Xiong Y., RA Kang S.U., Lee Y., Dawson V.L., Dawson T.M.; RT "PARIS induced defects in mitochondrial biogenesis drive dopamine neuron RT loss under conditions of parkin or PINK1 deficiency."; RL Mol. Neurodegener. 15:17-17(2020). RN [36] {ECO:0000305} RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF THR-433 AND CYS-449. 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 [37] {ECO:0007744|PDB:2LWR, ECO:0007744|PDB:2M48} RP STRUCTURE BY NMR OF 342-482 IN COMPLEX WITH ZINC, FUNCTION, CATALYTIC RP ACTIVITY, PATHWAY, DOMAIN, AND ACTIVE SITE. 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). CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from E2 CC ubiquitin-conjugating enzymes in the form of a thioester and then CC directly transfers the ubiquitin to targeted substrates, such as Paris, CC Marf, Opa1, Miro, pnut, Septin1, Tom20 and porin (PubMed:16002472, CC PubMed:17456438, PubMed:20194754, PubMed:23770917, PubMed:24192653, CC PubMed:24901221, PubMed:25474007, PubMed:27906179, PubMed:31714929, CC PubMed:32047033, PubMed:32138754). Mediates monoubiquitination as well CC as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked CC polyubiquitination of substrates, depending on the context CC (PubMed:18957282, PubMed:23650379, PubMed:24901221, PubMed:25474007, CC PubMed:27906179, PubMed:31714929, PubMed:32047033). Protects against CC mitochondrial dysfunction during cellular stress, by acting downstream CC of Pink1, to coordinate mitochondrial quality control mechanisms that CC remove and replace dysfunctional mitochondrial components CC (PubMed:12642658, PubMed:15073152, PubMed:16672980, PubMed:16672981, CC PubMed:17123504, PubMed:18230723, PubMed:18443288, PubMed:18799731, CC PubMed:18957282, PubMed:20194754, PubMed:20496123, PubMed:23509287, CC PubMed:24192653, PubMed:24901221, PubMed:25474007, PubMed:27906179, CC PubMed:29497364, PubMed:32047033). Depending on the severity of CC mitochondrial damage and/or dysfunction, activity ranges from CC preventing apoptosis and stimulating mitochondrial biogenesis to CC regulating mitochondrial dynamics and eliminating severely damaged CC mitochondria via mitophagy (PubMed:12642658, PubMed:15073152, CC PubMed:16002472, PubMed:16672980, PubMed:16672981, PubMed:17123504, CC PubMed:18230723, PubMed:18443288, PubMed:18799731, PubMed:18957282, CC PubMed:20194754, PubMed:20496123, PubMed:23509287, PubMed:24192653, CC PubMed:24901221, PubMed:25474007, PubMed:27906179, PubMed:29497364, CC PubMed:32047033). Appears to be particularly important in maintaining CC the physiology and function of cells with high energy demands that are CC undergoing stress or altered metabolic environment, including CC spermatids, muscle cells and neurons such as the dopaminergic (DA) CC neurons (PubMed:12642658, PubMed:15073152, PubMed:16002472, CC PubMed:16672980, PubMed:17123504, PubMed:18799731, PubMed:20483372, CC PubMed:22396657, PubMed:24901221, PubMed:28435104, PubMed:29497364, CC PubMed:31714929). Activation and recruitment onto the outer membrane of CC damaged/dysfunctional mitochondria (OMM) requires Pink1-mediated CC phosphorylation of both park and ubiquitin (PubMed:18230723, CC PubMed:18799731, PubMed:18957282, PubMed:20194754, PubMed:22396657, CC PubMed:24901221, PubMed:25474007, PubMed:27906179). In depolarized CC mitochondria, mediates the decision between mitophagy or preventing CC apoptosis by inducing either the poly- or monoubiquitination of CC porin/VDAC; polyubiquitination of porin promotes mitophagy, while CC monoubiquitination of porin decreases mitochondrial calcium influx CC which ultimately inhibits apoptosis (PubMed:32047033). When cellular CC stress results in irreversible mitochondrial damage, promotes the CC autophagic degradation of dysfunctional depolarized