PINK1_DROME
ID PINK1_DROME Reviewed; 721 AA.
AC Q0KHV6; Q961J3;
DT 07-APR-2021, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 145.
DE RecName: Full=Serine/threonine-protein kinase Pink1, mitochondrial {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:27906179};
DE AltName: Full=PTEN-induced putative kinase 1 {ECO:0000303|PubMed:16672980};
DE Flags: Precursor;
GN Name=Pink1 {ECO:0000303|PubMed:16672980, ECO:0000312|FlyBase:FBgn0029891};
GN ORFNames=CG4523 {ECO:0000312|FlyBase:FBgn0029891};
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:AAK92983.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley {ECO:0000312|EMBL:AAK92983.1};
RC TISSUE=Head {ECO:0000312|EMBL:AAK92983.1};
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:AFA28429.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Carlson J., Booth B., Frise E., Park S., Wan K., Yu C., Celniker S.;
RL Submitted (FEB-2012) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE,
RP 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 [6] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE,
RP AND DISRUPTION PHENOTYPE.
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 [7] {ECO:0000305}
RP FUNCTION.
RX PubMed=16818890; DOI=10.1073/pnas.0602493103;
RA Yang Y., Gehrke S., Imai Y., Huang Z., Ouyang Y., Wang J.W., Yang L.,
RA Beal M.F., Vogel H., Lu B.;
RT "Mitochondrial pathology and muscle and dopaminergic neuron degeneration
RT caused by inactivation of Drosophila Pink1 is rescued by Parkin.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10793-10798(2006).
RN [8] {ECO:0000305}
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16938835; DOI=10.1073/pnas.0604661103;
RA Wang D., Qian L., Xiong H., Liu J., Neckameyer W.S., Oldham S., Xia K.,
RA Wang J., Bodmer R., Zhang Z.;
RT "Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:13520-13525(2006).
RN [9] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-337; ASP-479 AND
RP ASP-501.
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 [10] {ECO:0000305}
RP INTERACTION WITH PARK; HTRA2 AND RHO-7, SUBCELLULAR LOCATION, AND
RP PROTEOLYTIC PROCESSING.
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 [11] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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 [12] {ECO:0000305}
RP ERRATUM OF PUBMED:18443288.
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. 105:17585-17585(2008).
RN [13] {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 [14] {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 [15] {ECO:0000305}
RP FUNCTION.
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 [16] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF ASP-501.
RX PubMed=22645651; DOI=10.1098/rsob.110012;
RA Woodroof H.I., Pogson J.H., Begley M., Cantley L.C., Deak M.,
RA Campbell D.G., van Aalten D.M., Whitworth A.J., Alessi D.R., Muqit M.M.;
RT "Discovery of catalytically active orthologues of the Parkinson's disease
RT kinase PINK1: analysis of substrate specificity and impact of mutations.";
RL Open Biol. 1:110012-110012(2011).
RN [17] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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 [18] {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 [19] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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 [20] {ECO:0000305}
RP FUNCTION, AND PHOSPHORYLATION AT SER-346.
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 [21] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-346, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF SER-346; ASP-479 AND SER-519.
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 [22] {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 [23] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP LYS-337; ASP-479 AND ASP-501.
RX PubMed=30772175; DOI=10.1016/j.molcel.2019.01.013;
RA Zhang Y., Wang Z.H., Liu Y., Chen Y., Sun N., Gucek M., Zhang F., Xu H.;
RT "PINK1 Inhibits Local Protein Synthesis to Limit Transmission of
RT Deleterious Mitochondrial DNA Mutations.";
RL Mol. Cell 73:1127-1137(2019).
RN [24] {ECO:0000305}
RP FUNCTION.
RX PubMed=32484300; DOI=10.15252/embr.201948686;
RA Han H., Tan J., Wang R., Wan H., He Y., Yan X., Guo J., Gao Q., Li J.,
RA Shang S., Chen F., Tian R., Liu W., Liao L., Tang B., Zhang Z.;
RT "PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent
RT mitochondrial dynamics.";
RL EMBO Rep. 21:48686-48686(2020).
RN [25] {ECO:0000305}
RP FUNCTION, 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).
CC -!- FUNCTION: Acts as a serine/threonine-protein kinase (PubMed:16672980,
CC PubMed:18799731, PubMed:16672981, PubMed:16818890, PubMed:16938835,
CC PubMed:18230723, PubMed:18443288, PubMed:18957282, PubMed:20194754,
CC PubMed:22645651, PubMed:24901221, PubMed:25474007, PubMed:32484300).
