PINK1_HUMAN
ID PINK1_HUMAN Reviewed; 581 AA.
AC Q9BXM7; Q8N6T9; Q8NBU3; Q96DE4;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 195.
DE RecName: Full=Serine/threonine-protein kinase PINK1, mitochondrial;
DE EC=2.7.11.1 {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:32484300};
DE AltName: Full=BRPK;
DE AltName: Full=PTEN-induced putative kinase protein 1;
DE Flags: Precursor;
GN Name=PINK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAK28062.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Endometrium {ECO:0000269|PubMed:11494141};
RX PubMed=11494141; DOI=10.1038/sj.onc.1204608;
RA Unoki M., Nakamura Y.;
RT "Growth-suppressive effects of BPOZ and EGR2, two genes involved in the
RT PTEN signaling pathway.";
RL Oncogene 20:4457-4465(2001).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND AUTOPHOSPHORYLATION.
RC TISSUE=Placenta {ECO:0000312|EMBL:AAK28062.1};
RX PubMed=14607334; DOI=10.1016/s0304-3835(03)00443-9;
RA Nakajima A., Kataoka K., Hong M., Sakaguchi M., Huh N.-H.;
RT "BRPK, a novel protein kinase showing increased expression in mouse cancer
RT cell lines with higher metastatic potential.";
RL Cancer Lett. 201:195-201(2003).
RN [3] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANTS THR-340
RP AND THR-521.
RC TISSUE=Placenta {ECO:0000312|EMBL:BAC11484.1};
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Leukocyte {ECO:0000312|EMBL:AAH28215.1}, and
RC Lung {ECO:0000312|EMBL:AAH09534.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP SUBCELLULAR LOCATION.
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND
RP MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384.
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 [8]
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 [9]
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 [10]
RP SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY.
RX PubMed=18687899; DOI=10.1073/pnas.0802814105;
RA Zhou C., Huang Y., Shao Y., May J., Prou D., Perier C., Dauer W.,
RA Schon E.A., Przedborski S.;
RT "The kinase domain of mitochondrial PINK1 faces the cytoplasm.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12022-12027(2008).
RN [11]
RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1,
RP SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, CHARACTERIZATION OF VARIANTS
RP PARK6 ASP-309 AND MET-313, AND CHARACTERIZATION OF VARIANT LEU-399.
RX PubMed=19229105; DOI=10.1172/jci37617;
RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W.,
RA Ronai Z., Zhuang X., Zhang Z.;
RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting
RT unfolded protein degradation.";
RL J. Clin. Invest. 119:650-660(2009).
RN [12]
RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH
RP PRKN, AND CHARACTERIZATION OF VARIANTS PARK6 PRO-126; ASP-309 AND PRO-347.
RX PubMed=20798600; DOI=10.4161/auto.6.7.13286;
RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C.,
RA Kahle P.J., Springer W.;
RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated
RT mutations.";
RL Autophagy 6:871-878(2010).
RN [13]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 492-ARG--LYS-581 DEL.
RX PubMed=20547144; DOI=10.1016/j.brainres.2010.06.005;
RA Yuan X.L., Guo J.F., Shi Z.H., Xiao Z.Q., Yan X.X., Zhao B.L., Tang B.S.;
RT "R492X mutation in PTEN-induced putative kinase 1 induced cellular
RT mitochondrial dysfunction and oxidative stress.";
RL Brain Res. 1351:229-237(2010).
RN [14]
RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND PHOSPHORYLATION.
RX PubMed=20404107; DOI=10.1083/jcb.200910140;
RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A.,
RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M.,
RA Hattori N., Tanaka K.;
RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to
RT damaged mitochondria and activates latent Parkin for mitophagy.";
RL J. Cell Biol. 189:211-221(2010).
RN [15]
RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND INTERACTION WITH PRKN.
RX PubMed=19966284; DOI=10.1073/pnas.0911187107;
RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J.,
RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L.,
RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.;
RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010).
RN [16]
RP INVOLVEMENT IN PARK6.
RX PubMed=22043288; DOI=10.1371/journal.pone.0025622;
RA Abramov A.Y., Gegg M., Grunewald A., Wood N.W., Klein C., Schapira A.H.;
RT "Bioenergetic consequences of PINK1 mutations in Parkinson disease.";
RL PLoS ONE 6:E25622-E25622(2011).
RN [17]
RP PROTEOLYTIC CLEAVAGE, AND SUBCELLULAR LOCATION.
RX PubMed=22354088; DOI=10.1038/embor.2012.14;
RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R.,
RA Haque M.E., McBride H.M., Park D.S., Fon E.A.;
RT "Mitochondrial processing peptidase regulates PINK1 processing, import and
RT Parkin recruitment.";
RL EMBO Rep. 13:378-385(2012).
RN [18]
RP PHOSPHORYLATION AT SER-228 AND SER-402.
RX PubMed=22910362; DOI=10.1038/ncomms2016;
RA Okatsu K., Oka T., Iguchi M., Imamura K., Kosako H., Tani N., Kimura M.,
RA Go E., Koyano F., Funayama M., Shiba-Fukushima K., Sato S., Shimizu H.,
RA Fukunaga Y., Taniguchi H., Komatsu M., Hattori N., Mihara K., Tanaka K.,
RA Matsuda N.;
RT "PINK1 autophosphorylation upon membrane potential dissipation is essential
RT for Parkin recruitment to damaged mitochondria.";
RL Nat. Commun. 3:1016-1016(2012).
RN [19]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 PRO-347.
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 [20]
RP FUNCTION.
RX PubMed=23754282; DOI=10.1074/jbc.m113.467530;
RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M.,
RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.;
RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent
RT phosphorylation.";
RL J. Biol. Chem. 288:22019-22032(2013).
RN [21]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7.
RX PubMed=23933751; DOI=10.1038/nn.3489;
RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M.,
RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H.,
RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H.,
RA Plun-Favreau H.;
RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to
RT mediate mitophagy.";
RL Nat. Neurosci. 16:1257-1265(2013).
RN [22]
RP FUNCTION IN MITOPHAGY, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384.
RX PubMed=23620051; DOI=10.1126/science.1231031;
RA Chen Y., Dorn G.W. II;
RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged
RT mitochondria.";
RL Science 340:471-475(2013).
RN [23]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24660806; DOI=10.1042/bj20140334;
RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S.,
RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.;
RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at
RT Ser65.";
RL Biochem. J. 460:127-139(2014).
RN [24]
RP FUNCTION.
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 [25]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24751536; DOI=10.1083/jcb.201402104;
RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A.,
RA Banerjee S., Youle R.J.;
RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase
RT activity.";
RL J. Cell Biol. 205:143-153(2014).
RN [26]
RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANTS PARK6
RP PRO-168 AND ALA-386.
RX PubMed=24784582; DOI=10.1038/nature13392;
RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y.,
RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F.,
RA Saeki Y., Tanaka K., Matsuda N.;
RT "Ubiquitin is phosphorylated by PINK1 to activate parkin.";
RL Nature 510:162-166(2014).
RN [27]
RP FUNCTION.
RX PubMed=24896179; DOI=10.1038/nature13418;
RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q.,
RA Foreman O., Kirkpatrick D.S., Sheng M.;
RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated
RT mitophagy.";
RL Nature 510:370-375(2014).