mitochondria CC (mitophagy) by promoting the ubiquitination of mitochondrial proteins CC (PubMed:16672980, PubMed:16672981, PubMed:18957282, PubMed:20194754, CC PubMed:23509287, PubMed:24192653, PubMed:25474007, PubMed:29497364). CC Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked CC polyubiquitin chains following mitochondrial damage, leading to CC mitophagy (PubMed:23650379, PubMed:32047033). In developing tissues, CC inhibits JNK-mediated apoptosis by negatively regulating bsk CC transcription (PubMed:16002472, PubMed:20496123). The Pink1-park CC pathway also promotes fission and/or inhibits fusion of damaged CC mitochondria by mediating the ubiquitination and subsequent degradation CC of proteins involved in mitochondrial fusion/fission such as Marf, Opa1 CC and fzo (PubMed:17123504, PubMed:18230723, PubMed:18443288, CC PubMed:18799731, PubMed:20194754, PubMed:23650379, PubMed:24192653, CC PubMed:24901221, PubMed:29497364). This prevents the refusion of CC unhealthy mitochondria with the healthy mitochondrial network and/or CC initiates mitochondrial fragmentation facilitating their later CC engulfment by autophagosomes (PubMed:17123504, PubMed:18230723, CC PubMed:18443288, PubMed:18799731, PubMed:20194754, PubMed:23650379, CC PubMed:24192653, PubMed:24901221, PubMed:29497364). Regulates motility CC of damaged mitochondria by phosphorylating Miro which likely promotes CC its park-dependent degradation by the proteasome; in motor neurons, CC this inhibits mitochondrial intracellular anterograde transport along CC the axons which probably increases the chance of the mitochondria being CC eliminated in the soma (PubMed:22396657). The Pink1-park pathway is CC also involved in mitochondrial regeneration processes such as promoting CC mitochondrial biogenesis, activating localized mitochondrial repair, CC promoting selective turnover of mitochondrial proteins and initiating CC the mitochondrial import of endogenous proteins (PubMed:16672980, CC PubMed:20496123, PubMed:20869429, PubMed:23509287, PubMed:23650379, CC PubMed:24192653, PubMed:25565208, PubMed:29497364). Involved in CC mitochondrial biogenesis via the ubiquitination of transcriptional CC repressor Paris which leads to its subsequent proteasomal degradation CC and allows activation of the transcription factor srl (PubMed:23509287, CC PubMed:29497364, PubMed:32138754). Promotes localized mitochondrial CC repair by activating the translation of specific nuclear-encoded CC mitochondrial RNAs (nc-mtRNAs) on the mitochondrial surface, including CC several key electron transport chain component nc-mtRNAs CC (PubMed:23509287, PubMed:25565208). {ECO:0000269|PubMed:12642658, CC ECO:0000269|PubMed:15073152, ECO:0000269|PubMed:16002472, CC ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:16672981, CC ECO:0000269|PubMed:17123504, ECO:0000269|PubMed:17456438, CC ECO:0000269|PubMed:18230723, ECO:0000269|PubMed:18443288, CC ECO:0000269|PubMed:18799731, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:20483372, CC ECO:0000269|PubMed:20496123, ECO:0000269|PubMed:20869429, CC ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23509287, CC ECO:0000269|PubMed:23650379, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:24192653, ECO:0000269|PubMed:24901221, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25565208, CC ECO:0000269|PubMed:27906179, ECO:0000269|PubMed:28435104, CC ECO:0000269|PubMed:29497364, ECO:0000269|PubMed:31714929, CC ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:32138754}. 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:17456438, CC ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:24901221}; CC -!- ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe- CC 481 inserts into a hydrophobic groove in RING-0, occluding the CC ubiquitin acceptor site Cys-449, whereas the REP repressor element CC binds RING-1 and blocks its E2-binding site (By similarity). Activation CC of park requires 2 steps: (1) phosphorylation at Ser-94 by Pink1 and CC (2) binding to phosphorylated ubiquitin, leading to unlock repression CC of the catalytic Cys-449 by the RING-0 region via an allosteric CC mechanism and converting park to its fully-active form CC (PubMed:18957282, PubMed:20194754, PubMed:24901221, PubMed:25474007, CC PubMed:27906179). According to another report, phosphorylation at Ser- CC 94 by Pink1 is not essential for activation and only binding to CC phosphorylated ubiquitin is essential to unlock repression (By CC similarity). {ECO:0000250|UniProtKB:O60260, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20194754, CC ECO:0000269|PubMed:24901221, ECO:0000269|PubMed:25474007, CC ECO:0000269|PubMed:27906179}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:17456438, ECO:0000269|PubMed:20194754, CC ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:24901221}. CC -!- SUBUNIT: Forms an E3 ubiquitin ligase complex with E2 ubiquitin- CC conjugating enzymes (PubMed:17456438). Interacts with Pink1 CC (PubMed:19048081). Interacts with Marf (PubMed:20194754, CC PubMed:24898855). Interacts with Paris (PubMed:32138754). Interacts CC with septins Septin1 and pnut (PubMed:17456438). CC {ECO:0000269|PubMed:17456438, ECO:0000269|PubMed:19048081, CC ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:24898855, CC ECO:0000269|PubMed:32138754}. CC -!- INTERACTION: CC Q7KTX7; Q7YU24: Marf; NbExp=2; IntAct=EBI-131530, EBI-83262; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:27906179}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:20869429}. CC Note=Translocates from the cytosol to dysfunctional mitochondria that CC have lost their mitochondrial membrane potential; recruitment to CC mitochondria is Pink1-dependent. {ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:27906179}. CC -!- TISSUE SPECIFICITY: In oocytes, accumulates in early egg chambers where CC it is enriched until stages 9-10, localizing mainly to the posterior CC pole and anterior margin (at protein level) (PubMed:20869429). After CC stage 10 it is no longer detected in the oocyte (at protein level) CC (PubMed:20869429). In embryos, ubiquitously expressed in the early CC stages (stages 2 to 5) (at protein level) (PubMed:14646593). Expression CC levels decrease at later stages and becomes restricted to the brain and CC nerve cord from stage 9 (at protein level) (PubMed:14646593). CC Relatively higher levels of expression in the head compared to the body CC (PubMed:16002472). Enriched in the dorsomedial (DM) dopaminergic CC neurons (PubMed:16002472). {ECO:0000269|PubMed:14646593, CC ECO:0000269|PubMed:16002472, ECO:0000269|PubMed:20869429}. CC -!- DEVELOPMENTAL STAGE: Expressed throughout development (PubMed:12642658, CC PubMed:14646593, PubMed:15073152, PubMed:16002472). Highest levels of CC expression in adults and early embryos (PubMed:14646593, CC PubMed:15073152). First detected in 0-2 hour embryos, likely due to a CC maternal contribution as it is not detected during the rest of CC embryogenesis (PubMed:15073152). Expressed in third instar larvae, CC throughout pupal development and in adults (PubMed:15073152). CC {ECO:0000269|PubMed:12642658, ECO:0000269|PubMed:14646593, CC ECO:0000269|PubMed:15073152, ECO:0000269|PubMed:16002472}. CC -!- DOMAIN: The RING-type 1 zinc finger domain is required for CC ubiquitination activity. {ECO:0000269|PubMed:17456438}. CC -!