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E3 ubiquitin-protein ligase parkin (Parkin) (EC 2.3.2.-) (Parkin RBR E3 ubiquitin-protein ligase) (Parkinson juvenile disease protein 2) (Parkinson disease protein 2)

 PRKN_HUMAN              Reviewed;         465 AA.
O60260; A3FG77; A8K975; D3JZW7; D3K2X0; Q5TFV8; Q5VVX4; Q6Q2I6;
Q8NI41; Q8NI43; Q8NI44; Q8WW07;
11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
17-OCT-2006, sequence version 2.
05-JUL-2017, entry version 180.
RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000305};
Short=Parkin;
EC=2.3.2.- {ECO:0000269|PubMed:23770887};
AltName: Full=Parkin RBR E3 ubiquitin-protein ligase {ECO:0000312|HGNC:HGNC:8607};
AltName: Full=Parkinson juvenile disease protein 2;
Short=Parkinson disease protein 2;
Name=PRKN {ECO:0000312|HGNC:HGNC:8607}; Synonyms=PARK2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND INVOLVEMENT IN
PARK2.
TISSUE=Fetal brain, and Skeletal muscle;
PubMed=9560156; DOI=10.1038/33416;
Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y.,
Minoshima S., Yokochi M., Mizuno Y., Shimizu N.;
"Mutations in the parkin gene cause autosomal recessive juvenile
parkinsonism.";
Nature 392:605-608(1998).
[2]
NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
VARIANTS ARG-311 AND THR-371, AND IDENTIFICATION BY MASS SPECTROMETRY.
PubMed=19501131; DOI=10.1016/j.neulet.2009.05.079;
Kasap M., Akpinar G., Sazci A., Idrisoglu H.A., Vahaboglu H.;
"Evidence for the presence of full-length PARK2 mRNA and Parkin
protein in human blood.";
Neurosci. Lett. 460:196-200(2009).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
D'Agata V., Scapagnini G., Cavallaro S.;
"Functional and molecular diversity of parkin.";
Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 7 AND 8).
TISSUE=Retina;
Campello L., Esteve-Rudd J., Cuenca N., Martin-Nieto J.;
"Homo sapiens PARK2 transcript variants.";
Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Testis;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=14574404; DOI=10.1038/nature02055;
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
"The DNA sequence and analysis of human chromosome 6.";
Nature 425:805-811(2003).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
TISSUE=Testis;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[9]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 312-361.
Zou H.Q., Chan P.;
Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
[10]
SUBCELLULAR LOCATION.
PubMed=10319893;
DOI=10.1002/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z;
Shimura H., Hattori N., Kubo S., Yoshikawa M., Kitada T.,
Matsumine H., Asakawa S., Minoshima S., Yamamura Y., Shimizu N.,
Mizuno Y.;
"Immunohistochemical and subcellular localization of Parkin protein:
absence of protein in autosomal recessive juvenile parkinsonism
patients.";
Ann. Neurol. 45:668-672(1999).
[11]
FUNCTION IN UBIQUITINATION.
PubMed=10973942; DOI=10.1074/jbc.C000447200;
Imai Y., Soda M., Takahashi R.;
"Parkin suppresses unfolded protein stress-induced cell death through
its E3 ubiquitin-protein ligase activity.";
J. Biol. Chem. 275:35661-35664(2000).
[12]
FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240.
PubMed=10888878; DOI=10.1038/77060;
Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S.,
Shimizu N., Iwai K., Chiba T., Tanaka K., Suzuki T.;
"Familial Parkinson disease gene product, parkin, is a ubiquitin-
protein ligase.";
Nat. Genet. 25:302-305(2000).
[13]
INTERACTION WITH UBE2L6 AND SEPT5, AND UBIQUITINATION OF SEPT5.
PubMed=11078524; DOI=10.1073/pnas.240347797;
Zhang Y., Gao J., Chung K.K.K., Huang H., Dawson V.L., Dawson T.M.;
"Parkin functions as an E2-dependent ubiquitin-protein ligase and
promotes the degradation of the synaptic vesicle-associated protein,
CDCrel-1.";
Proc. Natl. Acad. Sci. U.S.A. 97:13354-13359(2000).
[14]
UBIQUITINATION OF GPR37.
PubMed=11439185; DOI=10.1016/S0092-8674(01)00407-X;
Imai Y., Soda M., Inoue H., Hattori N., Mizuno Y., Takahashi R.;
"An unfolded putative transmembrane polypeptide, which can lead to
endoplasmic reticulum stress, is a substrate of Parkin.";
Cell 105:891-902(2001).
[15]
FUNCTION, CHARACTERIZATION OF VARIANTS PARK2 ARG-240; CYS-256; TRP-275
AND ASN-415, AND MUTAGENESIS OF CYS-337; CYS-421 AND CYS-431.
PubMed=11590439; DOI=10.1038/nm1001-1144;
Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J.,
Ross C.A., Dawson V.L., Dawson T.M.;
"Parkin ubiquitinates the alpha-synuclein-interacting protein,
synphilin-1: implications for Lewy-body formation in Parkinson
disease.";
Nat. Med. 7:1144-1150(2001).
[16]
FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK2
PRO-42 AND ARG-240.
PubMed=11431533; DOI=10.1126/science.1060627;
Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P.,
Trockenbacher A., Schneider R., Mizuno Y., Kosik K.S., Selkoe D.J.;
"Ubiquitination of a new form of alpha-synuclein by parkin from human
brain: implications for Parkinson's disease.";
Science 293:263-269(2001).
[17]
PRESENCE OF ATYPICAL RING FINGER DOMAINS.
PubMed=12446796; DOI=10.1093/oxfordjournals.molbev.a004029;
Marin I., Ferrus A.;
"Comparative genomics of the RBR family, including the Parkinson's
disease-related gene parkin and the genes of the ariadne subfamily.";
Mol. Biol. Evol. 19:2039-2050(2002).
[18]
INTERACTION WITH STUB1 AND HSP70, AND UBIQUITINATION OF STUB1.
PubMed=12150907; DOI=10.1016/S1097-2765(02)00583-X;
Imai Y., Soda M., Hatakeyama S., Akagi T., Hashikawa T., Nakayama K.,
Takahashi R.;
"CHIP is associated with Parkin, a gene responsible for familial
Parkinson's disease, and enhances its ubiquitin ligase activity.";
Mol. Cell 10:55-67(2002).
[19]
INTERACTION WITH SYT11, AND CHARACTERIZATION OF VARIANTS PARK2 GLY-289
AND ARG-418.
PubMed=12925569; DOI=10.1093/hmg/ddg269;
Huynh D.P., Scoles D.R., Nguyen D., Pulst S.M.;
"The autosomal recessive juvenile Parkinson disease gene product,
parkin, interacts with and ubiquitinates synaptotagmin XI.";
Hum. Mol. Genet. 12:2587-2597(2003).
[20]
INTERACTION WITH PACRG.
PubMed=14532270; DOI=10.1074/jbc.M309655200;
Imai Y., Soda M., Murakami T., Shoji M., Abe K., Takahashi R.;
"A product of the human gene adjacent to parkin is a component of Lewy
bodies and suppresses Pael receptor-induced cell death.";
J. Biol. Chem. 278:51901-51910(2003).
[21]
FUNCTION, INTERACTION WITH FBXW7 AND CUL1, AND UBIQUITINATION OF
CYCLIN E.
PubMed=12628165; DOI=10.1016/S0896-6273(03)00084-9;
Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E.,
Abeliovich A.;
"Parkin is a component of an SCF-like ubiquitin ligase complex and
protects postmitotic neurons from kainate excitotoxicity.";
Neuron 37:735-749(2003).