RN [28]
RP FUNCTION.
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 [29]
RP VARIANTS PARK6 GLY-170 AND 456-GLN--LEU-581 DEL.
RX PubMed=24652937; DOI=10.1126/science.1249161;
RA Morais V.A., Haddad D., Craessaerts K., De Bock P.J., Swerts J., Vilain S.,
RA Aerts L., Overbergh L., Gruenewald A., Seibler P., Klein C., Gevaert K.,
RA Verstreken P., De Strooper B.;
RT "PINK1 loss-of-function mutations affect mitochondrial complex I activity
RT via NdufA10 ubiquinone uncoupling.";
RL Science 344:203-207(2014).
RN [30]
RP FUNCTION.
RX PubMed=25527291; DOI=10.15252/embj.201489847;
RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N.,
RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.;
RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain
RT assembly and hydrolysis.";
RL EMBO J. 34:307-325(2015).
RN [31]
RP PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 112-GLU--GLU-117.
RX PubMed=30733118; DOI=10.1016/j.molcel.2019.01.002;
RA Sekine S., Wang C., Sideris D.P., Bunker E., Zhang Z., Youle R.J.;
RT "Reciprocal roles of Tom7 and OMA1 during mitochondrial import and
RT activation of PINK1.";
RL Mol. Cell 73:1028-1043(2019).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH NENF, AND SUBCELLULAR
RP LOCATION.
RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057;
RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A.,
RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J.,
RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G.,
RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y.,
RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.;
RT "Rewiring of the Human Mitochondrial Interactome during Neuronal
RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis.";
RL IScience 19:1114-1132(2019).
RN [33]
RP FUNCTION, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384.
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 [34]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLY-309 AND ASP-384, AND
RP CHARACTERIZATION OF VARIANTS ASP-309; MET-313 AND 492-ARG--LYS-581 DEL.
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 [35]
RP VARIANTS PARK6 PHE-92; PRO-168 AND HIS-464, AND VARIANTS LEU-296; THR-340;
RP THR-442; LYS-476; THR-521 AND ASN-525.
RX PubMed=15349860; DOI=10.1002/ana.20256;
RA Valente E.M., Salvi S., Ialongo T., Marongiu R., Elia A.E., Caputo V.,
RA Romito L., Albanese A., Dallapiccola B., Bentivoglio A.R.;
RT "PINK1 mutations are associated with sporadic early-onset parkinsonism.";
RL Ann. Neurol. 56:336-341(2004).
RN [36]
RP VARIANTS PARK6 GLN-271; PRO-347 AND GLY-417.
RX PubMed=15349870; DOI=10.1002/ana.20251;
RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H.,
RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R.,
RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.;
RT "Novel PINK1 mutations in early-onset parkinsonism.";
RL Ann. Neurol. 56:424-427(2004).
RN [37]
RP ERRATUM OF PUBMED:15349870.
RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H.,
RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R.,
RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.;
RL Ann. Neurol. 56:603-603(2004).
RN [38]
RP VARIANTS PARK6 LYS-240; PRO-347 AND PRO-489, AND VARIANTS GLY-231; ILE-235;
RP GLY-263; LEU-318; THR-339; THR-340; HIS-362; SER-425; LYS-476 AND THR-521.
RX PubMed=15596610; DOI=10.1001/archneur.61.12.1898;
RA Rogaeva E., Johnson J., Lang A.E., Gulick C., Gwinn-Hardy K., Kawarai T.,
RA Sato C., Morgan A., Werner J., Nussbaum R., Petit A., Okun M.S.,
RA McInerney A., Mandel R., Groen J.L., Fernandez H.H., Postuma R.,
RA Foote K.D., Salehi-Rad S., Liang Y., Reimsnider S., Tandon A., Hardy J.,
RA St George-Hyslop P., Singleton A.B.;
RT "Analysis of the PINK1 gene in a large cohort of cases with Parkinson
RT disease.";
RL Arch. Neurol. 61:1898-1904(2004).
RN [39]
RP VARIANT PARK6 HIS-147.
RX PubMed=15505171; DOI=10.1212/01.wnl.0000142089.38301.8e;
RA Healy D.G., Abou-Sleiman P.M., Gibson J.M., Ross O.A., Jain S., Gandhi S.,
RA Gosal D., Muqit M.M.K., Wood N.W., Lynch T.;
RT "PINK1 (PARK6) associated Parkinson disease in Ireland.";
RL Neurology 63:1486-1488(2004).
RN [40]
RP VARIANT PARK6 ASP-309, CHARACTERIZATION OF VARIANT PARK6 ASP-309, FUNCTION,
RP AND SUBCELLULAR LOCATION.
RX PubMed=15087508; DOI=10.1126/science.1096284;
RA Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M.K., Harvey K.,
RA Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G.,
RA Albanese A., Nussbaum R., Gonzalez-Maldonado R., Deller T., Salvi S.,
RA Cortelli P., Gilks W.P., Latchman D.S., Harvey R.J., Dallapiccola B.,
RA Auburger G., Wood N.W.;
RT "Hereditary early-onset Parkinson's disease caused by mutations in PINK1.";
RL Science 304:1158-1160(2004).
RN [41]
RP VARIANT PARK6 VAL-268.
RX PubMed=16207217; DOI=10.1111/j.1399-0004.2005.00500.x;
RA Tan E.K., Yew K., Chua E., Shen H., Jamora R.D., Lee E., Puong K.Y.,
RA Zhao Y., Pavanni R., Wong M.C., Puvan K., Yih Y., Tan L.C.S.;
RT "Analysis of PINK1 in Asian patients with familial parkinsonism.";
RL Clin. Genet. 68:468-470(2005).
RN [42]
RP VARIANTS PARK6 HIS-279 AND GLN-534 INS, AND VARIANT LEU-115.
RX PubMed=15970950; DOI=10.1038/sj.ejhg.5201455;
RA Klein C., Djarmati A., Hedrich K., Schaefer N., Scaglione C., Marchese R.,
RA Kock N., Schuele B., Hiller A., Lohnau T., Winkler S., Wiegers K.,
RA Hering R., Bauer P., Riess O., Abbruzzese G., Martinelli P.,
RA Pramstaller P.P.;
RT "PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset
RT parkinsonism.";
RL Eur. J. Hum. Genet. 13:1086-1093(2005).
RN [43]
RP CHARACTERIZATION OF VARIANTS PARK6 PRO-168 AND ASP-309.
RX PubMed=16207731; DOI=10.1093/hmg/ddi377;
RA Silvestri L., Caputo V., Bellacchio E., Atorino L., Dallapiccola B.,
RA Valente E.M., Casari G.;
RT "Mitochondrial import and enzymatic activity of PINK1 mutants associated to
RT recessive parkinsonism.";
RL Hum. Mol. Genet. 14:3477-3492(2005).
RN [44]
RP VARIANT PARK6 ARG-388.
RX PubMed=15955953; DOI=10.1212/01.wnl.0000164009.36740.4e;
RA Li Y., Tomiyama H., Sato K., Hatano Y., Yoshino H., Atsumi M.,
RA Kitaguchi M., Sasaki S., Kawaguchi S., Miyajima H., Toda T., Mizuno Y.,
RA Hattori N.;
RT "Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset
RT parkinsonism.";
RL Neurology 64:1955-1957(2005).