- DOMAIN: Members of the RBR family are atypical E3 ligases CC (PubMed:17456438, PubMed:23770917). They interact with E2 conjugating CC enzymes and function like HECT-type E3 enzymes: they bind E2s via the CC first RING domain, but require an obligate trans-thiolation step during CC the ubiquitin transfer, requiring a conserved cysteine residue in the CC second RING domain (PubMed:17456438, PubMed:23770917). CC {ECO:0000269|PubMed:17456438, ECO:0000269|PubMed:23770917}. CC -!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own CC degradation. {ECO:0000269|PubMed:17456438}. CC -!- PTM: Phosphorylated (PubMed:18957282, PubMed:24901221, PubMed:25474007, CC PubMed:27906179). Activation requires phosphorylation at Ser-94 by CC Pink1 and binding to Pink1-phosphorylated polyubiquitin chains CC (PubMed:18957282, PubMed:24901221, PubMed:25474007, PubMed:27906179). CC Phosphorylation at Thr-187 by Pink1 is also important for mitochondrial CC localization (PubMed:18957282). {ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:24901221, ECO:0000269|PubMed:25474007, CC ECO:0000269|PubMed:27906179}. CC -!- DISRUPTION PHENOTYPE: Pupal lethal; large percentage fail to enclose CC (PubMed:15073152). Escapers that develop into adults display various CC phenotypes that appear to be the result of mitochondrial abnormalities CC and/or mitochondrial dysfunction (PubMed:16672980, PubMed:23509287, CC PubMed:24192653, PubMed:29497364). In various tissues including the CC indirect flight muscles (IFM), thoracic muscles, sperm, cardiomyocytes CC and neurons such as the dopaminergic (DA) neurons, mitochondria display CC abnormalities such as swelling, loss of cristae, fragmentation, CC aggregation and/or mitochondrial disorganization, and they are CC dysfunctional resulting in defects such as mitochondrial CC depolarization, increased reactive oxygen species (ROS) production, CC reduced ATP, decreased mitochondrial DNA and reduced mitochondrial CC protein levels (PubMed:15073152, PubMed:17123504, PubMed:18799731, CC PubMed:18957282, PubMed:20483372, PubMed:24192653, PubMed:24901221, CC PubMed:29497364). As a result adults are reduced in size, display CC reduced survival and decreased fertility (PubMed:15073152, CC PubMed:16672980, PubMed:17123504, PubMed:24192653, PubMed:24901221, CC PubMed:29497364). They also exhibit age-dependent and progressive CC degradation of the IFM and the DA neurons, especially in the CC protocerebral posterior lateral 1 (PPL1) cluster, which likely CC contribute to the observed locomotive defects, down-turned rigid wings CC and crushed thorax phenotypes (PubMed:15073152, PubMed:16002472, CC PubMed:18799731, PubMed:18957282, PubMed:24901221, PubMed:29497364). CC However, another report did not observe any age-dependent dopaminergic CC neuron loss within 21 days post-eclosion (PubMed:15073152). Also CC affects non-motor behaviors such as reduced three-hour memory CC performance and irregular circadian rhythms under constant darkness, CC likely as a result of the neurodegradation (PubMed:28435104). Double CC knockout of Pink1 and park display no increase in the severity of their CC phenotypes compared to single mutants (PubMed:16672980). However, CC expression of park in Pink1 mutants markedly rescues most of the Pink1 CC mutant phenotypes, whereas expression of Pink1 in park mutants fails to CC rescue the defective thorax and abnormal wing position CC (PubMed:16672980). Double knockdown with Paris, improves climbing CC performance defects and rescues decreased mRNA levels of srl, ewg and CC TFAM, observed in park mutants (PubMed:32138754). CC {ECO:0000269|PubMed:15073152, ECO:0000269|PubMed:16002472, CC ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:17123504, CC ECO:0000269|PubMed:18799731, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:20483372, ECO:0000269|PubMed:23509287, CC ECO:0000269|PubMed:24192653, ECO:0000269|PubMed:24901221, CC ECO:0000269|PubMed:28435104, ECO:0000269|PubMed:29497364, CC ECO:0000269|PubMed:32138754}. CC -!