CC Exhibits a substrate preference for proline at position P+1 and a
CC general preference at several residues for basic residues such as
CC arginine (By similarity). Also exhibits moderate preferences for a
CC phosphotyrosine at position P-3 and a tryptophan at P-5 (By
CC similarity). Protects against mitochondrial dysfunction during cellular
CC stress by phosphorylating mitochondrial proteins such as park and
CC likely Drp1, to coordinate mitochondrial quality control mechanisms
CC that remove and replace dysfunctional mitochondrial components
CC (PubMed:16672980, PubMed:18799731, PubMed:16672981, PubMed:16818890,
CC PubMed:16938835, PubMed:18230723, PubMed:18443288, PubMed:18957282,
CC PubMed:20194754, PubMed:22645651, PubMed:24901221, PubMed:25474007,
CC PubMed:32484300). Depending on the severity of mitochondrial damage
CC and/or dysfunction, activity ranges from preventing apoptosis and
CC stimulating mitochondrial biogenesis to regulating mitochondrial
CC dynamics and eliminating severely damaged mitochondria via mitophagy
CC (PubMed:16672980, PubMed:16672981, PubMed:16818890, PubMed:16938835,
CC PubMed:18230723, PubMed:18443288, PubMed:18799731, PubMed:18957282,
CC PubMed:20194754, PubMed:23509287, PubMed:24901221, PubMed:25474007).
CC Appears to be particularly important in maintaining the physiology and
CC function of cells with high energy demands that are undergoing stress
CC or altered metabolic environment, including spermatids, muscle cells
CC and neurons such as the dopaminergic (DA) neurons (PubMed:16672980,
CC PubMed:16672981, PubMed:16818890, PubMed:16938835, PubMed:18443288,
CC PubMed:18799731, PubMed:22396657, PubMed:24901221, PubMed:28435104,
CC PubMed:32138754). Mediates the translocation and activation of park at
CC the outer membrane (OMM) of dysfunctional/depolarized mitochondria
CC (PubMed:24901221, PubMed:20194754, PubMed:18957282, PubMed:18799731,
CC PubMed:25474007, PubMed:27906179). At the OMM of damaged mitochondria,
CC phosphorylates pre-existing polyubiquitin chains, the Pink1-
CC phosphorylated polyubiquitin then recruits park from the cytosol to the
CC OMM where park is fully activated by phosphorylation at 'Ser-94' by
CC Pink1 (PubMed:24901221, PubMed:20194754, PubMed:18957282,
CC PubMed:18799731, PubMed:25474007, PubMed:27906179). When cellular
CC stress results in irreversible mitochondrial damage, functions with
CC park to promote the clearance of dysfunctional and/or depolarized
CC mitochondria by selective autophagy (mitophagy) (PubMed:16672980,
CC PubMed:16672981, PubMed:20194754, PubMed:18957282, PubMed:23509287,
CC PubMed:25474007). The Pink1-park pathway also promotes fission and/or
CC inhibits fusion of damaged mitochondria, by phosphorylating and thus
CC promoting the park-dependent degradation of proteins involved in
CC mitochondrial fusion/fission such as Marf, Opa1 and fzo
CC (PubMed:18443288, PubMed:18799731, PubMed:18230723, PubMed:20194754,
CC PubMed:24901221). This prevents the refusion of unhealthy mitochondria
CC with the mitochondrial network or initiates mitochondrial fragmentation
CC facilitating their later engulfment by autophagosomes (PubMed:18443288,
CC PubMed:18799731, PubMed:18230723, PubMed:20194754, PubMed:24901221).