RN [45]
RP VARIANTS PARK6 PRO-168 AND LEU-196, AND VARIANTS LEU-115; THR-340; LYS-476
RP AND THR-521.
RX PubMed=16009891; DOI=10.1212/01.wnl.0000167546.39375.82;
RG The Italian Parkinson genetics network;
RA Bonifati V., Rohe C.F., Breedveld G.J., Fabrizio E., De Mari M.,
RA Tassorelli C., Tavella A., Marconi R., Nicholl D.J., Chien H.F.,
RA Fincati E., Abbruzzese G., Marini P., De Gaetano A., Horstink M.W.,
RA Maat-Kievit J.A., Sampaio C., Antonini A., Stocchi F., Montagna P.,
RA Toni V., Guidi M., Dalla Libera A., Tinazzi M., De Pandis F., Fabbrini G.,
RA Goldwurm S., de Klein A., Barbosa E., Lopiano L., Martignoni E.,
RA Lamberti P., Vanacore N., Meco G., Oostra B.A.;
RT "Early-onset parkinsonism associated with PINK1 mutations: frequency,
RT genotypes, and phenotypes.";
RL Neurology 65:87-95(2005).
RN [46]
RP VARIANTS ILE-317; THR-339; THR-383; SER-411; HIS-431; SER-451; SER-461;
RP LYS-476; PRO-501 AND ARG-575, AND CHARACTERIZATION OF VARIANTS HIS-431;
RP SER-451; LYS-476; PRO-501 AND ARG-575.
RX PubMed=16969854; DOI=10.1002/ana.20960;
RA Abou-Sleiman P.M., Muqit M.M.K., McDonald N.Q., Yang Y.X., Gandhi S.,
RA Healy D.G., Harvey K., Harvey R.J., Deas E., Bhatia K., Quinn N., Lees A.,
RA Latchman D.S., Wood N.W.;
RT "A heterozygous effect for PINK1 mutations in Parkinson's disease?";
RL Ann. Neurol. 60:414-419(2006).
RN [47]
RP VARIANT PARK6 ASP-217.
RX PubMed=16966503; DOI=10.1001/archneur.63.9.1257;
RA Leutenegger A.-L., Salih M.A.M., Ibanez P., Mukhtar M.M., Lesage S.,
RA Arabi A., Lohmann E., Duerr A., Ahmed A.E.M., Brice A.;
RT "Juvenile-onset Parkinsonism as a result of the first mutation in the
RT adenosine triphosphate orientation domain of PINK1.";
RL Arch. Neurol. 63:1257-1261(2006).
RN [48]
RP VARIANT PARK6 MET-313.
RX PubMed=17030667; DOI=10.1001/archneur.63.10.1483;
RA Chishti M.A., Bohlega S., Ahmed M., Loualich A., Carroll P., Sato C.,
RA St George-Hyslop P., Westaway D., Rogaeva E.;
RT "T313M PINK1 mutation in an extended highly consanguineous Saudi family
RT with early-onset Parkinson disease.";
RL Arch. Neurol. 63:1483-1485(2006).
RN [49]
RP VARIANTS PARK6 GLY-125; LYS-240; PRO-369; ALA-386 AND VAL-409.
RX PubMed=16401616; DOI=10.1093/brain/awl005;
RG The French Parkinson's disease genetics study group;
RA Ibanez P., Lesage S., Lohmann E., Thobois S., De Michele G., Borg M.,
RA Agid Y., Durr A., Brice A.;
RT "Mutational analysis of the PINK1 gene in early-onset parkinsonism in
RT Europe and North Africa.";
RL Brain 129:686-694(2006).
RN [50]
RP VARIANT LEU-399.
RX PubMed=16632486; DOI=10.1093/hmg/ddl104;
RA Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q.,
RA Xia J.-H., Xia K., Zhang Z.;
RT "Association of PINK1 and DJ-1 confers digenic inheritance of early-onset
RT Parkinson's disease.";
RL Hum. Mol. Genet. 15:1816-1825(2006).
RN [51]
RP VARIANT PARK6 THR-280, AND VARIANTS THR-340 AND THR-521.
RX PubMed=16482571; DOI=10.1002/mds.20810;
RA Tan E.-K., Yew K., Chua E., Puvan K., Shen H., Lee E., Puong K.-Y.,
RA Zhao Y., Pavanni R., Wong M.-C., Jamora D., de Silva D., Moe K.-T.,
RA Woon F.-P., Yuen Y., Tan L.;
RT "PINK1 mutations in sporadic early-onset Parkinson's disease.";
RL Mov. Disord. 21:789-793(2006).
RN [52]
RP VARIANT PARK6 GLN-407, AND VARIANTS THR-340 AND THR-521.
RX PubMed=16257123; DOI=10.1016/j.neulet.2005.10.005;
RA Fung H.-C., Chen C.-M., Hardy J., Singleton A.B., Lee-Chen G.-J., Wu Y.-R.;
RT "Analysis of the PINK1 gene in a cohort of patients with sporadic early-
RT onset parkinsonism in Taiwan.";
RL Neurosci. Lett. 394:33-36(2006).
RN [53]
RP VARIANTS [LARGE SCALE ANALYSIS] TRP-148; SER-196; LEU-209; LEU-215;
RP THR-339; THR-340; ILE-341; PHE-377; THR-477 AND THR-521.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [54]
RP VARIANTS PHE-67; PRO-68; TRP-98; SER-111; VAL-124; MET-145; ASN-186;
RP ILE-257 VAL-268; GLN-276; LEU-296; ILE-317; LEU-322; THR-339; THR-383;
RP VAL-395; THR-442; LYS-476; ASN-525 AND THR-537.
RX PubMed=18330912; DOI=10.1002/humu.20719;
RG The Italian PD study group;
RA Marongiu R., Ferraris A., Ialongo T., Michiorri S., Soleti F., Ferrari F.,
RA Elia A.E., Ghezzi D., Albanese A., Altavista M.C., Antonini A., Barone P.,
RA Brusa L., Cortelli P., Martinelli P., Pellecchia M.T., Pezzoli G.,
RA Scaglione C., Stanzione P., Tinazzi M., Zecchinelli A., Zeviani M.,
RA Cassetta E., Garavaglia B., Dallapiccola B., Bentivoglio A.R.,
RA Valente E.M.;
RT "PINK1 heterozygous rare variants: prevalence, significance and phenotypic
RT spectrum.";
RL Hum. Mutat. 29:565-565(2008).
RN [55]
RP VARIANT PARK6 PRO-126.
RX PubMed=18286320; DOI=10.1007/s00415-008-0763-4;
RA Prestel J., Gempel K., Hauser T.K., Schweitzer K., Prokisch H., Ahting U.,
RA Freudenstein D., Bueltmann E., Naegele T., Berg D., Klopstock T.,
RA Gasser T.;
RT "Clinical and molecular characterisation of a Parkinson family with a novel
RT PINK1 mutation.";
RL J. Neurol. 255:643-648(2008).
RN [56]
RP VARIANTS PARK6 MET-313 AND 492-ARG--LYS-581 DEL.