[22]
INVOLVEMENT IN CANCER.
PubMed=14614460; DOI=10.1038/sj.onc.1207072;
Denison S.R., Wang F., Becker N.A., Schuele B., Kock N.,
Phillips L.A., Klein C., Smith D.I.;
"Alterations in the common fragile site gene Parkin in ovarian and
other cancers.";
Oncogene 22:8370-8378(2003).
[23]
FUNCTION, AND INVOLVEMENT IN CANCER.
PubMed=12719539; DOI=10.1073/pnas.0931262100;
Cesari R., Martin E.S., Calin G.A., Pentimalli F., Bichi R.,
McAdams H., Trapasso F., Drusco A., Shimizu M., Masciullo V.,
D'Andrilli G., Scambia G., Picchio M.C., Alder H., Godwin A.K.,
Croce C.M.;
"Parkin, a gene implicated in autosomal recessive juvenile
parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-
q27.";
Proc. Natl. Acad. Sci. U.S.A. 100:5956-5961(2003).
[24]
REVIEW.
PubMed=15229644; DOI=10.1038/sj.embor.7400188;
Kahle P.J., Haass C.;
"How does parkin ligate ubiquitin to Parkinson's disease?";
EMBO Rep. 5:681-685(2004).
[25]
FUNCTION, UBIQUITINATION, AND S-NITROSYLATION.
PubMed=15105460; DOI=10.1126/science.1093891;
Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C.,
Marsh L., Dawson V.L., Dawson T.M.;
"S-nitrosylation of parkin regulates ubiquitination and compromises
parkin's protective function.";
Science 304:1328-1331(2004).
[26]
INTERACTION WITH PSMA7.
PubMed=15987638; DOI=10.1016/j.febslet.2005.06.003;
Dachsel J.C., Lucking C.B., Deeg S., Schultz E., Lalowski M.,
Casademunt E., Corti O., Hampe C., Patenge N., Vaupel K., Yamamoto A.,
Dichgans M., Brice A., Wanker E.E., Kahle P.J., Gasser T.;
"Parkin interacts with the proteasome subunit alpha4.";
FEBS Lett. 579:3913-3919(2005).
[27]
FUNCTION, AND INTERACTION WITH SNCAIP.
PubMed=15728840; DOI=10.1523/JNEUROSCI.4474-04.2005;
Lim K.L., Chew K.C., Tan J.M., Wang C., Chung K.K., Zhang Y.,
Tanaka Y., Smith W., Engelender S., Ross C.A., Dawson V.L.,
Dawson T.M.;
"Parkin mediates nonclassical, proteasomal-independent ubiquitination
of synphilin-1: implications for Lewy body formation.";
J. Neurosci. 25:2002-2009(2005).
[28]
FUNCTION, AND INTERACTION WITH AIMP2.
PubMed=16135753; DOI=10.1523/JNEUROSCI.2172-05.2005;
Ko H.S., von Coelln R., Sriram S.R., Kim S.W., Chung K.K.K.,
Pletnikova O., Troncoso J., Johnson B., Saffary R., Goh E.L., Song H.,
Park B.-J., Kim M.J., Kim S., Dawson V.L., Dawson T.M.;
"Accumulation of the authentic parkin substrate aminoacyl-tRNA
synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell
death.";
J. Neurosci. 25:7968-7978(2005).
[29]
INTERACTION WITH LRRK2.
PubMed=16352719; DOI=10.1073/pnas.0508052102;
Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B.,
Dawson V.L., Dawson T.M., Ross C.A.;
"Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant
LRRK2 induces neuronal degeneration.";
Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005).
[30]
INTERACTION WITH RANBP2.
PubMed=16332688; DOI=10.1074/jbc.M504994200;
Um J.W., Min D.S., Rhim H., Kim J., Paik S.R., Chung K.C.;
"Parkin ubiquitinates and promotes the degradation of RanBP2.";
J. Biol. Chem. 281:3595-3603(2006).
[31]
INTERACTION WITH SUMO1, AND SUBCELLULAR LOCATION.
PubMed=16955485; DOI=10.1002/jnr.21041;
Um J.W., Chung K.C.;
"Functional modulation of parkin through physical interaction with
SUMO-1.";
J. Neurosci. Res. 84:1543-1554(2006).
[32]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=17846173; DOI=10.1083/jcb.200611128;
Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D.,
Chin L.S.;
"Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1
to aggresomes via binding to HDAC6.";
J. Cell Biol. 178:1025-1038(2007).
[33]
FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND SUBCELLULAR LOCATION.
PubMed=19029340; DOI=10.1083/jcb.200809125;
Narendra D., Tanaka A., Suen D.F., Youle R.J.;
"Parkin is recruited selectively to impaired mitochondria and promotes
their autophagy.";
J. Cell Biol. 183:795-803(2008).
[34]
INTERACTION WITH RNF41, UBIQUITINATION, MUTAGENESIS OF CYS-421, AND
FUNCTION.
PubMed=18541373; DOI=10.1016/j.neulet.2008.05.052;
Yu F., Zhou J.;
"Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced
oxidative stress.";
Neurosci. Lett. 440:4-8(2008).
[35]
FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1,
SUBCELLULAR LOCATION, UBIQUITINATION, AND CHARACTERIZATION OF VARIANT
PARK2 PRO-42.
PubMed=19229105; DOI=10.1172/JCI37617;
Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K.,
Jiang W., Ronai Z., Zhuang X., Zhang Z.;
"Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting
unfolded protein degradation.";
J. Clin. Invest. 119:650-660(2009).
[36]
FUNCTION IN PROTECTION OF APOPTOSIS, CHARACTERIZATION OF VARIANTS
PARK2 ASN-161; CYS-256; TRP-275; ARG-418 AND ARG-441, AND DOMAIN.
PubMed=19801972; DOI=10.1038/ncb1981;
da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A.,
Safe S., Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S.,
Shen J., Checler F.;
"Transcriptional repression of p53 by parkin and impairment by
mutations associated with autosomal recessive juvenile Parkinson's
disease.";
Nat. Cell Biol. 11:1370-1375(2009).
[37]
INTERACTION WITH PINK1.
PubMed=20798600; DOI=10.4161/auto.6.7.13286;
Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S.,
Fiesel F.C., Kahle P.J., Springer W.;
"The PINK1/Parkin-mediated mitophagy is compromised by PD-associated
mutations.";
Autophagy 6:871-878(2010).
[38]
FUNCTION, INTERACTION WITH BCL2, SUBCELLULAR LOCATION, AND
CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND
LEU-437.
PubMed=20889974; DOI=10.1074/jbc.M110.101469;
Chen D., Gao F., Li B., Wang H., Xu Y., Zhu C., Wang G.;
"Parkin mono-ubiquitinates Bcl-2 and regulates autophagy.";
J. Biol. Chem. 285:38214-38223(2010).
[39]
FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION
WITH PINK1, AND CHARACTERIZATION OF VARIANTS PARK ASN-415 AND ASP-430.
PubMed=19966284; DOI=10.1073/pnas.0911187107;
Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J.,
May J., Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J.,
Dawson V.L., Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.;
"PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.";
Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010).
[40]
FUNCTION, INTERACTION WITH ZNF746, AND CHARACTERIZATION OF VARIANTS
PARK2 TRP-275; ASP-430 AND PHE-431.