CC Also likely to promote mitochondrial fission independently of park and
CC Atg7-mediated mitophagy, via the phosphorylation and activation of Drp1
CC (PubMed:18443288, PubMed:32484300). Regulates motility of damaged
CC mitochondria by phosphorylating Miro which likely promotes its park-
CC dependent degradation by the proteasome; in motor neurons, this
CC inhibits mitochondrial intracellular anterograde transport along the
CC 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:23509287, PubMed:30772175). Involved in mitochondrial biogenesis
CC by promoting the park-dependent ubiquitination of transcriptional
CC repressor Paris which leads to its subsequent proteasomal degradation
CC and allows activation of the transcription factor srl
CC (PubMed:32138754). Functions with park to promote localized
CC mitochondrial repair by activating the translation of specific nuclear-
CC encoded mitochondrial RNAs (nc-mtRNAs) on the mitochondrial surface,
CC including several key electron transport chain component nc-mtRNAs
CC (PubMed:23509287). During oogenesis, phosphorylates and inactivates
CC larp on the membrane of defective mitochondria, thus impairing local
CC translation and mtDNA replication and consequently, reducing
CC transmission of deleterious mtDNA mutations to the mature oocyte
CC (PubMed:30772175). {ECO:0000250|UniProtKB:D6WMX4,
CC ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:16672981,
CC ECO:0000269|PubMed:16818890, ECO:0000269|PubMed:16938835,
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:22396657,
CC ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:23509287,
CC ECO:0000269|PubMed:24901221, ECO:0000269|PubMed:25474007,
CC ECO:0000269|PubMed:27906179, ECO:0000269|PubMed:28435104,
CC ECO:0000269|PubMed:30772175, ECO:0000269|PubMed:32138754,
CC ECO:0000269|PubMed:32484300}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:27906179};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:22645651,
CC ECO:0000269|PubMed:27906179};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:22645651};
CC -!- SUBUNIT: Interacts with park (PubMed:19048081). Interacts with rho-7
CC and HtrA2 (PubMed:19048081). {ECO:0000269|PubMed:19048081}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:30772175,
CC ECO:0000305|PubMed:16672980, ECO:0000305|PubMed:16672981,
CC ECO:0000305|PubMed:19048081}; Single-pass membrane protein
CC {ECO:0000255}. Mitochondrion inner membrane
CC {ECO:0000305|PubMed:16672980, ECO:0000305|PubMed:16672981,
CC ECO:0000305|PubMed:19048081}; Single-pass membrane protein
CC {ECO:0000255}. Cytoplasm, cytosol {ECO:0000269|PubMed:18957282,
CC ECO:0000269|PubMed:19048081}. Note=Localizes mostly in mitochondrion,
CC and the smaller proteolytic processed fragment localizes in the cytosol
CC as well (PubMed:19048081). When mitochondria are damaged, defective
CC and/or enriched with deleterious mtDNA mutations, Pink1 import is
CC arrested which induces its accumulation on the outer mitochondrial
CC membrane where it acquires kinase activity (PubMed:18957282,
CC PubMed:30772175). Detected in nebenkerns (PubMed:16672981).
CC {ECO:0000269|PubMed:16672981, ECO:0000269|PubMed:18957282,
CC ECO:0000269|PubMed:19048081, ECO:0000269|PubMed:30772175}.
CC -!- TISSUE SPECIFICITY: High expression in the brain and retinas
CC (PubMed:16938835). High expression in the head and testes
CC (PubMed:16672981). High expression in the thorax compared to the head
CC and abdomen (PubMed:16672980). {ECO:0000269|PubMed:16672980,
CC ECO:0000269|PubMed:16672981, ECO:0000269|PubMed:16938835}.
CC -!- DEVELOPMENTAL STAGE: Expressed throughout development, with high levels
CC of expression in adults and low levels of expression in larvae and
CC pupae (PubMed:16672980, PubMed:16672981). Adult males display higher
CC levels of expression than females (PubMed:16672980).
CC {ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:16672981}.
CC -!- PTM: Proteolytically cleaved (PubMed:19048081). In healthy cells, the
CC precursor is continuously imported into mitochondria where it is
CC proteolytically cleaved into its short form by the mitochondrial
CC rhomboid protease rho-7 (PubMed:19048081). The short form is then
CC released into the cytosol where it rapidly undergoes proteasome-
CC dependent degradation (Probable). In unhealthy cells, when cellular
CC stress conditions lead to the loss of mitochondrial membrane potential,
CC mitochondrial import is impaired leading to the precursor accumulating
CC on the outer mitochondrial membrane (OMM) (PubMed:27906179).
CC {ECO:0000269|PubMed:19048081, ECO:0000269|PubMed:27906179,
CC ECO:0000305|PubMed:19048081}.