RX PubMed=18785233; DOI=10.1002/mds.22156;
RA Guo J.F., Xiao B., Liao B., Zhang X.W., Nie L.L., Zhang Y.H., Shen L.,
RA Jiang H., Xia K., Pan Q., Yan X.X., Tang B.S.;
RT "Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese
RT patients with autosomal recessive early-onset Parkinsonism.";
RL Mov. Disord. 23:2074-2079(2008).
RN [57]
RP VARIANT PARK6 PRO-347.
RX PubMed=22956510; DOI=10.1002/mds.25132;
RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D.,
RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H.,
RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E.,
RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A.,
RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.;
RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-
RT 1) and LRRK2 in early-onset Parkinson's disease.";
RL Mov. Disord. 27:1522-1529(2012).
CC -!- FUNCTION: Serine/threonine-protein kinase which protects against
CC mitochondrial dysfunction during cellular stress by phosphorylating
CC mitochondrial proteins such as PRKN and DNM1L, to coordinate
CC mitochondrial quality control mechanisms that remove and replace
CC dysfunctional mitochondrial components (PubMed:14607334,
CC PubMed:18957282, PubMed:18443288, PubMed:15087508, PubMed:19229105,
CC PubMed:19966284, PubMed:20404107, PubMed:22396657, PubMed:20798600,
CC PubMed:23620051, PubMed:23754282, PubMed:23933751, PubMed:24660806,
CC PubMed:24898855, PubMed:24751536, PubMed:24784582, PubMed:24896179,
CC PubMed:25527291, PubMed:32484300, PubMed:20547144). Depending on the
CC severity of mitochondrial damage and/or dysfunction, activity ranges
CC from preventing apoptosis and stimulating mitochondrial biogenesis to
CC regulating mitochondrial dynamics and eliminating severely damaged
CC mitochondria via mitophagy (PubMed:18443288, PubMed:23620051,
CC PubMed:24898855, PubMed:20798600, PubMed:20404107, PubMed:19966284,
CC PubMed:32484300, PubMed:22396657, PubMed:32047033, PubMed:15087508).
CC Mediates the translocation and activation of PRKN at the outer membrane
CC (OMM) of dysfunctional/depolarized mitochondria (PubMed:19966284,
CC PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:24660806,
CC PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291). At
CC the OMM of damaged mitochondria, phosphorylates pre-existing
CC polyubiquitin chains at 'Ser-65', the PINK1-phosphorylated
CC polyubiquitin then recruits PRKN from the cytosol to the OMM where PRKN
CC is fully activated by phosphorylation at 'Ser-65' by PINK1
CC (PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282,
CC PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007,
CC PubMed:25527291). In damaged mitochondria, mediates the decision
CC between mitophagy or preventing apoptosis by promoting PRKN-dependent
CC poly- or monoubiquitination of VDAC1; polyubiquitination of VDAC1 by
CC PRKN promotes mitophagy, while monoubiquitination of VDAC1 by PRKN
CC decreases mitochondrial calcium influx which ultimately inhibits
CC apoptosis (PubMed:32047033). When cellular stress results in
CC irreversible mitochondrial damage, functions with PRKN to promote
CC clearance of damaged mitochondria via selective autophagy (mitophagy)
CC (PubMed:14607334, PubMed:20798600, PubMed:20404107, PubMed:19966284,
CC PubMed:23933751, PubMed:15087508). The PINK1-PRKN pathway also promotes
CC fission of damaged mitochondria by phosphorylating and thus promoting
CC the PRKN-dependent degradation of mitochondrial proteins involved in
CC fission such as MFN2 (PubMed:18443288, PubMed:23620051,
CC PubMed:24898855). 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:23620051). Also promotes mitochondrial fission independently of
CC PRKN and ATG7-mediated mitophagy, via the phosphorylation and
CC activation of DNM1L (PubMed:18443288, PubMed:32484300). Regulates
CC motility of damaged mitochondria by promoting the ubiquitination and
CC subsequent degradation of MIRO1 and MIRO2; in motor neurons, this
CC likely inhibits mitochondrial intracellular anterograde transport along
CC the axons which probably increases the chance of the mitochondria
CC undergoing mitophagy in the soma (PubMed:22396657). Required for
CC ubiquinone reduction by mitochondrial complex I by mediating
CC phosphorylation of complex I subunit NDUFA10 (By similarity).
CC {ECO:0000250|UniProtKB:Q99MQ3, ECO:0000269|PubMed:14607334,
CC ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:18443288,
CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105,
CC ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20404107,
CC ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:20798600,
CC ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23620051,
CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751,
CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536,
CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179,
CC ECO:0000269|PubMed:24898855, ECO:0000269|PubMed:25474007,
CC ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:32047033,
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:18957282, ECO:0000269|PubMed:24660806,
CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582,
CC ECO:0000269|PubMed:32484300};
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:18957282,
CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536,
CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:32484300};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- SUBUNIT: Interacts with PRKN (PubMed:20798600, PubMed:19966284).
CC Interacts with FBXO7 (PubMed:23933751). Forms a complex with PRKN and
CC PARK7 (PubMed:19229105). Interacts with NENF (PubMed:31536960).
CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284,
CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:23933751,
CC ECO:0000269|PubMed:31536960}.
CC -!- INTERACTION:
CC Q9BXM7; P63010-2: AP2B1; NbExp=3; IntAct=EBI-2846068, EBI-11529439;
CC Q9BXM7; P05067: APP; NbExp=3; IntAct=EBI-2846068, EBI-77613;
CC Q9BXM7; O15392: BIRC5; NbExp=3; IntAct=EBI-2846068, EBI-518823;
CC Q9BXM7; Q9Y3I1: FBXO7; NbExp=8; IntAct=EBI-2846068, EBI-1161222;
CC Q9BXM7; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-2846068, EBI-9102965;
CC Q9BXM7; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-2846068, EBI-396453;
CC Q9BXM7; P42858: HTT; NbExp=9; IntAct=EBI-2846068, EBI-466029;
CC Q9BXM7; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-2846068, EBI-21911304;
CC Q9BXM7; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-2846068, EBI-1108377;
CC Q9BXM7; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-2846068, EBI-373144;
CC Q9BXM7; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-2846068, EBI-716063;
CC Q9BXM7; P00491: PNP; NbExp=3; IntAct=EBI-2846068, EBI-712238;
CC Q9BXM7; O60260: PRKN; NbExp=7; IntAct=EBI-2846068, EBI-716346;
CC Q9BXM7; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-2846068, EBI-1396430;
CC Q9BXM7; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-2846068, EBI-3942425;
CC Q9BXM7; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-2846068, EBI-11959123;
CC Q9BXM7; P28347-2: TEAD1; NbExp=3; IntAct=EBI-2846068, EBI-12151837;
CC Q9BXM7; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-2846068, EBI-11141397;
CC Q9BXM7; Q8N895: ZNF366; NbExp=3; IntAct=EBI-2846068, EBI-2813661;
CC Q9BXM7-1; O60260: PRKN; NbExp=2; IntAct=EBI-15643376, EBI-716346;
CC Q9BXM7-1; Q12931: TRAP1; NbExp=4; IntAct=EBI-15643376, EBI-1055869;
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:16672980,
CC ECO:0000269|PubMed:18687899, ECO:0000269|PubMed:18957282,
CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600,
CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:31536960}; Single-pass
CC membrane protein {ECO:0000255}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:Q99MQ3}; Single-pass membrane protein
CC {ECO:0000255}. Cytoplasm, cytosol {ECO:0000269|PubMed:18957282,
CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600,
CC ECO:0000269|PubMed:22354088}. Note=Localizes mostly in mitochondrion
CC and the two smaller proteolytic processed fragments localize mainly in
CC cytosol (PubMed:19229105). When mitochondria lose mitochondrial
CC membrane potential following damage, PINK1 import is arrested, which
CC induces its accumulation in the outer mitochondrial membrane, where it
CC acquires kinase activity (PubMed:18957282).
CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000269|PubMed:14607334};
CC IsoId=Q9BXM7-1; Sequence=Displayed;
CC Name=2 {ECO:0000305};
CC IsoId=Q9BXM7-2; Sequence=VSP_050754, VSP_050755;
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle and
CC testis, and at lower levels in brain, placenta, liver, kidney,
CC pancreas, prostate, ovary and small intestine. Present in the embryonic
CC testis from an early stage of development.
CC {ECO:0000269|PubMed:11494141}.
CC -!- PTM: Proteolytically cleaved (PubMed:19229105, PubMed:22354088,
CC PubMed:30733118). In healthy cells, the precursor is continuously
CC imported into the inner mitochondrial membrane (IMM), where it is
CC proteolytically cleaved by mitochondrial-processing peptidase (MPP) and
CC then undergoes further proteolytic cleavage by PARL or AFG3L2 to give
CC rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088). The
CC 52 kDa short form is then released into the cytosol where it rapidly
CC undergoes proteasome-dependent degradation (PubMed:20404107). In
CC unhealthy cells, when cellular stress conditions lead to the loss of
CC mitochondrial membrane potential, mitochondrial import is impaired
CC leading to the precursor accumulating on the outer mitochondrial
CC membrane (OMM) (PubMed:20404107, PubMed:30733118). If accumulation at
CC the OMM fails and it is imported into the depolarized mitochondria, it
CC undergoes cleavage by the IMM protease OMA1, promoting its subsequent
CC degradation by the proteasome (PubMed:30733118).
CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20404107,
CC ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:30733118}.
CC -!- PTM: Autophosphorylated (PubMed:20404107, PubMed:22910362,
CC PubMed:18957282). Loss of mitochondrial membrane potential results in
CC the precursor accumulating on the outer mitochondrial membrane (OMM)
CC where it is activated by autophosphorylation (PubMed:20404107,
CC PubMed:22910362, PubMed:18957282). Autophosphorylation at Ser-228 and
CC Ser-402 is sufficient and essential for selective recruitment of PRKN
CC to depolarized mitochondria, via PINK1-dependent phosphorylation of
CC ubiquitin and maybe PRKN (PubMed:22910362, PubMed:18957282).
CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20404107,
CC ECO:0000269|PubMed:22910362}.
CC -!- DISEASE: Parkinson disease 6 (PARK6) [MIM:605909]: An early-onset form
CC of Parkinson disease, a neurodegenerative disorder characterized by
CC parkinsonian signs such as rigidity, resting tremor and bradykinesia. A
CC subset of patients manifest additional symptoms including
CC hyperreflexia, autonomic instability, dementia and psychiatric
CC disturbances. Symptoms show diurnal fluctuation and can improve after
CC sleep. PARK6 pathogenesis involves respiratory complex I deficiency
CC causing mitochondrial depolarization and dysfunction. Inheritance is
CC autosomal recessive. {ECO:0000269|PubMed:15087508,
CC ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15349870,
CC ECO:0000269|PubMed:15505171, ECO:0000269|PubMed:15596610,
CC ECO:0000269|PubMed:15955953, ECO:0000269|PubMed:15970950,
CC ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207217,
CC ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:16257123,
CC ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:16482571,
CC ECO:0000269|PubMed:16632486, ECO:0000269|PubMed:16966503,
CC ECO:0000269|PubMed:17030667, ECO:0000269|PubMed:18286320,
CC ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105,
CC ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:20798600,
CC ECO:0000269|PubMed:22043288, ECO:0000269|PubMed:22396657,
CC ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:24652937,
CC ECO:0000269|PubMed:24784582}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; AB053323; BAB55647.1; -; mRNA.
DR EMBL; AF316873; AAK28062.1; -; mRNA.
DR EMBL; AK075225; BAC11484.1; -; mRNA.
DR EMBL; AL391357; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC009534; AAH09534.1; -; mRNA.
DR EMBL; BC028215; AAH28215.1; -; mRNA.
DR CCDS; CCDS211.1; -. [Q9BXM7-1]
DR RefSeq; NP_115785.1; NM_032409.2. [Q9BXM7-1]
DR AlphaFoldDB; Q9BXM7; -.
DR SMR; Q9BXM7; -.
DR BioGRID; 122376; 683.
DR CORUM; Q9BXM7; -.
DR DIP; DIP-29427N; -.
DR IntAct; Q9BXM7; 38.
DR MINT; Q9BXM7; -.
DR STRING; 9606.ENSP00000364204; -.
DR ChEMBL; CHEMBL3337330; -.
DR CarbonylDB; Q9BXM7; -.
DR iPTMnet; Q9BXM7; -.
DR PhosphoSitePlus; Q9BXM7; -.
DR BioMuta; PINK1; -.
DR DMDM; 48428484; -.
DR EPD; Q9BXM7; -.
DR MassIVE; Q9BXM7; -.
DR PaxDb; Q9BXM7; -.
DR PeptideAtlas; Q9BXM7; -.
DR PRIDE; Q9BXM7; -.
DR ProteomicsDB; 79455; -. [Q9BXM7-1]
DR ProteomicsDB; 79456; -. [Q9BXM7-2]
DR ABCD; Q9BXM7; 4 sequenced antibodies.
DR Antibodypedia; 1105; 831 antibodies from 49 providers.
DR DNASU; 65018; -.
DR Ensembl; ENST00000321556.5; ENSP00000364204.3; ENSG00000158828.8. [Q9BXM7-1]
DR GeneID; 65018; -.
DR KEGG; hsa:65018; -.
DR MANE-Select; ENST00000321556.5; ENSP00000364204.3; NM_032409.3; NP_115785.1.
DR UCSC; uc001bdm.3; human. [Q9BXM7-1]
DR CTD; 65018; -.
DR DisGeNET; 65018; -.
DR GeneCards; PINK1; -.
DR GeneReviews; PINK1; -.
DR HGNC; HGNC:14581; PINK1.
DR HPA; ENSG00000158828; Tissue enhanced (skeletal muscle, tongue).
DR MalaCards; PINK1; -.
DR MIM; 168600; phenotype.
DR MIM; 605909; phenotype.
DR MIM; 608309; gene.
DR neXtProt; NX_Q9BXM7; -.
DR OpenTargets; ENSG00000158828; -.
DR Orphanet; 2828; Young-onset Parkinson disease.
DR PharmGKB; PA33325; -.
DR VEuPathDB; HostDB:ENSG00000158828; -.
DR eggNOG; KOG4158; Eukaryota.
DR GeneTree; ENSGT00390000001206; -.
DR HOGENOM; CLU_022208_1_0_1; -.