PubMed=21376232; DOI=10.1016/j.cell.2011.02.010;
Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O.,
Troconso J.C., Dawson V.L., Dawson T.M.;
"PARIS (ZNF746) repression of PGC-1alpha contributes to
neurodegeneration in Parkinson's disease.";
Cell 144:689-702(2011).
[41]
CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289.
PubMed=20889486; DOI=10.1093/hmg/ddq428;
Rose J.M., Novoselov S.S., Robinson P.A., Cheetham M.E.;
"Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1
domain mutant.";
Hum. Mol. Genet. 20:16-27(2011).
[42]
FUNCTION, REACTION MECHANISM, AND INTERACTION WITH UBE2L3.
PubMed=21532592; DOI=10.1038/nature09966;
Wenzel D.M., Lissounov A., Brzovic P.S., Klevit R.E.;
"UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT
hybrids.";
Nature 474:105-108(2011).
[43]
FUNCTION, INTERACTION WITH CHPF, AND SUBCELLULAR LOCATION.
PubMed=22082830; DOI=10.1093/hmg/ddr530;
Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y.,
Takahashi T., Kagawa N., Matsumoto M., Matsumoto M., Takahashi R.,
Kaji R., Mitsui T.;
"Parkin interacts with Klokin1 for mitochondrial import and
maintenance of membrane potential.";
Hum. Mol. Genet. 21:991-1003(2012).
[44]
PHOSPHORYLATION AT SER-65, FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=23754282; DOI=10.1074/jbc.M113.467530;
Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M.,
Suzuki N., Uchiyama S., Tanaka K., Matsuda N.;
"Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-
dependent phosphorylation.";
J. Biol. Chem. 288:22019-22032(2013).
[45]
FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7.
PubMed=23933751; DOI=10.1038/nn.3489;
Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M.,
Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H.,
Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H.,
Plun-Favreau H.;
"The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to
mediate mitophagy.";
Nat. Neurosci. 16:1257-1265(2013).
[46]
INTERACTION WITH BAG4; BAG5; HSPA1L; HSPA1A AND HSPA8.
PubMed=24270810; DOI=10.1038/nature12748;
Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A.,
Buehler E., Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E.,
Youle R.J.;
"High-content genome-wide RNAi screens identify regulators of parkin
upstream of mitophagy.";
Nature 504:291-295(2013).
[47]
FUNCTION IN MITOPHAGY, INTERACTION WITH MFN2, AND SUBCELLULAR
LOCATION.
PubMed=23620051; DOI=10.1126/science.1231031;
Chen Y., Dorn G.W. II;
"PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling
damaged mitochondria.";
Science 340:471-475(2013).
[48]
FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ENZYME
REGULATION, AND MUTAGENESIS OF SER-65.
PubMed=24660806; DOI=10.1042/BJ20140334;
Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G.,
Ritorto M.S., Hofmann K., Alessi D.R., Knebel A., Trost M.,
Muqit M.M.;
"Parkin is activated by PINK1-dependent phosphorylation of ubiquitin
at Ser65.";
Biochem. J. 460:127-139(2014).
[49]
FUNCTION, AND ENZYME REGULATION.
PubMed=24751536; DOI=10.1083/jcb.201402104;
Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A.,
Banerjee S., Youle R.J.;
"PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase
activity.";
J. Cell Biol. 205:143-153(2014).
[50]
FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ENZYME
REGULATION, AND MUTAGENESIS OF SER-65 AND TRP-403.
PubMed=24784582; DOI=10.1038/nature13392;
Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M.,
Kimura Y., Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A.,
Trempe J.F., Saeki Y., Tanaka K., Matsuda N.;
"Ubiquitin is phosphorylated by PINK1 to activate parkin.";
Nature 510:162-166(2014).
[51]
FUNCTION.
PubMed=24896179; DOI=10.1038/nature13418;
Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q.,
Foreman O., Kirkpatrick D.S., Sheng M.;
"The mitochondrial deubiquitinase USP30 opposes parkin-mediated
mitophagy.";
Nature 510:370-375(2014).
[52]
FUNCTION, AND ENZYME REGULATION.
PubMed=25527291; DOI=10.15252/embj.201489847;
Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N.,
Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.;
"Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain
assembly and hydrolysis.";
EMBO J. 34:307-325(2015).
[53]
FUNCTION.
PubMed=25621951; DOI=10.1038/ncb3097;
Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M.,
Kirkpatrick D.S., Bingol B., Corn J.E.;
"USP30 and parkin homeostatically regulate atypical ubiquitin chains
on mitochondria.";
Nat. Cell Biol. 17:160-169(2015).
[54]
STRUCTURE BY NMR OF 1-76, AND INTERACTION WITH PSMD4.
PubMed=12634850; DOI=10.1038/sj.embor.embor764;
Sakata E., Yamaguchi Y., Kurimoto E., Kikuchi J., Yokoyama S.,
Yamada S., Kawahara H., Yokosawa H., Hattori N., Mizuno Y., Tanaka K.,
Kato K.;
"Parkin binds the Rpn10 subunit of 26S proteasomes through its
ubiquitin-like domain.";
EMBO Rep. 4:301-306(2003).
[55]
STRUCTURE BY NMR OF 307-384 IN COMPLEX WITH ZINC IONS,
CHARACTERIZATION OF VARIANT PARK2 PRO-351, MUTAGENESIS OF CYS-332 AND
CYS-365, AND IDENTIFICATION BY MASS SPECTROMETRY.
PubMed=17360614; DOI=10.1073/pnas.0610548104;
Beasley S.A., Hristova V.A., Shaw G.S.;
"Structure of the Parkin in-between-ring domain provides insights for
E3-ligase dysfunction in autosomal recessive Parkinson's disease.";
Proc. Natl. Acad. Sci. U.S.A. 104:3095-3100(2007).
[56]
X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 137-465, ENZYME REGULATION,
AND MUTAGENESIS OF CYS-431; HIS-433 AND GLU-444.
PubMed=23727886; DOI=10.1038/emboj.2013.125;
Wauer T., Komander D.;
"Structure of the human Parkin ligase domain in an autoinhibited
state.";
EMBO J. 32:2099-2112(2013).
[57]
X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 137-465, ACTIVE SITE,
CATALYTIC ACTIVITY, ENZYME REGULATION, AND MUTAGENESIS OF CYS-431;
HIS-433 AND GLU-444.
PubMed=23770887; DOI=10.1038/ncomms2982;
Riley B.E., Lougheed J.C., Callaway K., Velasquez M., Brecht E.,
Nguyen L., Shaler T., Walker D., Yang Y., Regnstrom K., Diep L.,
Zhang Z., Chiou S., Bova M., Artis D.R., Yao N., Baker J., Yednock T.,
Johnston J.A.;
"Structure and function of Parkin E3 ubiquitin ligase reveals aspects
of RING and HECT ligases.";
Nat. Commun. 4:1982-1982(2013).
[58]
REVIEW ON VARIANTS.
PubMed=14976155; DOI=10.1093/hmg/ddh089;
Mata I.F., Lockhart P.J., Farrer M.J.;
"Parkin genetics: one model for Parkinson's disease.";
Hum. Mol. Genet. 13:R127-R133(2004).
[59]
VARIANT PARK2 ARG-240.
PubMed=9731209; DOI=10.1006/bbrc.1998.9134;
Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H.,
Elibol B., Brookes A.J., Yamamura Y., Kobayashi T., Wang M.,
Yoritaka A., Minoshima S., Shimizu N., Mizuno Y.;
"Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene.";
Biochem. Biophys. Res. Commun. 249:754-758(1998).
[60]
ERRATUM.
Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H.,
Elibol B., Brookes A.J., Yamamura Y., Kobayashi T., Wang M.,
Yoritaka A., Minoshima S., Shimizu N., Mizuno Y.;
Biochem. Biophys. Res. Commun. 251:666-666(1998).
[61]
VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415, AND VARIANTS
ASN-167; LEU-380 AND ASN-394.
PubMed=10072423; DOI=10.1093/hmg/8.4.567;
Abbas N., Luecking C.B., Ricard S., Duerr A., Bonifati V.,
De Michele G., Bouley S., Vaughan J.R., Gasser T., Marconi R.,
Broussolle E., Brefel-Courbon C., Harhangi B.S., Oostra B.A.,
Fabrizio E., Bohme G.A., Pradier L., Wood N.W., Filla A., Meco G.,
Denefle P., Agid Y., Brice A.;
"A wide variety of mutations in the parkin gene are responsible for
autosomal recessive parkinsonism in Europe.";
Hum. Mol. Genet. 8:567-574(1999).
[62]
VARIANT ASN-167.
PubMed=10511432; DOI=10.1097/00001756-199909090-00008;
Satoh J., Kuroda Y.;
"Association of codon 167 Ser/Asn heterozygosity in the parkin gene
with sporadic Parkinson's disease.";
NeuroReport 10:2735-2739(1999).
[63]
VARIANT PARK2 PHE-431.
PubMed=10939576;
DOI=10.1002/1531-8249(200008)48:2<245::AID-ANA15>3.0.CO;2-2;
Maruyama M., Ikeuchi T., Saito M., Ishikawa A., Yuasa T., Tanaka H.,
Hayashi S., Wakabayashi K., Takahashi H., Tsuji S.;
"Novel mutations, pseudo-dominant inheritance, and possible familial
affects in patients with autosomal recessive juvenile parkinsonism.";
Ann. Neurol. 48:245-250(2000).
[64]
VARIANTS ASN-167; TRP-366 AND LEU-380.
PubMed=10965160; DOI=10.1159/000008203;
Hu C.-J., Sung S.-M., Liu H.-C., Lee C.-C., Tsai C.-H., Chang J.-G.;
"Polymorphisms of the parkin gene in sporadic Parkinson's disease
among Chinese in Taiwan.";
Eur. Neurol. 44:90-93(2000).
[65]
VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289;
GLU-328; ASN-415 AND ASP-430, AND VARIANT CYS-334.
PubMed=10824074; DOI=10.1056/NEJM200005253422103;
Luecking C.B., Duerr A., Bonifati V., Vaughan J.R., De Michele G.,
Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y.,
Brice A.;
"Association between early-onset Parkinson's disease and mutations in
the parkin gene.";
N. Engl. J. Med. 342:1560-1567(2000).
[66]
VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430.
PubMed=11179010; DOI=10.1086/318791;
Periquet M., Luecking C.B., Vaughan J.R., Bonifati V., Duerr A.,
De Michele G., Horstink M., Farrer M., Illarioshkin S.N., Pollak P.,
Borg M., Brefel-Courbon C., Denefle P., Meco G., Gasser T.,
Breteler M.M., Wood N.W., Agid Y., Brice A.;
"Origin of the mutations in the parkin gene in Europe: exon
rearrangements are independent recurrent events, whereas point
mutations may result from founder effects.";
Am. J. Hum. Genet. 68:617-626(2001).
[67]
VARIANT PARK2 GLU-82.
PubMed=11487568; DOI=10.1093/hmg/10.16.1649;
Hedrich K., Kann M., Lanthaler A.J., Dalski A., Eskelson C., Landt O.,
Schwinger E., Vieregge P., Lang A.E., Breakefield X.O., Ozelius L.J.,
Pramstaller P.P., Klein C.;
"The importance of gene dosage studies: mutational analysis of the
parkin gene in early-onset parkinsonism.";
Hum. Mol. Genet. 10:1649-1656(2001).
[68]
VARIANT PARK2 TYR-212.
PubMed=11163284; DOI=10.1016/S0304-3940(00)01733-X;
Pineda-Trujillo N., Carvajal-Carmona L.G., Buritica O., Moreno S.,
Uribe C., Pineda D., Toro M., Garcia F., Arias W., Bedoya G.,
Lopera F., Ruiz-Linares A.;
"A novel Cys212Tyr founder mutation in parkin and allelic
heterogeneity of juvenile parkinsonism in a population from North West
Colombia.";
Neurosci. Lett. 298:87-90(2001).
[69]
VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441.
PubMed=12116199; DOI=10.1002/ajmg.10525;
French Parkinson's disease genetics study group;
European consortium on genetic susceptibility on Parkinson's disease;
West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D.,
Bonifati V., Rawal N., Gasser T., Lohmann E., Deleuze J.-F.,
Maraganore D., Levey A., Wood N.W., Duerr A., Hardy J., Brice A.,
Farrer M.;
"Complex relationship between parkin mutations and Parkinson
disease.";
Am. J. Med. Genet. 114:584-591(2002).
[70]
ERRATUM.
French Parkinson's disease genetics study group;
European consortium on genetic susceptibility on Parkinson's disease;
West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D.,
Bonifati V., Rawal N., Gasser T., Lohmann E., Deleuze J.-F.,
Maraganore D., Levey A., Wood N.W., Duerr A., Hardy J., Brice A.,
Farrer M.J.;
Am. J. Med. Genet. 114:992-992(2002).
[71]
VARIANTS PARK2 LEU-37 AND PRO-351.
PubMed=12112109; DOI=10.1002/ana.10179;
Kann M., Jacobs H., Mohrmann K., Schumacher K., Hedrich K.,
Garrels J., Wiegers K., Schwinger E., Pramstaller P.P.,
Breakefield X.O., Ozelius L.J., Vieregge P., Klein C.;
"Role of parkin mutations in 111 community-based patients with early-
onset parkinsonism.";
Ann. Neurol. 51:621-625(2002).
[72]
VARIANTS PARK2 GLU-56 AND TYR-212.
PubMed=12056932; DOI=10.1001/archneur.59.6.966;
Hoenicka J., Vidal L., Morales B., Ampuero I., Jimenez-Jimenez F.J.,
Berciano J., del Ser T., Jimenez A., Ruiz P.G., de Yebenes J.G.;
"Molecular findings in familial Parkinson disease in Spain.";
Arch. Neurol. 59:966-970(2002).
[73]
VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437.
PubMed=12114481; DOI=10.1136/jmg.39.7.489;
Nichols W.C., Pankratz N., Uniacke S.K., Pauciulo M.W., Halter C.,
Rudolph A., Conneally P.M., Foroud T.;
"Linkage stratification and mutation analysis at the parkin locus
identifies mutation positive Parkinson's disease families.";
J. Med. Genet. 39:489-492(2002).
[74]
VARIANT PARK2 MET-15, AND VARIANTS LEU-380 AND ASN-394.
PubMed=12397156; DOI=10.1136/jnnp.73.5.582;
Munoz E., Tolosa E., Pastor P., Marti M.J., Valldeoriola F.,
Campdelacreu J., Oliva R.;
"Relative high frequency of the c.255delA parkin gene mutation in
Spanish patients with autosomal recessive parkinsonism.";
J. Neurol. Neurosurg. Psych. 73:582-584(2002).
[75]
VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437.
PubMed=11971093; DOI=10.1212/WNL.58.8.1239;
Hedrich K., Marder K., Harris J., Kann M., Lynch T., Meija-Santana H.,
Pramstaller P.P., Schwinger E., Bressman S.B., Fahn S., Klein C.;
"Evaluation of 50 probands with early-onset Parkinson's disease for
parkin mutations.";
Neurology 58:1239-1246(2002).