CC -!- PTM: Autophosphorylated on Ser-346, which activates kinase activity
CC (PubMed:25474007, PubMed:27906179). Loss of mitochondrial membrane
CC potential results in the precursor accumulating on the outer
CC mitochondrial membrane (OMM) where it is activated by
CC autophosphorylation at Ser-346 (PubMed:27906179). Autophosphorylation
CC is sufficient and essential for selective recruitment of park to
CC depolarized mitochondria, likely via Pink1-dependent phosphorylation of
CC polyubiquitin chains (PubMed:25474007, PubMed:27906179).
CC {ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:27906179}.
CC -!- DISRUPTION PHENOTYPE: Adults display various phenotypes that appear to
CC be the result of mitochondrial abnormalities and/or mitochondrial
CC dysfunction (PubMed:16672980, PubMed:16672981, PubMed:18799731,
CC PubMed:18443288, PubMed:24901221, PubMed:27906179, PubMed:30772175). In
CC various tissues including the indirect flight muscles (IFM), thoracic
CC muscles, sperm, cardiomyocytes and neurons including the dopaminergic
CC (DA) neurons, mitochondria display abnormalities such as swelling, loss
CC of cristae, fragmentation, aggregation and/or mitochondrial
CC disorganization, and they are dysfunctional resulting in defects such
CC as mitochondrial depolarization, increased reactive oxygen species
CC (ROS) production, reduced ATP, decreased mitochondrial DNA and reduced
CC mitochondrial protein levels (PubMed:16672980, PubMed:16672981,
CC PubMed:18443288, PubMed:18799731, PubMed:24901221, PubMed:27906179,
CC PubMed:23509287). As a result adults are reduced in size, display
CC reduced survival and decreased fertility (PubMed:16672980,
CC PubMed:16672981, PubMed:18799731). They also exhibit age-dependent and
CC progressive degradation of the IFM and 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:16672980, PubMed:18443288,
CC PubMed:24901221, PubMed:27906179). Also affects non-motor behaviors
CC such as reduced learning, intermediate-term memory and irregular
CC circadian rhythms under constant darkness, likely as a result of the
CC neurodegradation (PubMed:28435104). On the surface of mitochondria
CC enriched with a deleterious mutation, negative regulation of larp-
CC mediated protein synthesis is reduced, and as a consequence the
CC transmission of the deleterious mtDNA mutation to the mature oocyte is
CC more random compared to control oocytes which display decreased
CC inheritance of the mutation (PubMed:30772175). RNAi-mediated knockdown
CC increases the net velocity of anterograde mitochondrial transport in
CC motor neurons, whereas retrograde transport is largely unaffected
CC (PubMed:22396657). Double knockout of Pink1 and park display no
CC increase in the severity of their phenotypes compared to single mutants
CC (PubMed:16672980). However, expression of park in Pink1 mutants
CC markedly rescues most of the Pink1 mutant phenotypes, whereas
CC expression of Pink1 in park mutants fails to rescue the defective
CC thorax and abnormal wing position (PubMed:16672980). Double knockout of
CC Pink1 and Drp1 severely disrupts mitochondrial fusion resulting in
CC mitochondrial aggregates and long threads of mitochondrial tubules
CC (PubMed:18443288). Double knockdown with Paris, improves climbing
CC performance defects and rescues decreased mRNA levels of srl, ewg and
CC TFAM, observed in Pink1 mutants (PubMed:32138754).
CC {ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:16672981,
CC ECO:0000269|PubMed:18443288, ECO:0000269|PubMed:18799731,
CC ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23509287,
CC ECO:0000269|PubMed:24901221, ECO:0000269|PubMed:27906179,
CC ECO:0000269|PubMed:28435104, ECO:0000269|PubMed:30772175,
CC ECO:0000269|PubMed:32138754}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC ---------------------------------------------------------------------------
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DR EMBL; AE014298; AAF46188.1; -; Genomic_DNA.
DR EMBL; AE014298; AAN09178.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52497.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52498.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52499.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52500.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52501.1; -; Genomic_DNA.
DR EMBL; AE014298; AAZ52502.1; -; Genomic_DNA.
DR EMBL; AE014298; AHN59423.1; -; Genomic_DNA.
DR EMBL; AY051559; AAK92983.1; -; mRNA.
DR EMBL; BT133188; AFA28429.1; -; mRNA.
DR RefSeq; NP_001027049.1; NM_001031878.2.
DR RefSeq; NP_001027050.1; NM_001031879.3.
DR RefSeq; NP_001027051.1; NM_001031880.3.
DR RefSeq; NP_001027052.1; NM_001031881.3.