DR InParanoid; Q9BXM7; -.
DR OMA; MMILQLL; -.
DR OrthoDB; 314975at2759; -.
DR PhylomeDB; Q9BXM7; -.
DR TreeFam; TF313183; -.
DR PathwayCommons; Q9BXM7; -.
DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy.
DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes.
DR SignaLink; Q9BXM7; -.
DR SIGNOR; Q9BXM7; -.
DR BioGRID-ORCS; 65018; 17 hits in 1117 CRISPR screens.
DR ChiTaRS; PINK1; human.
DR GeneWiki; PINK1; -.
DR GenomeRNAi; 65018; -.
DR Pharos; Q9BXM7; Tbio.
DR PRO; PR:Q9BXM7; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9BXM7; protein.
DR Bgee; ENSG00000158828; Expressed in tendon of biceps brachii and 208 other tissues.
DR Genevisible; Q9BXM7; HS.
DR GO; GO:0097449; C:astrocyte projection; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030424; C:axon; IDA:ParkinsonsUK-UCL.
DR GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL.
DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR GO; GO:0031307; C:integral component of mitochondrial outer membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL.
DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0055131; F:C3HC4-type RING finger domain binding; IPI:BHF-UCL.
DR GO; GO:0010857; F:calcium-dependent protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0016301; F:kinase activity; IDA:MGI.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0016504; F:peptidase activator activity; TAS:ParkinsonsUK-UCL.
DR GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB.
DR GO; GO:0043422; F:protein kinase B binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IMP:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IMP:ParkinsonsUK-UCL.
DR GO; GO:1904841; F:TORC2 complex binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0032148; P:activation of protein kinase B activity; IC:ParkinsonsUK-UCL.
DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:UniProtKB.
DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IMP:ParkinsonsUK-UCL.
DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0097237; P:cellular response to toxic substance; TAS:ParkinsonsUK-UCL.
DR GO; GO:0014046; P:dopamine secretion; IEA:Ensembl.
DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; IMP:UniProtKB.
DR GO; GO:0030097; P:hemopoiesis; IGI:ARUK-UCL.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0072656; P:maintenance of protein location in mitochondrion; IMP:ParkinsonsUK-UCL.
DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR GO; GO:0099074; P:mitochondrion to lysosome transport; IMP:ParkinsonsUK-UCL.
DR GO; GO:0000423; P:mitophagy; IGI:ARUK-UCL.
DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ParkinsonsUK-UCL.
DR GO; GO:1903384; P:negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL.
DR GO; GO:1903298; P:negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:1903751; P:negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide; IDA:ParkinsonsUK-UCL.
DR GO; GO:0046329; P:negative regulation of JNK cascade; TAS:ParkinsonsUK-UCL.
DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL.
DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ParkinsonsUK-UCL.
DR GO; GO:1901525; P:negative regulation of mitophagy; IMP:ParkinsonsUK-UCL.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:ParkinsonsUK-UCL.
DR GO; GO:1903202; P:negative regulation of oxidative stress-induced cell death; IDA:ParkinsonsUK-UCL.
DR GO; GO:1903204; P:negative regulation of oxidative stress-induced neuron death; TAS:ParkinsonsUK-UCL.
DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; TAS:ParkinsonsUK-UCL.
DR GO; GO:1903852; P:positive regulation of cristae formation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IEA:Ensembl.
DR GO; GO:0033603; P:positive regulation of dopamine secretion; IEA:Ensembl.
DR GO; GO:1904544; P:positive regulation of free ubiquitin chain polymerization; ISS:ParkinsonsUK-UCL.
DR GO; GO:1901727; P:positive regulation of histone deacetylase activity; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:BHF-UCL.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IMP:ParkinsonsUK-UCL.
DR GO; GO:1902958; P:positive regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL.
DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IBA:GO_Central.
DR GO; GO:0098779; P:positive regulation of mitophagy in response to mitochondrial depolarization; IMP:ParkinsonsUK-UCL.
DR GO; GO:1904783; P:positive regulation of NMDA glutamate receptor activity; IEA:Ensembl.
DR GO; GO:0010952; P:positive regulation of peptidase activity; TAS:ParkinsonsUK-UCL.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; IEA:Ensembl.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IC:ParkinsonsUK-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:AgBase.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:ParkinsonsUK-UCL.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:BHF-UCL.
DR GO; GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; IEA:Ensembl.
DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein transferase activity; TAS:ParkinsonsUK-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL.
DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; IEA:Ensembl.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR GO; GO:0002082; P:regulation of oxidative phosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; NAS:ParkinsonsUK-UCL.
DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; IDA:AgBase.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IDA:BHF-UCL.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL.
DR GO; GO:1902803; P:regulation of synaptic vesicle transport; TAS:ParkinsonsUK-UCL.
DR GO; GO:0022904; P:respiratory electron transport chain; IEA:Ensembl.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IGI:ParkinsonsUK-UCL.
DR GO; GO:0038203; P:TORC2 signaling; IC:ParkinsonsUK-UCL.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL.
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 Alternative splicing; ATP-binding; Autophagy; Cytoplasm; Disease variant;
KW Kinase; Magnesium; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; Mitochondrion outer membrane;
KW Neurodegeneration; Nucleotide-binding; Parkinson disease; Parkinsonism;
KW Phosphoprotein; Primary mitochondrial disease; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Transit peptide;
KW Transmembrane; Transmembrane helix.