- SIMILARITY: Belongs to the RBR family. Parkin subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF510072; AAM43930.1; -; Genomic_DNA. DR EMBL; AE014296; AAN12154.1; -; Genomic_DNA. DR EMBL; AE014296; AAN12155.1; -; Genomic_DNA. DR EMBL; AY058754; AAL13983.1; -; mRNA. DR EMBL; BT044504; ACH95278.1; -; mRNA. DR EMBL; AY093423; AAM18800.2; -; mRNA. DR EMBL; AY207374; AAO48768.1; -; mRNA. DR EMBL; AY261675; AAP20871.1; -; mRNA. DR RefSeq; NP_730600.1; NM_168884.2. DR RefSeq; NP_730601.1; NM_168885.3. DR PDB; 2LWR; NMR; -; A=417-482. DR PDB; 2M48; NMR; -; A=342-482. DR PDB; 9C5E; NMR; -; A=410-482. DR AlphaFoldDB; Q7KTX7; -. DR SMR; Q7KTX7; -. DR DIP; DIP-58616N; -. DR FunCoup; Q7KTX7; 797. DR IntAct; Q7KTX7; 28. DR STRING; 7227.FBpp0077974; -. DR iPTMnet; Q7KTX7; -. DR PaxDb; 7227-FBpp0077974; -. DR PeptideAtlas; Q7KTX7; -. DR DNASU; 40336; -. DR EnsemblMetazoa; FBtr0078318; FBpp0077974; FBgn0041100. DR EnsemblMetazoa; FBtr0078319; FBpp0077975; FBgn0041100. DR GeneID; 40336; -. DR KEGG; dme:Dmel_CG10523; -. DR UCSC; CG10523-RB; d. melanogaster. DR AGR; FB:FBgn0041100; -. DR CTD; 40336; -. DR FlyBase; FBgn0041100; park. DR VEuPathDB; VectorBase:FBgn0041100; -. DR eggNOG; KOG0006; Eukaryota. DR HOGENOM; CLU_050804_0_0_1; -. DR InParanoid; Q7KTX7; -. DR OMA; DPKWDIK; -. DR OrthoDB; 1431934at2759; -. DR PhylomeDB; Q7KTX7; -. DR Reactome; R-DME-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-DME-5689877; Josephin domain DUBs. DR Reactome; R-DME-9646399; Aggrephagy. DR Reactome; R-DME-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 40336; 0 hits in 1 CRISPR screen. DR EvolutionaryTrace; Q7KTX7; -. DR GenomeRNAi; 40336; -. DR PRO; PR:Q7KTX7; -. DR Proteomes; UP000000803; Chromosome 3L. DR Bgee; FBgn0041100; Expressed in spermatocyte in testis and 42 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IBA:GO_Central. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0000151; C:ubiquitin ligase complex; IBA:GO_Central. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IBA:GO_Central. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0008344; P:adult locomotory behavior; IMP:FlyBase. DR GO; GO:0008345; P:larval locomotory behavior; IMP:FlyBase. DR GO; GO:0000266; P:mitochondrial fission; IGI:FlyBase. DR GO; GO:0007005; P:mitochondrion organization; IMP:FlyBase. DR GO; GO:0000423; P:mitophagy; IMP:FlyBase. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0046329; P:negative regulation of JNK cascade; IDA:FlyBase. DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; IMP:FlyBase. DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:FlyBase. DR GO; GO:0048477; P:oogenesis; IMP:FlyBase. DR GO; GO:1903599; P:positive regulation of autophagy of mitochondrion; IMP:UniProtKB. DR GO; GO:0048078; P:positive regulation of compound eye pigmentation; IMP:BHF-UCL. DR GO; GO:1904061; P:positive regulation of locomotor rhythm; IMP:UniProtKB. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IMP:FlyBase. DR GO; GO:1901526; P:positive regulation of mitophagy; IMP:UniProtKB. DR GO; GO:1904457; P:positive regulation of neuronal action potential; IMP:UniProtKB. DR GO; GO:0051865; P:protein autoubiquitination; IDA:FlyBase. DR GO; GO:0006513; P:protein monoubiquitination; IDA:FlyBase. DR GO; GO:0000209; P:protein polyubiquitination; IDA:FlyBase. DR GO; GO:0016567; P:protein ubiquitination; IDA:FlyBase. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:FlyBase. DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:FlyBase. DR GO; GO:0006979; P:response to oxidative stress; IMP:FlyBase. DR GO; GO:0030382; P:sperm mitochondrion organization; IMP:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; IMP:FlyBase. DR GO; GO:0061734; P:type 2 mitophagy; IMP:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:FlyBase. 