[76]
VARIANT PARK2 PRO-46.
PubMed=12362318;
Xu Y., Liu Z., Wang Y., Tao E., Chen G., Chen B.;
"A new point mutation on exon 2 of parkin gene in Parkinson's
disease.";
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:409-411(2002).
[77]
VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437, VARIANTS PARK
TYR-253; CYS-256; TRP-275 AND ASN-280, AND VARIANTS LEU-380 AND
ASN-394.
PubMed=12730996; DOI=10.1002/ana.10524;
Oliveira S.A., Scott W.K., Martin E.R., Nance M.A., Watts R.L.,
Hubble J.P., Koller W.C., Pahwa R., Stern M.B., Hiner B.C., Ondo W.G.,
Allen F.H. Jr., Scott B.L., Goetz C.G., Small G.W., Mastaglia F.,
Stajich J.M., Zhang F., Booze M.W., Winn M.P., Middleton L.T.,
Haines J.L., Pericak-Vance M.A., Vance J.M.;
"Parkin mutations and susceptibility alleles in late-onset Parkinson's
disease.";
Ann. Neurol. 53:624-629(2003).
[78]
VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437, VARIANT ASN-167,
AND INVOLVEMENT IN LATE-ONSET PARK.
PubMed=12629236; DOI=10.1212/01.WNL.0000049470.00180.07;
Foroud T., Uniacke S.K., Liu L., Pankratz N., Rudolph A., Halter C.,
Shults C., Marder K., Conneally P.M., Nichols W.C.;
"Heterozygosity for a mutation in the parkin gene leads to later onset
Parkinson disease.";
Neurology 60:796-801(2003).
[79]
VARIANTS HIS-100; SER-271 AND SER-339.
PubMed=12781599; DOI=10.1016/S1353-8020(03)00018-X;
Chen R., Gosavi N.S., Langston J.W., Chan P.;
"Parkin mutations are rare in patients with young-onset parkinsonism
in a US population.";
Parkinsonism Relat. Disord. 9:309-312(2003).
[80]
VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418.
PubMed=15584030; DOI=10.1002/mds.20343;
Italian Parkinson Genetics Network;
Bertoli-Avella A.M., Giroud-Benitez J.L., Akyol A., Barbosa E.,
Schaap O., van der Linde H.C., Martignoni E., Lopiano L., Lamberti P.,
Fincati E., Antonini A., Stocchi F., Montagna P., Squitieri F.,
Marini P., Abbruzzese G., Fabbrini G., Marconi R., Dalla Libera A.,
Trianni G., Guidi M., De Gaetano A., Boff Maegawa G., De Leo A.,
Gallai V., de Rosa G., Vanacore N., Meco G., van Duijn C.M.,
Oostra B.A., Heutink P., Bonifati V.;
"Novel parkin mutations detected in patients with early-onset
Parkinson's disease.";
Mov. Disord. 20:424-431(2005).
[81]
CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ASN-211; ARG-240; ASN-280
AND GLU-328.
PubMed=20404107; DOI=10.1083/jcb.200910140;
Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A.,
Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M.,
Hattori N., Tanaka K.;
"PINK1 stabilized by mitochondrial depolarization recruits Parkin to
damaged mitochondria and activates latent Parkin for mitophagy.";
J. Cell Biol. 189:211-221(2010).
[82]
VARIANT PARK2 TRP-275.
PubMed=22956510; DOI=10.1002/mds.25132;
Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D.,
Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H.,
Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E.,
Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A.,
Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.;
"Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7
(DJ-1) and LRRK2 in early-onset Parkinson's disease.";
Mov. Disord. 27:1522-1529(2012).
[83]
VARIANT CYS-334.
PubMed=27535533; DOI=10.1038/nature19057;
Exome Aggregation Consortium;
Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E.,
Fennell T., O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B.,
Tukiainen T., Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K.,
Zhao F., Zou J., Pierce-Hoffman E., Berghout J., Cooper D.N.,
Deflaux N., DePristo M., Do R., Flannick J., Fromer M., Gauthier L.,
Goldstein J., Gupta N., Howrigan D., Kiezun A., Kurki M.I.,
Moonshine A.L., Natarajan P., Orozco L., Peloso G.M., Poplin R.,
Rivas M.A., Ruano-Rubio V., Rose S.A., Ruderfer D.M., Shakir K.,
Stenson P.D., Stevens C., Thomas B.P., Tiao G., Tusie-Luna M.T.,
Weisburd B., Won H.H., Yu D., Altshuler D.M., Ardissino D.,
Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C.,
Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S.,
Laakso M., McCarroll S., McCarthy M.I., McGovern D., McPherson R.,
Neale B.M., Palotie A., Purcell S.M., Saleheen D., Scharf J.M.,
Sklar P., Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C.,
Wilson J.G., Daly M.J., MacArthur D.G.;
"Analysis of protein-coding genetic variation in 60,706 humans.";
Nature 536:285-291(2016).
-!- FUNCTION: Functions within a multiprotein E3 ubiquitin ligase
complex, catalyzing the covalent attachment of ubiquitin moieties
onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37,
RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30,
ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878,
PubMed:11431533, PubMed:12150907, PubMed:12628165,
PubMed:16135753, PubMed:21376232, PubMed:23754282,
PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates
monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked
and 'Lys-63'-linked polyubiquitination of substrates depending on
the context (PubMed:19229105, PubMed:20889974, PubMed:25621951).
Participates in the removal and/or detoxification of abnormally
folded or damaged protein by mediating 'Lys-63'-linked
polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-
linked polyubiquitinated misfolded proteins are then recognized by
HDAC6, leading to their recruitment to aggresomes, followed by
degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-
linked polyubiquitination of a 22 kDa O-linked glycosylated
isoform of SNCAIP, possibly playing a role in Lewy-body formation
(PubMed:11590439, PubMed:11431533, PubMed:19229105,
PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of
BCL2, thereby acting as a positive regulator of autophagy
(PubMed:20889974). Promotes the autophagic degradation of
dysfunctional depolarized mitochondria (mitophagy) by promoting
the ubiquitination of mitochondrial proteins such as TOMM20,
RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284,
PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially
assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin
chains following mitochondrial damage, leading to mitophagy
(PubMed:25621951). Mediates 'Lys-48'-linked polyubiquitination of
ZNF746, followed by degradation of ZNF746 by the proteasome;
possibly playing a role in the regulation of neuron death
(PubMed:21376232). Limits the production of reactive oxygen
species (ROS). Regulates cyclin-E during neuronal apoptosis. In
collaboration with CHPF isoform 2, may enhance cell viability and
protect cells from oxidative stress (PubMed:22082830).
Independently of its ubiquitin ligase activity, protects from
apoptosis by the transcriptional repression of p53/TP53
(PubMed:19801972). May protect neurons against alpha synuclein
toxicity, proteasomal dysfunction, GPR37 accumulation, and
kainate-induced excitotoxicity (PubMed:11439185). May play a role
in controlling neurotransmitter trafficking at the presynaptic
terminal and in calcium-dependent exocytosis. May represent a
tumor suppressor gene. {ECO:0000269|PubMed:10888878,
ECO:0000269|PubMed:10973942, ECO:0000269|PubMed:11431533,
ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12628165,
ECO:0000269|PubMed:12719539, ECO:0000269|PubMed:15105460,
ECO:0000269|PubMed:15728840, ECO:0000269|PubMed:16135753,
ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:18541373,
ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105,
ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284,
ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232,
ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830,
ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282,
ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806,
ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582,
ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25527291,
ECO:0000269|PubMed:25621951}.