FT TRANSIT 1..77
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 78..581
FT /note="Serine/threonine-protein kinase PINK1,
FT mitochondrial"
FT /id="PRO_0000024369"
FT TOPO_DOM 78..93
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000255"
FT TRANSMEM 94..110
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 111..581
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 156..511
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000305"
FT REGION 111..117
FT /note="Required for outer membrane localization"
FT /evidence="ECO:0000269|PubMed:30733118"
FT REGION 189..208
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 362
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 162..170
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q02750,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 186
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 228
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:22910362"
FT MOD_RES 402
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:22910362"
FT VAR_SEQ 1..307
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050754"
FT VAR_SEQ 308..320
FT /note="LGHGRTLFLVMKN -> MCGSQRPSPLSTS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_050755"
FT VARIANT 67
FT /note="L -> F (in dbSNP:rs763142730)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046566"
FT VARIANT 68
FT /note="R -> P (in dbSNP:rs1385309950)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046567"
FT VARIANT 92
FT /note="C -> F (in PARK6; dbSNP:rs1553145550)"
FT /evidence="ECO:0000269|PubMed:15349860"
FT /id="VAR_046568"
FT VARIANT 98
FT /note="R -> W (in dbSNP:rs575668171)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046569"
FT VARIANT 111
FT /note="I -> S (in dbSNP:rs1553145560)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046570"
FT VARIANT 115
FT /note="Q -> L (in dbSNP:rs148871409)"
FT /evidence="ECO:0000269|PubMed:15970950,
FT ECO:0000269|PubMed:16009891"
FT /id="VAR_046571"
FT VARIANT 124
FT /note="A -> V (in dbSNP:rs1274588239)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046572"
FT VARIANT 125
FT /note="C -> G (in PARK6)"
FT /evidence="ECO:0000269|PubMed:16401616"
FT /id="VAR_062773"
FT VARIANT 126
FT /note="Q -> P (in PARK6; strongly reduces interaction with
FT PRKN; dbSNP:rs775809722)"
FT /evidence="ECO:0000269|PubMed:18286320,
FT ECO:0000269|PubMed:20798600"
FT /id="VAR_064344"
FT VARIANT 145
FT /note="T -> M (in dbSNP:rs45604240)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046573"
FT VARIANT 147
FT /note="R -> H (in PARK6; unknown pathological significance;
FT dbSNP:rs138050841)"
FT /evidence="ECO:0000269|PubMed:15505171"
FT /id="VAR_046574"
FT VARIANT 148
FT /note="L -> W (in dbSNP:rs56297806)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041010"
FT VARIANT 168
FT /note="A -> P (in PARK6; no effect on autophosphorylation;
FT localizes to the mitochondria and immunogold experiments
FT reveal that both wild-type and mutant proteins face the
FT mitochondrial intermembrane space; dbSNP:rs768091663)"
FT /evidence="ECO:0000269|PubMed:15349860,
FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207731,
FT ECO:0000269|PubMed:24784582"
FT /id="VAR_046575"
FT VARIANT 170
FT /note="V -> G (in PARK6; dbSNP:rs1553145929)"
FT /evidence="ECO:0000269|PubMed:24652937"
FT /id="VAR_078934"
FT VARIANT 186
FT /note="K -> N (in dbSNP:rs143204084)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046576"
FT VARIANT 196
FT /note="P -> L (in PARK6; dbSNP:rs138302371)"
FT /evidence="ECO:0000269|PubMed:16009891"
FT /id="VAR_046577"
FT VARIANT 196
FT /note="P -> S (in dbSNP:rs35802484)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041011"
FT VARIANT 209
FT /note="P -> L (in dbSNP:rs34677717)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041012"
FT VARIANT 215
FT /note="P -> L (in a glioblastoma multiforme sample; somatic
FT mutation; dbSNP:rs371854396)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041013"
FT VARIANT 217
FT /note="A -> D (in PARK6; dbSNP:rs74315360)"
FT /evidence="ECO:0000269|PubMed:16966503"
FT /id="VAR_046578"
FT VARIANT 231
FT /note="E -> G (in dbSNP:rs1303935100)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046579"
FT VARIANT 235
FT /note="N -> I (in dbSNP:rs1557562082)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046580"
FT VARIANT 240
FT /note="E -> K (in PARK6; dbSNP:rs573931674)"
FT /evidence="ECO:0000269|PubMed:15596610,
FT ECO:0000269|PubMed:16401616"
FT /id="VAR_046581"
FT VARIANT 257
FT /note="T -> I (in dbSNP:rs370906995)"
FT /id="VAR_046582"
FT VARIANT 263
FT /note="R -> G (in dbSNP:rs1553146419)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046583"
FT VARIANT 268
FT /note="L -> V (in PARK6; dbSNP:rs372280083)"
FT /evidence="ECO:0000269|PubMed:16207217,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046584"
FT VARIANT 271
FT /note="H -> Q (in PARK6; dbSNP:rs28940284)"
FT /evidence="ECO:0000269|PubMed:15349870"
FT /id="VAR_046585"
FT VARIANT 276
FT /note="R -> Q (in dbSNP:rs548506734)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046586"
FT VARIANT 279
FT /note="R -> H (in PARK6; dbSNP:rs74315358)"
FT /evidence="ECO:0000269|PubMed:15970950"
FT /id="VAR_046587"
FT VARIANT 280
FT /note="A -> T (in PARK6; early-onset; dbSNP:rs772510148)"
FT /evidence="ECO:0000269|PubMed:16482571"
FT /id="VAR_062774"
FT VARIANT 296
FT /note="P -> L (in dbSNP:rs779060308)"
FT /evidence="ECO:0000269|PubMed:15349860,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046588"
FT VARIANT 305
FT /note="P -> L (in dbSNP:rs7349186)"
FT /id="VAR_018993"
FT VARIANT 309
FT /note="G -> D (in PARK6; fails to maintain mitochondrial
FT membrane potential; full-length mutant has no effect on
FT autophosphorylation; strongly reduces interaction with
FT PRKN; decreases PRKN and SNCAIP ubiquitination and
FT degradation; decreases Drp1 phosphorylation;
FT dbSNP:rs74315355)"
FT /evidence="ECO:0000269|PubMed:15087508,
FT ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:19229105,
FT ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:32484300"
FT /id="VAR_018994"
FT VARIANT 313
FT /note="T -> M (in PARK6; decreases PRKN and SNCAIP
FT ubiquitination and degradation; slightly decreases Drp1
FT phosphorylation; dbSNP:rs74315359)"
FT /evidence="ECO:0000269|PubMed:17030667,
FT ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105,
FT ECO:0000269|PubMed:32484300"
FT /id="VAR_046589"
FT VARIANT 317
FT /note="V -> I (in dbSNP:rs200949139)"
FT /evidence="ECO:0000269|PubMed:16969854,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046590"
FT VARIANT 318
FT /note="M -> L (in dbSNP:rs139226733)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046591"
FT VARIANT 322
FT /note="P -> L (in dbSNP:rs768019187)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046592"
FT VARIANT 339
FT /note="A -> T (in dbSNP:rs55831733)"
FT /evidence="ECO:0000269|PubMed:15596610,
FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_041014"
FT VARIANT 340
FT /note="A -> T (in dbSNP:rs3738136)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610,
FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123,
FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846"
FT /id="VAR_018995"
FT VARIANT 341
FT /note="M -> I (in dbSNP:rs35813094)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041015"
FT VARIANT 347
FT /note="L -> P (in PARK6; strongly reduces interaction with
FT PRKN; reduced ubiquitination of MIRO1; dbSNP:rs28940285)"