DR RefSeq; NP_001027053.1; NM_001031882.3.
DR RefSeq; NP_001027054.1; NM_001031883.3.
DR RefSeq; NP_001284952.1; NM_001298023.1.
DR RefSeq; NP_572340.2; NM_132112.5.
DR RefSeq; NP_727110.1; NM_167083.4.
DR AlphaFoldDB; Q0KHV6; -.
DR SMR; Q0KHV6; -.
DR IntAct; Q0KHV6; 4.
DR STRING; 7227.FBpp0099837; -.
DR PaxDb; Q0KHV6; -.
DR EnsemblMetazoa; FBtr0070956; FBpp0070917; FBgn0029891.
DR EnsemblMetazoa; FBtr0070957; FBpp0070918; FBgn0029891.
DR EnsemblMetazoa; FBtr0100413; FBpp0099830; FBgn0029891.
DR EnsemblMetazoa; FBtr0100414; FBpp0099831; FBgn0029891.
DR EnsemblMetazoa; FBtr0100415; FBpp0099832; FBgn0029891.
DR EnsemblMetazoa; FBtr0100416; FBpp0099833; FBgn0029891.
DR EnsemblMetazoa; FBtr0100419; FBpp0099835; FBgn0029891.
DR EnsemblMetazoa; FBtr0100420; FBpp0099837; FBgn0029891.
DR EnsemblMetazoa; FBtr0345295; FBpp0311462; FBgn0029891.
DR GeneID; 31607; -.
DR KEGG; dme:Dmel_CG4523; -.
DR UCSC; CG4523-RA; d. melanogaster.
DR CTD; 65018; -.
DR FlyBase; FBgn0029891; Pink1.
DR VEuPathDB; VectorBase:FBgn0029891; -.
DR eggNOG; KOG4158; Eukaryota.
DR GeneTree; ENSGT00390000001206; -.
DR HOGENOM; CLU_022208_0_0_1; -.
DR InParanoid; Q0KHV6; -.
DR OMA; FGQHARK; -.
DR OrthoDB; 314975at2759; -.
DR PhylomeDB; Q0KHV6; -.
DR Reactome; R-DME-5205685; PINK1-PRKN Mediated Mitophagy.
DR SignaLink; Q0KHV6; -.
DR BioGRID-ORCS; 31607; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 31607; -.
DR Proteomes; UP000000803; Chromosome X.
DR Bgee; FBgn0029891; Expressed in adult Malpighian tubule (Drosophila) and 27 other tissues.
DR ExpressionAtlas; Q0KHV6; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IDA:FlyBase.
DR GO; GO:0005829; C:cytosol; IDA:FlyBase.
DR GO; GO:0031315; C:extrinsic component of mitochondrial outer membrane; IDA:FlyBase.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:FlyBase.
DR GO; GO:0016006; C:Nebenkern; IDA:FlyBase.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043008; F:ATP-dependent protein binding; IPI:FlyBase.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; IDA:FlyBase.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:FlyBase.
DR GO; GO:0048749; P:compound eye development; IMP:FlyBase.
DR GO; GO:0035234; P:ectopic germ cell programmed cell death; IMP:FlyBase.
DR GO; GO:0051654; P:establishment of mitochondrion localization; IMP:FlyBase.
DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; IMP:UniProtKB.
DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:CACAO.
DR GO; GO:0072375; P:medium-term memory; IMP:UniProtKB.
DR GO; GO:0000266; P:mitochondrial fission; IGI:FlyBase.
DR GO; GO:0000001; P:mitochondrion inheritance; IMP:FlyBase.
DR GO; GO:0007005; P:mitochondrion organization; IDA:FlyBase.
DR GO; GO:0047497; P:mitochondrion transport along microtubule; IMP:CACAO.
DR GO; GO:2000766; P:negative regulation of cytoplasmic translation; IMP:FlyBase.
DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; IMP:FlyBase.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:FlyBase.
DR GO; GO:0043069; P:negative regulation of programmed cell death; IMP:FlyBase.
DR GO; GO:0007274; P:neuromuscular synaptic transmission; IMP:FlyBase.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; 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:1904457; P:positive regulation of neuronal action potential; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:FlyBase.
DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:1902956; P:regulation of mitochondrial electron transport, NADH to ubiquinone; IGI: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:0007614; P:short-term memory; IMP:UniProtKB.