-!- CATALYTIC ACTIVITY: S-ubiquitinyl-[E2 ubiquitin-conjugating
enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-
conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor
protein]-L-lysine. {ECO:0000269|PubMed:23770887}.
-!- ENZYME REGULATION: In the autoinhibited state the side chain of
Phe-463 inserts into a hydrophobic groove in RING-0, occluding the
ubiquitin acceptor site Cys-431, whereas the REP repressor element
binds RING-1 and blocks its E2-binding site (PubMed:23727886,
PubMed:23770887). Activation of PRKN requires 2 steps: (1)
phosphorylation at Ser-65 by PINK1 and (2) binding to
phosphorylated ubiquitin, leading to unlock repression of the
catalytic Cys-431 by the RING-0 region via an allosteric mechanism
and converting PRKN to its fully-active form (PubMed:24660806,
PubMed:24784582, PubMed:25527291). According to another report,
phosphorylation at Ser-65 by PINK1 is not essential for activation
and only binding to phosphorylated ubiquitin is essential to
unlock repression (PubMed:24751536). {ECO:0000269|PubMed:23727886,
ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:24660806,
ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582,
ECO:0000269|PubMed:25527291}.
-!- PATHWAY: Protein modification; protein ubiquitination.
-!- SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or
UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating
with UBE2V1. Part of a SCF-like complex, consisting of PRKN, CUL1
and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains
of SYT11. Interacts and regulates the turnover of SEPT5. Part of a
complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in
the complex increases during ER stress. STUB1 promotes the
dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-
mediated GPR37 ubiquitination. HSP70 transiently associates with
unfolded GPR37 and inhibits the E3 activity of PRKN, whereas,
STUB1 enhances the E3 activity of PRKN through promotion of
dissociation of HSP70 from PRKN-GPR37 complexes. Interacts with
PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2.
Interacts with SUMO1 but not SUMO2, which promotes nuclear
localization and autoubiquitination. Interacts (via first RING-
type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and
RNF41. Interacts with PINK1. Interacts with CHPF, the interaction
with isoform 2 may facilitate PRKN transport into the
mitochondria. Interacts with MFN2 (phosphorylated), promotes PRKN
localization in dysfunctional depolarized mitochondria. Interacts
with FBXO7; this promotes translocation to dysfunctional
depolarized mitochondria. Interacts with heat shock protein 70
family members, including HSPA1L, HSPA1A and HSPA8; interaction
HSPA1L promotes translocation to damaged mitochondria. Interacts
with BAG4 and, to a lesser extent, BAG5; interaction with BAG4
inhibits translocation to damaged mitochondria. Forms a complex
with PINK1 and PARK7 (PubMed:19229105).
{ECO:0000269|PubMed:11078524, ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165,
ECO:0000269|PubMed:12634850, ECO:0000269|PubMed:12925569,
ECO:0000269|PubMed:14532270, ECO:0000269|PubMed:15728840,
ECO:0000269|PubMed:15987638, ECO:0000269|PubMed:16135753,
ECO:0000269|PubMed:16332688, ECO:0000269|PubMed:16352719,
ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:17360614,
ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:19229105,
ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20798600,
ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232,
ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830,
ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23933751,
ECO:0000269|PubMed:24270810}.
-!- INTERACTION:
Self; NbExp=5; IntAct=EBI-716346, EBI-716346;
Q99IB8:- (xeno); NbExp=3; IntAct=EBI-716346, EBI-6858513;
P54252-2:ATXN3; NbExp=5; IntAct=EBI-716346, EBI-9684323;
Q8IZ52-2:CHPF; NbExp=5; IntAct=EBI-716346, EBI-9029620;
Q9Y3I1:FBXO7; NbExp=10; IntAct=EBI-716346, EBI-1161222;
Q9Y3I1-1:FBXO7; NbExp=2; IntAct=EBI-716346, EBI-9102965;
Q5S007:LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863;
Q16342:PDCD2; NbExp=5; IntAct=EBI-716346, EBI-359462;
Q9BXM7:PINK1; NbExp=7; IntAct=EBI-716346, EBI-2846068;
P49792:RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138;
Q8IXI2:RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430;
Q9Z2Q6:Sept5 (xeno); NbExp=2; IntAct=EBI-716346, EBI-772125;
Q15645:TRIP13; NbExp=3; IntAct=EBI-716346, EBI-358993;
P68510:Ywhah (xeno); NbExp=6; IntAct=EBI-716346, EBI-444641;
Q6NUN9:ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525;
-!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
{ECO:0000269|PubMed:19229105}. Nucleus. Endoplasmic reticulum.
Mitochondrion {ECO:0000269|PubMed:19229105}. Note=Mainly localizes
in the cytosol. Co-localizes with SYT11 in neutrites. Co-localizes
with SNCAIP in brainstem Lewy bodies. Mitochondrial localization
gradually increases with cellular growth. Also relocates to
dysfunctional mitochondria that have lost the mitochondrial
membrane potential; recruitment to mitochondria is PINK1-
dependent.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=8;
Name=1;
IsoId=O60260-1; Sequence=Displayed;
Name=2; Synonyms=SV5DEL;
IsoId=O60260-2; Sequence=VSP_011707;
Name=3;
IsoId=O60260-3; Sequence=VSP_011706, VSP_011709, VSP_011710;
Name=4;
IsoId=O60260-4; Sequence=VSP_011705;
Name=5;
IsoId=O60260-5; Sequence=VSP_011708, VSP_011711, VSP_011712;
Name=6;
IsoId=O60260-6; Sequence=VSP_041563;
Name=7; Synonyms=SV5,9DEL;
IsoId=O60260-7; Sequence=VSP_011707, VSP_053651;
Name=8; Synonyms=SV9DEL;
IsoId=O60260-8; Sequence=VSP_053651;
-!- TISSUE SPECIFICITY: Highly expressed in the brain including the
substantia nigra. Expressed in heart, testis and skeletal muscle.
Expression is down-regulated or absent in tumor biopsies, and
absent in the brain of PARK2 patients. Overexpression protects
dopamine neurons from kainate-mediated apoptosis. Found in serum
(at protein level). {ECO:0000269|PubMed:19501131}.
-!- DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S
proteasomes. {ECO:0000269|PubMed:19801972}.
-!- DOMAIN: The RING-type 1 zinc finger domain is required to repress
p53/TP53 transcription. {ECO:0000269|PubMed:19801972}.
-!- DOMAIN: Members of the RBR family are atypical E3 ligases. They
interact with the E2 conjugating enzyme UBE2L3 and function like
HECT-type E3 enzymes: they bind E2s via the first RING domain, but
require an obligate trans-thiolation step during the ubiquitin
transfer, requiring a conserved cysteine residue in the second
RING domain (PubMed:21532592). {ECO:0000305|PubMed:21532592}.
-!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its
own degradation (PubMed:19229105). Also polyubiquitinated by RNF41
for proteasomal degradation. {ECO:0000269|PubMed:19229105}.
-!- PTM: S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase
activity by S-nitrosylation could contribute to the degenerative
process in PD by impairing the ubiquitination of PRKN substrates.
{ECO:0000269|PubMed:15105460}.
-!- PTM: Phosphorylation at Ser-65 by PINK1 contributes to activate
PRKN activity. It is however not sufficient and requires binding
to phosphorylated ubiquitin as well. {ECO:0000269|PubMed:23754282,
ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24784582}.