FT /evidence="ECO:0000269|PubMed:15349870,
FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:20798600,
FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510"
FT /id="VAR_046593"
FT VARIANT 362
FT /note="D -> H"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046594"
FT VARIANT 369
FT /note="L -> P (in PARK6; dbSNP:rs1195888869)"
FT /evidence="ECO:0000269|PubMed:16401616"
FT /id="VAR_062775"
FT VARIANT 377
FT /note="C -> F (in dbSNP:rs34203620)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041016"
FT VARIANT 383
FT /note="A -> T (in dbSNP:rs45515602)"
FT /evidence="ECO:0000269|PubMed:16969854,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046595"
FT VARIANT 386
FT /note="G -> A (in PARK6; abolishes kinase activity)"
FT /evidence="ECO:0000269|PubMed:16401616,
FT ECO:0000269|PubMed:24784582"
FT /id="VAR_062776"
FT VARIANT 388
FT /note="C -> R (in PARK6; dbSNP:rs1553146806)"
FT /evidence="ECO:0000269|PubMed:15955953"
FT /id="VAR_046596"
FT VARIANT 395
FT /note="G -> V (in dbSNP:rs1035071310)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046597"
FT VARIANT 399
FT /note="P -> L (probable disease-associated variant found in
FT early-onset Parkinson disease with digenic inheritance;
FT found in a patient also carrying mutation S-39 in PARK7;
FT decreases PRKN and SNCAIP ubiquitination and degradation;
FT dbSNP:rs119451946)"
FT /evidence="ECO:0000269|PubMed:16632486,
FT ECO:0000269|PubMed:19229105"
FT /id="VAR_062777"
FT VARIANT 407
FT /note="R -> Q (in PARK6; early-onset; dbSNP:rs556540177)"
FT /evidence="ECO:0000269|PubMed:16257123"
FT /id="VAR_062778"
FT VARIANT 409
FT /note="G -> V (in PARK6; dbSNP:rs1553146818)"
FT /evidence="ECO:0000269|PubMed:16401616"
FT /id="VAR_062779"
FT VARIANT 411
FT /note="G -> S (in dbSNP:rs45478900)"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046598"
FT VARIANT 417
FT /note="E -> G (in PARK6; dbSNP:rs1553146822)"
FT /evidence="ECO:0000269|PubMed:15349870"
FT /id="VAR_046599"
FT VARIANT 425
FT /note="P -> S (in dbSNP:rs554114655)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046600"
FT VARIANT 431
FT /note="Y -> H (may predispose to Parkinson disease
FT development; shows decreased mitochondrial membrane
FT potential under stress conditions; dbSNP:rs74315361)"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046601"
FT VARIANT 442
FT /note="I -> T (in dbSNP:rs1553146877)"
FT /evidence="ECO:0000269|PubMed:15349860,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046602"
FT VARIANT 451
FT /note="N -> S (may predispose to Parkinson disease
FT development; shows decreased mitochondrial membrane
FT potential under stress conditions; dbSNP:rs747400197)"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046603"
FT VARIANT 456..581
FT /note="Missing (in PARK6)"
FT /evidence="ECO:0000269|PubMed:24652937"
FT /id="VAR_078935"
FT VARIANT 461
FT /note="L -> S"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046604"
FT VARIANT 464
FT /note="R -> H (in PARK6; dbSNP:rs764328076)"
FT /evidence="ECO:0000269|PubMed:15349860"
FT /id="VAR_046605"
FT VARIANT 476
FT /note="E -> K (may predispose to Parkinson disease
FT development; shows decreased mitochondrial membrane
FT potential under stress conditions; dbSNP:rs115477764)"
FT /evidence="ECO:0000269|PubMed:15349860,
FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:16009891,
FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:18330912"
FT /id="VAR_046606"
FT VARIANT 477
FT /note="S -> T (in dbSNP:rs34416410)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041017"
FT VARIANT 489
FT /note="L -> P (in PARK6; dbSNP:rs1553146903)"
FT /evidence="ECO:0000269|PubMed:15596610"
FT /id="VAR_046607"
FT VARIANT 492..581
FT /note="Missing (in PARK6; mitochondria are deformed and
FT dysfunctional with decreased mitochondrial membrane
FT potential; shows increased apoptosis; increased oxidative
FT stress; decreased phosphorylation of DNM1L and Drp1;
FT dbSNP:rs34208370)"
FT /evidence="ECO:0000269|PubMed:18785233,
FT ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:32484300"
FT /id="VAR_084338"
FT VARIANT 501
FT /note="R -> P (may predispose to Parkinson disease
FT development; shows decreased mitochondrial membrane
FT potential under stress conditions; dbSNP:rs61744200)"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046608"
FT VARIANT 521
FT /note="N -> T (in dbSNP:rs1043424)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610,
FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123,
FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846"
FT /id="VAR_018996"
FT VARIANT 525
FT /note="D -> N (in dbSNP:rs531477772)"
FT /evidence="ECO:0000269|PubMed:15349860,
FT ECO:0000269|PubMed:18330912"
FT /id="VAR_046609"
FT VARIANT 534
FT /note="Q -> QQ (in PARK6)"
FT /evidence="ECO:0000269|PubMed:15970950"
FT /id="VAR_046610"
FT VARIANT 537
FT /note="A -> T (in dbSNP:rs771032673)"
FT /evidence="ECO:0000269|PubMed:18330912"
FT /id="VAR_046611"
FT VARIANT 575
FT /note="C -> R (may predispose to Parkinson disease
FT development; shows decreased mitochondrial membrane
FT potential under stress conditions; dbSNP:rs1553147052)"
FT /evidence="ECO:0000269|PubMed:16969854"
FT /id="VAR_046612"
FT MUTAGEN 112..117
FT /note="EEKQAE->AAKQAA: In 3EA; impaired ability to localize
FT to the outer mitochondrial membrane."
FT /evidence="ECO:0000269|PubMed:30733118"
FT MUTAGEN 219
FT /note="K->A: Abolishes MFN2 phosphorylation and interaction
FT with PRKN; when associated with ALA-362 and ALA-384."
FT /evidence="ECO:0000269|PubMed:23620051"
FT MUTAGEN 219
FT /note="K->M: Loss of enzyme activity and impaired
FT localization of PRKN to mitochondria; when associated with
FT A-362 and A-384."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:32047033"
FT MUTAGEN 362
FT /note="D->A: Abolishes MFN2 phosphorylation and interaction
FT with PRKN; when associated with A-219 and A-384. Loss of
FT enzyme activity and impaired localization of PRKN to
FT mitochondria; when associated with M-219 and A-384."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033"
FT MUTAGEN 384
FT /note="D->A: Abolishes MFN2 phosphorylation and interaction
FT with PRKN; when associated with A-219 and A-362. Loss of
FT enzyme activity and impaired localization of PRKN to
FT mitochondria; when associated with M-219 and A-362."
FT /evidence="ECO:0000269|PubMed:18957282,
FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033"
FT MUTAGEN 384
FT /note="D->N: Loss of activity. Abolishes Drp1
FT phosphorylation. No effect on localization to
FT mitochondria."
FT /evidence="ECO:0000269|PubMed:32484300"
FT CONFLICT 209
FT /note="P -> A (in Ref. 5; AAH28215)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="S -> P (in Ref. 3; BAC11484)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 581 AA; 62769 MW; 721FE01F63263A64 CRC64;
MAVRQALGRG LQLGRALLLR FTGKPGRAYG LGRPGPAAGC VRGERPGWAA GPGAEPRRVG
LGLPNRLRFF RQSVAGLAAR LQRQFVVRAW GCAGPCGRAV FLAFGLGLGL IEEKQAESRR
AVSACQEIQA IFTQKSKPGP DPLDTRRLQG FRLEEYLIGQ SIGKGCSAAV YEATMPTLPQ
NLEVTKSTGL LPGRGPGTSA PGEGQERAPG APAFPLAIKM MWNISAGSSS EAILNTMSQE
LVPASRVALA GEYGAVTYRK SKRGPKQLAP HPNIIRVLRA FTSSVPLLPG ALVDYPDVLP
SRLHPEGLGH GRTLFLVMKN YPCTLRQYLC VNTPSPRLAA MMLLQLLEGV DHLVQQGIAH
RDLKSDNILV ELDPDGCPWL VIADFGCCLA DESIGLQLPF SSWYVDRGGN GCLMAPEVST
ARPGPRAVID YSKADAWAVG AIAYEIFGLV NPFYGQGKAH LESRSYQEAQ LPALPESVPP
DVRQLVRALL QREASKRPSA RVAANVLHLS LWGEHILALK NLKLDKMVGW LLQQSAATLL
ANRLTEKCCV ETKMKMLFLA NLECETLCQA ALLLCSWRAA L
