PRKN_DROME
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 03-AUG-2022, entry version 171.
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, 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; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; 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 SEP1 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, Sep1, Tom20 and porin (PubMed:16002472,
CC PubMed:17456438, PubMed:25474007, PubMed:20194754, PubMed:24192653,
CC PubMed:24901221, PubMed:27906179, PubMed:31714929, PubMed:32138754,
CC PubMed:32047033, PubMed:23770917). 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:24901221, PubMed:25474007, PubMed:23650379,
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:18957282, PubMed:18799731, PubMed:18230723,
CC PubMed:18443288, PubMed:20496123, PubMed:20194754, 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:18957282, PubMed:18799731, PubMed:18230723, PubMed:18443288,
CC PubMed:20496123, PubMed:20194754, 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:18957282,
CC PubMed:24901221, PubMed:20194754, PubMed:22396657, PubMed:18799731,
CC PubMed:18230723, 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:20194754, PubMed:18957282,
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:32047033, PubMed:23650379). 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:18443288, PubMed:17123504, PubMed:18799731,
CC PubMed:18230723, 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:18443288, PubMed:17123504,
CC PubMed:18799731, PubMed:18230723, 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:25474007, PubMed:18957282, PubMed:20194754, PubMed:24901221,
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:24898855,
CC PubMed:20194754). Interacts with Paris (PubMed:32138754). Interacts
CC with septins Sep1 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 -!- 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:14646593,
CC PubMed:12642658, PubMed:16002472, PubMed:15073152). Highest levels of
CC expression in adults and early embryos (PubMed:15073152,
CC PubMed:14646593). 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:24192653,
CC PubMed:23509287, 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:18957282,
CC PubMed:18799731, 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:18957282, PubMed:18799731, 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 ---------------------------------------------------------------------------
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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 PDBsum; 2LWR; -.
DR PDBsum; 2M48; -.
DR AlphaFoldDB; Q7KTX7; -.
DR SMR; Q7KTX7; -.
DR DIP; DIP-58616N; -.
DR IntAct; Q7KTX7; 28.
DR STRING; 7227.FBpp0077974; -.
DR PaxDb; Q7KTX7; -.
DR PRIDE; 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 CTD; 40336; -.
DR FlyBase; FBgn0041100; park.
DR VEuPathDB; VectorBase:FBgn0041100; -.
DR eggNOG; KOG0006; Eukaryota.
DR GeneTree; ENSGT00390000011034; -.
DR HOGENOM; CLU_050804_0_0_1; -.
DR InParanoid; Q7KTX7; -.
DR OMA; FAEFFFK; -.
DR OrthoDB; 1140368at2759; -.
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 GenomeRNAi; 40336; -.
DR Proteomes; UP000000803; Chromosome 3L.
DR Bgee; FBgn0041100; Expressed in testis and 20 other tissues.
DR ExpressionAtlas; Q7KTX7; baseline and differential.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IPI:FlyBase.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:CACAO.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:FlyBase.
DR GO; GO:0000422; P:autophagy of mitochondrion; 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:0046329; P:negative regulation of JNK cascade; IDA:FlyBase.
DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; IMP:FlyBase.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IBA:GO_Central.
DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:FlyBase.
DR GO; GO:0048477; P:oogenesis; IMP:FlyBase.
DR GO; GO:0061734; P:parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; IMP:UniProtKB.
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:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IBA:GO_Central.
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:0042981; P:regulation of apoptotic process; IBA:GO_Central.
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:0006511; P:ubiquitin-dependent protein catabolic process; IMP:FlyBase.
DR GO; GO:0055069; P:zinc ion homeostasis; IMP:FlyBase.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR002867; IBR_dom.
DR InterPro; IPR003977; Parkin.
DR InterPro; IPR041565; Parkin_Znf-RING.
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 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; SSF54236; SSF54236; 1.
DR PROSITE; PS51873; TRIAD; 1.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
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 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 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