-!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex
neurodegenerative disorder characterized by bradykinesia, resting
tremor, muscular rigidity and postural instability. Additional
features are characteristic postural abnormalities, dysautonomia,
dystonic cramps, and dementia. The pathology of Parkinson disease
involves the loss of dopaminergic neurons in the substantia nigra
and the presence of Lewy bodies (intraneuronal accumulations of
aggregated proteins), in surviving neurons in various areas of the
brain. The disease is progressive and usually manifests after the
age of 50 years, although early-onset cases (before 50 years) are
known. The majority of the cases are sporadic suggesting a
multifactorial etiology based on environmental and genetic
factors. However, some patients present with a positive family
history for the disease. Familial forms of the disease usually
begin at earlier ages and are associated with atypical clinical
features. {ECO:0000269|PubMed:12629236,
ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284}.
Note=Disease susceptibility may be associated with variations
affecting the gene represented in this entry. Heterozygous
mutations act as susceptibility alleles for late-onset Parkinson
disease (PubMed:12730996 and PubMed:12629236).
-!- DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: A
neurodegenerative disorder characterized by bradykinesia,
rigidity, postural instability, tremor, and onset usually before
40. It differs from classic Parkinson disease by early DOPA-
induced dyskinesia, diurnal fluctuation of the symptoms, sleep
benefit, dystonia and hyper-reflexia. Dementia is absent.
Pathologically, patients show loss of dopaminergic neurons in the
substantia nigra, similar to that seen in Parkinson disease;
however, Lewy bodies (intraneuronal accumulations of aggregated
proteins) are absent. {ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:10888878,
ECO:0000269|PubMed:10939576, ECO:0000269|PubMed:11163284,
ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11431533,
ECO:0000269|PubMed:11487568, ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12056932,
ECO:0000269|PubMed:12112109, ECO:0000269|PubMed:12114481,
ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12362318,
ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12629236,
ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:12925569,
ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:17360614,
ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972,
ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889486,
ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232,
ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:9560156,
ECO:0000269|PubMed:9731209}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Note=Defects in PRKN may be involved in the development
and/or progression of ovarian cancer.
-!- MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q
telomere is hyper-recombinable and lies within FRA6E, the third
most common fragile site in tumor tissue.
-!- SIMILARITY: Belongs to the RBR family. Parkin subfamily.
{ECO:0000305}.
-!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue
131 of September 2011;
URL="http://web.expasy.org/spotlight/back_issues/131";
-----------------------------------------------------------------------
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EMBL; AB009973; BAA25751.1; -; mRNA.
EMBL; EF375726; ABN46990.1; -; mRNA.
EMBL; AF381282; AAM21457.1; -; mRNA.
EMBL; AF381283; AAM21458.1; -; mRNA.
EMBL; AF381286; AAM21461.1; -; mRNA.
EMBL; GU345839; ADB90270.1; -; mRNA.
EMBL; GU345840; ADB90271.1; -; mRNA.
EMBL; GU361467; ADB91979.1; -; mRNA.
EMBL; AK292590; BAF85279.1; -; mRNA.
EMBL; AL445215; CAH73681.1; -; Genomic_DNA.
EMBL; AL035697; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AL132982; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP000886; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP000887; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP001576; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP001577; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP001578; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AP003699; CAH73681.1; JOINED; Genomic_DNA.
EMBL; AL035697; CAI21385.1; -; Genomic_DNA.
EMBL; AL132982; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AL445215; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP000886; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP000887; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP001576; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP001577; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP001578; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AP003699; CAI21385.1; JOINED; Genomic_DNA.
EMBL; AL132982; CAI23601.1; -; Genomic_DNA.
EMBL; AL035697; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AL445215; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP000886; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP000887; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP001576; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP001577; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP001578; CAI23601.1; JOINED; Genomic_DNA.
EMBL; AP003699; CAI23601.1; JOINED; Genomic_DNA.
EMBL; CH471051; EAW47573.1; -; Genomic_DNA.
EMBL; CH471051; EAW47574.1; -; Genomic_DNA.
EMBL; BC022014; AAH22014.1; -; mRNA.
EMBL; AY564225; AAS88422.1; -; Genomic_DNA.
CCDS; CCDS5281.1; -. [O60260-1]
CCDS; CCDS5282.1; -. [O60260-2]
CCDS; CCDS5283.1; -. [O60260-6]
RefSeq; NP_004553.2; NM_004562.2. [O60260-1]
RefSeq; NP_054642.2; NM_013987.2. [O60260-2]
RefSeq; NP_054643.2; NM_013988.2. [O60260-6]
UniGene; Hs.132954; -.
PDB; 1IYF; NMR; -; A=1-76.
PDB; 2JMO; NMR; -; A=308-384.
PDB; 4BM9; X-ray; 2.25 A; A=137-465.
PDB; 4I1F; X-ray; 1.58 A; A=141-465.
PDB; 4I1H; X-ray; 2.00 A; A=141-465.
PDB; 5C1Z; X-ray; 1.79 A; A/B=1-465.
PDB; 5C23; X-ray; 2.37 A; A/B=1-465.
PDB; 5C9V; X-ray; 2.35 A; A=137-465.
PDB; 5N2W; X-ray; 2.68 A; A=1-465.
PDB; 5N38; X-ray; 2.60 A; A=1-465.
PDB; 5TR5; NMR; -; A=1-76.
PDBsum; 1IYF; -.
PDBsum; 2JMO; -.
PDBsum; 4BM9; -.
PDBsum; 4I1F; -.
PDBsum; 4I1H; -.
PDBsum; 5C1Z; -.
PDBsum; 5C23; -.
PDBsum; 5C9V; -.
PDBsum; 5N2W; -.
PDBsum; 5N38; -.
PDBsum; 5TR5; -.
ProteinModelPortal; O60260; -.
SMR; O60260; -.
BioGrid; 111105; 422.
DIP; DIP-37655N; -.
IntAct; O60260; 34.
MINT; MINT-1351124; -.
STRING; 9606.ENSP00000355865; -.
iPTMnet; O60260; -.
PhosphoSitePlus; O60260; -.
BioMuta; PARK2; -.
PaxDb; O60260; -.
PeptideAtlas; O60260; -.
PRIDE; O60260; -.
DNASU; 5071; -.
Ensembl; ENST00000338468; ENSP00000343589; ENSG00000185345. [O60260-4]
Ensembl; ENST00000366894; ENSP00000355860; ENSG00000185345. [O60260-4]
Ensembl; ENST00000366896; ENSP00000355862; ENSG00000185345. [O60260-6]
Ensembl; ENST00000366897; ENSP00000355863; ENSG00000185345. [O60260-2]
Ensembl; ENST00000366898; ENSP00000355865; ENSG00000185345. [O60260-1]
Ensembl; ENST00000479615; ENSP00000434414; ENSG00000185345. [O60260-3]
GeneID; 5071; -.
KEGG; hsa:5071; -.
UCSC; uc003qty.5; human. [O60260-1]
CTD; 5071; -.
DisGeNET; 5071; -.
GeneCards; PARK2; -.
GeneReviews; PARK2; -.
HGNC; HGNC:8607; PRKN.
HPA; CAB016257; -.
MalaCards; PARK2; -.
MIM; 168600; phenotype.
MIM; 600116; phenotype.
MIM; 602544; gene.
neXtProt; NX_O60260; -.
OpenTargets; ENSG00000185345; -.
Orphanet; 2828; Young adult-onset Parkinsonism.
PharmGKB; PA32942; -.
eggNOG; KOG0006; Eukaryota.
eggNOG; ENOG410YG4B; LUCA.
GeneTree; ENSGT00390000011034; -.
HOGENOM; HOG000013184; -.