DR GO; GO:0030382; P:sperm mitochondrion organization; IMP:FlyBase.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:FlyBase.
DR CDD; cd14018; STKc_PINK1; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR040110; PINK1_STKc.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Autophagy; Cytoplasm; Kinase; Magnesium; Membrane;
KW Metal-binding; Mitochondrion; Mitochondrion inner membrane;
KW Mitochondrion outer membrane; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Transit peptide; Transmembrane; Transmembrane helix.
FT TRANSIT 1..5
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 6..721
FT /note="Serine/threonine-protein kinase Pink1,
FT mitochondrial"
FT /evidence="ECO:0000255"
FT /id="PRO_0000452365"
FT TOPO_DOM 6..136
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000305"
FT TRANSMEM 137..153
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 154..721
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 304..638
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 279..322
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 284..299
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 300..322
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 479
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 310..318
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 337
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 358
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:D6WMX4"
FT BINDING 484
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:D6WMX4"
FT BINDING 501
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:D6WMX4"
FT BINDING 501
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:D6WMX4"
FT MOD_RES 346
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:25474007,
FT ECO:0000269|PubMed:27906179"
FT MUTAGEN 337
FT /note="K->R: Loss of kinase activity resulting in impaired
FT mitochondrial integrity and function; when associated with
FT A-479 and A-501."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:30772175"
FT MUTAGEN 346
FT /note="S->A: Abolishes activity and autophosphorylation.
FT Fails to recruit park to mitochondria."
FT /evidence="ECO:0000269|PubMed:27906179"
FT MUTAGEN 346
FT /note="S->D: Phosphomimetic mutant; no effect on activity
FT and promotes translocation of park to mitochondria."
FT /evidence="ECO:0000269|PubMed:27906179"
FT MUTAGEN 479
FT /note="D->A: Loss of kinase activity and impaired
FT recruitment of park to mitochondria. Loss of kinase
FT activity resulting in impaired mitochondrial integrity and
FT function; when associated with R-337 and A-501."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:27906179, ECO:0000269|PubMed:30772175"
FT MUTAGEN 501
FT /note="D->A: Loss of kinase activity. Loss of kinase
FT activity resulting in impaired mitochondrial integrity and
FT function; when associated with R-337 and A-479."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:30772175"
FT MUTAGEN 519
FT /note="S->A: No effect on activity and
FT autophosphorylation."
FT /evidence="ECO:0000269|PubMed:27906179"
FT CONFLICT 186
FT /note="D -> H (in Ref. 3; AAK92983)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 721 AA; 80228 MW; 9764EBF46B443F2E CRC64;
MSVRLLTVRL IKHGRYILRS YCKRDIHANI LDQNQLKTRS KRGFPLPSTA ANVLRTTPQQ
AAKSVVNVVP RTINSPSGSP FNGSGSSPTS SSGIFRVGQH ARKLFIDNIL SRVTTTYSED
LRQRATRKLF FGDSAPFFAL IGVSLASGSG VLSKEDELEG VCWEIREAAS RLQNAWNHDE
ISDTLDSKFT IDDLEIGPPI AKGCAAVVYA ADFKKDVASD GASLHTDAQP QATPAFAPNS
WSTHEMMSPL QNMSRFVHNF GGSVDNVFHY SQPSAASDFV GAQSREQDQR HHEQQQHQNQ
EQEQHQNQEP SSSAFNVTSP ANSNINSSVD SYPLALKMMF NYDIQSNALS ILRAMYKETV
PARQRGMNEA ADEWERLLQN QTVHLPRHPN IVCMFGFFCD EVRNFPDGHL LYPVAQPQRI
NPQGYGRNMS LYLLMKRYDH SLRGLLDSQD LSTRNRILLL AQMLEAVNHL SRHGVAHRDL
KSDNVLIELQ DDAAPVLVLS DFGCCLADKV HGLRLPYVSH DVDKGGNAAL MAPEIFNTMP
GPFAVLNYGK ADLWACGALA YEIFGNRNPF YSSSGGMARE RGEMTLSLRN SDYRQDQLPP
MSDACPPLLQ QLVYNILNPN PSKRVSPDIA ANVVQLFLWA PSNWLKAGGM PNSPEILQWL
LSLTTKIMCE GRPQMGAGLM PVASCGNRRA YVEYLLICSF LARARLRRIR GALNWIQNVV
A