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 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:000484; 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 Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR047534; BRcat_RBR_parkin. DR InterPro; IPR031127; E3_UB_ligase_RBR. 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; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR041170; Znf-RING_14. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR11685; RBR FAMILY RING FINGER AND IBR DOMAIN-CONTAINING; 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; 3. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. DR PDBsum; 2LWR; -. DR PDBsum; 2M48; -. DR PDBsum; 9C5E; -. PE 1: Evidence at protein level; KW 3D-structure; Autophagy; Cytoplasm; Metal-binding; Mitochondrion; KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation; KW Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..482 FT /note="E3 ubiquitin-protein ligase parkin" FT /id="PRO_0000452364" FT DOMAIN 30..99 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT ZN_FING 157..246 FT /note="RING-type 0; atypical" FT /evidence="ECO:0000250|UniProtKB:O60260" FT ZN_FING 259..314 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 334..394 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 432..473 FT /note="IBR-type" FT /evidence="ECO:0000255" FT ZN_FING 436..467 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT REGION 255..482 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ACT_SITE 449 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:32047033" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 166 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 178 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 181 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 208 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 232 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 235 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:E0VIU9" FT BINDING 259 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 262 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 274 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 278 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 281 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 284 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 310 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 314 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 353 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, ECO:0007744|PDB:2M48" FT BINDING 358 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, ECO:0007744|PDB:2M48" FT BINDING 373 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, ECO:0007744|PDB:2M48" FT BINDING 377 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, ECO:0007744|PDB:2M48" FT BINDING 382 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, ECO:0007744|PDB:2M48" FT BINDING 385 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, ECO:0007744|PDB:2M48" FT BINDING 390 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, ECO:0007744|PDB:2M48" FT BINDING 394 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, ECO:0007744|PDB:2M48" FT BINDING 436 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 439 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 454 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 459 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 464 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 467 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 475 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT BINDING 479 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917, ECO:0007744|PDB:2LWR, FT ECO:0007744|PDB:2M48" FT MOD_RES 94 FT /note="Phosphoserine; by Pink1" FT /evidence="ECO:0000269|PubMed:24901221" FT MOD_RES 187 FT /note="Phosphothreonine; by Pink1" FT /evidence="ECO:0000269|PubMed:24901221" FT MUTAGEN 71 FT /note="K->P: Abolishes self-ubiquitination resulting in FT decreased E3 ligase activity." FT /evidence="ECO:0000269|PubMed:16002472, FT ECO:0000269|PubMed:17456438" FT MUTAGEN 94 FT /note="S->A: Abolishes phosphorylation by Pink1 and reduces FT enzyme activity. Mitochondrial morphology and function is FT relatively normal however, expression in TH-neurons results FT in impaired flying ability, impaired dopamine release and FT an age-dependent loss of DA neurons, spherical clustering FT of mitochondria in DA neurons and disturbed mitochondrial FT transport. Able to rescue all mitochondrial and behavioral FT defects caused by the loss of Pink1. Partially rescues FT mitochondrial morphology and abnormal wing posture caused FT by loss of park. No effect on translocation to FT mitochondria." FT /evidence="ECO:0000269|PubMed:24901221, FT ECO:0000269|PubMed:27906179" FT MUTAGEN 94 FT /note="S->G: Phosphomimetic mutant with increased enzyme FT activity. Lethal when ubiquitously expressed. Constitutive FT phosphorylation results in impaired motor activity and FT fragmented mitochondria, likely due to reduced levels of FT the outer mitochondrial membrane proteins Marf and Miro. FT Expression in TH-neurons results in impaired flying FT ability, impaired dopamine release and substantial loss of FT DA neurons in very young adults (5-day old), single large FT mitochondria in each DA neuronal cell and loss of FT mitochondrial transport. Able to rescue reduced adult FT survival caused by loss of Pink1." FT /evidence="ECO:0000269|PubMed:24901221" FT MUTAGEN 187 FT /note="T->A: Reduced mitochondrial localization in the FT presence of Pink1. Reduced rescue of mitochondrial defects FT when expressed in null mutants." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 296 FT /note="R->W: Loss of self-ubiquitination." FT /evidence="ECO:0000269|PubMed:17456438" FT MUTAGEN 310 FT /note="C->G: Loss of self-ubiquitination." FT /evidence="ECO:0000269|PubMed:17456438" FT MUTAGEN 433 FT /note="T->N: Fails to rescue mitochondrial abnormalities FT and increases apoptosis in null mutants." FT /evidence="ECO:0000269|PubMed:32047033" FT MUTAGEN 449 FT /note="C->S: Loss of monoubiquitination and FT polyubiquitination of porin." FT /evidence="ECO:0000269|PubMed:32047033" FT CONFLICT 254 FT /note="I -> F (in Ref. 3; AAL13983)" FT /evidence="ECO:0000305" FT STRAND 383..389 FT /evidence="ECO:0007829|PDB:2M48" FT HELIX 412..414 FT /evidence="ECO:0007829|PDB:9C5E" FT STRAND 432..435 FT /evidence="ECO:0007829|PDB:2LWR" FT TURN 437..439 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 442..444 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 447..450 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:9C5E" FT TURN 457..459 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 462..464 FT /evidence="ECO:0007829|PDB:9C5E" FT STRAND 467..470 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 473..475 FT /evidence="ECO:0007829|PDB:2LWR" FT TURN 476..478 FT /evidence="ECO:0007829|PDB:2LWR" FT STRAND 479..481 FT /evidence="ECO:0007829|PDB:2LWR" SQ SEQUENCE 482 AA; 54105 MW; 4A89C695475B213D CRC64; MSFIFKFIAT FVRKMLELLQ FGGKTLTHTL SIYVKTNTGK TLTVNLEPQW DIKNVKELVA PQLGLQPDDL KIIFAGKELS DATTIEQCDL GQQSVLHAIR LRPPVQRQKI QSATLEEEEP SLSDEASKPL NETLLDLQLE SEERLNITDE ERVRAKAHFF VHCSQCDKLC NGKLRVRCAL CKGGAFTVHR DPECWDDVLK SRRIPGHCES LEVACVDNAA GDPPFAEFFF KCAEHVSGGE KDFAAPLNLI KNNIKNVPCL ACTDVSDTVL VFPCASQHVT CIDCFRHYCR SRLGERQFMP HPDFGYTLPC PAGCEHSFIE EIHHFKLLTR EEYDRYQRFA TEEYVLQAGG VLCPQPGCGM GLLVEPDCRK VTCQNGCGYV FCRNCLQGYH IGECLPEGTG ASATNSCEYT VDPNRAAEAR WDEASNVTIK VSTKPCPKCR TPTERDGGCM HMVCTRAGCG FEWCWVCQTE WTRDCMGAHW FG //