HOVERGEN; HBG053682; -.
InParanoid; O60260; -.
KO; K04556; -.
OMA; WVCQTEW; -.
OrthoDB; EOG091G09PU; -.
PhylomeDB; O60260; -.
TreeFam; TF314529; -.
BRENDA; 2.3.2.B10; 2681.
Reactome; R-HSA-5205685; Pink/Parkin Mediated Mitophagy.
Reactome; R-HSA-5689877; Josephin domain DUBs.
Reactome; R-HSA-977225; Amyloid fiber formation.
Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
SignaLink; O60260; -.
SIGNOR; O60260; -.
UniPathway; UPA00143; -.
EvolutionaryTrace; O60260; -.
GeneWiki; Parkin_(ligase); -.
GenomeRNAi; 5071; -.
PRO; PR:O60260; -.
Proteomes; UP000005640; Chromosome 6.
Bgee; ENSG00000185345; -.
CleanEx; HS_PARK2; -.
ExpressionAtlas; O60260; baseline and differential.
Genevisible; O60260; HS.
GO; GO:0016235; C:aggresome; IDA:BHF-UCL.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0005829; C:cytosol; IDA:UniProtKB.
GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL.
GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL.
GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL.
GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL.
GO; GO:1990452; C:Parkin-FBXW7-Cul1 ubiquitin ligase complex; IPI:ParkinsonsUK-UCL.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
GO; GO:0098793; C:presynapse; IEA:GOC.
GO; GO:0043234; C:protein complex; IEA:Ensembl.
GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL.
GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL.
GO; GO:0051087; F:chaperone binding; IPI:BHF-UCL.
GO; GO:0097602; F:cullin family protein binding; IDA:ParkinsonsUK-UCL.
GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL.
GO; GO:1990444; F:F-box domain binding; IPI:ParkinsonsUK-UCL.
GO; GO:0001664; F:G-protein coupled receptor binding; IPI:ParkinsonsUK-UCL.
GO; GO:0031072; F:heat shock protein binding; IPI:ParkinsonsUK-UCL.
GO; GO:0042826; F:histone deacetylase binding; IPI:ParkinsonsUK-UCL.
GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0019900; F:kinase binding; IPI:UniProtKB.
GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL.
GO; GO:0043274; F:phospholipase binding; IPI:ParkinsonsUK-UCL.
GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
GO; GO:0017124; F:SH3 domain binding; TAS:ParkinsonsUK-UCL.
GO; GO:0003700; F:transcription factor activity, sequence-specific DNA binding; IC:ParkinsonsUK-UCL.
GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; IDA:ParkinsonsUK-UCL.
GO; GO:0015631; F:tubulin binding; IPI:ParkinsonsUK-UCL.
GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:ParkinsonsUK-UCL.
GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB.
GO; GO:1904264; F:ubiquitin protein ligase activity involved in ERAD pathway; NAS:ParkinsonsUK-UCL.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL.
GO; GO:0008270; F:zinc ion binding; TAS:ParkinsonsUK-UCL.
GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL.
GO; GO:0070842; P:aggresome assembly; IMP:BHF-UCL.
GO; GO:0044257; P:cellular protein catabolic process; IMP:ParkinsonsUK-UCL.
GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
GO; GO:1903351; P:cellular response to dopamine; TAS:ParkinsonsUK-UCL.
GO; GO:0071287; P:cellular response to manganese ion; TAS:ParkinsonsUK-UCL.
GO; GO:0097237; P:cellular response to toxic substance; IMP:ParkinsonsUK-UCL.
GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL.
GO; GO:0007417; P:central nervous system development; TAS:ProtInc.
GO; GO:0042417; P:dopamine metabolic process; TAS:ParkinsonsUK-UCL.
GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl.
GO; GO:0036503; P:ERAD pathway; NAS:ParkinsonsUK-UCL.
GO; GO:0010994; P:free ubiquitin chain polymerization; IMP:ParkinsonsUK-UCL.
GO; GO:0007612; P:learning; IEA:Ensembl.
GO; GO:0016236; P:macroautophagy; TAS:Reactome.
GO; GO:0000423; P:macromitophagy; IEA:Ensembl.
GO; GO:0000266; P:mitochondrial fission; ISS:ParkinsonsUK-UCL.
GO; GO:0007005; P:mitochondrion organization; ISS:ParkinsonsUK-UCL.
GO; GO:0099074; P:mitochondrion to lysosome transport; IDA:ParkinsonsUK-UCL.
GO; GO:0000422; P:mitophagy; IDA:UniProtKB.
GO; GO:0044828; P:negative regulation by host of viral genome replication; IDA:AgBase.
GO; GO:0032232; P:negative regulation of actin filament bundle assembly; IDA:BHF-UCL.
GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL.
GO; GO:0060548; P:negative regulation of cell death; IDA:BHF-UCL.
GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL.
GO; GO:1903382; P:negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl.
GO; GO:1903542; P:negative regulation of exosomal secretion; IMP:ParkinsonsUK-UCL.
GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL.
GO; GO:0033132; P:negative regulation of glucokinase activity; IDA:MGI.
GO; GO:0046676; P:negative regulation of insulin secretion; IDA:MGI.
GO; GO:1905366; P:negative regulation of intralumenal vesicle formation; IMP:ParkinsonsUK-UCL.
GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:ParkinsonsUK-UCL.
GO; GO:0046329; P:negative regulation of JNK cascade; ISS:ParkinsonsUK-UCL.
GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISS:ParkinsonsUK-UCL.
GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:ParkinsonsUK-UCL.
GO; GO:1901215; P:negative regulation of neuron death; IGI:ParkinsonsUK-UCL.
GO; GO:1903202; P:negative regulation of oxidative stress-induced cell death; TAS:ParkinsonsUK-UCL.
GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL.
GO; GO:1902283; P:negative regulation of primary amine oxidase activity; IMP:ParkinsonsUK-UCL.
GO; GO:0001933; P:negative regulation of protein phosphorylation; IDA:BHF-UCL.
GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IGI:ParkinsonsUK-UCL.
GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:BHF-UCL.
GO; GO:1904049; P:negative regulation of spontaneous neurotransmitter secretion; IMP:ParkinsonsUK-UCL.
GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IMP:ParkinsonsUK-UCL.
GO; GO:0070050; P:neuron cellular homeostasis; ISS:ParkinsonsUK-UCL.
GO; GO:0042415; P:norepinephrine metabolic process; IEA:Ensembl.
GO; GO:0061734; P:parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; IDA:ParkinsonsUK-UCL.
GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl.
GO; GO:0043388; P:positive regulation of DNA binding; IDA:ParkinsonsUK-UCL.
GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL.
GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:ParkinsonsUK-UCL.
GO; GO:0098779; P:positive regulation of macromitophagy in response to mitochondrial depolarization; IDA:ParkinsonsUK-UCL.
GO; GO:0090141; P:positive regulation of mitochondrial fission; ISS:ParkinsonsUK-UCL.
GO; GO:0010636; P:positive regulation of mitochondrial fusion; IMP:ParkinsonsUK-UCL.
GO; GO:1903599; P:positive regulation of mitophagy; IDA:ParkinsonsUK-UCL.
GO; GO:0051582; P:positive regulation of neurotransmitter uptake; IMP:ParkinsonsUK-UCL.
GO; GO:1903378; P:positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl.
GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IGI:ParkinsonsUK-UCL.
GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL.
GO; GO:0032092; P:positive regulation of protein binding; IMP:ParkinsonsUK-UCL.
GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ParkinsonsUK-UCL.
GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; IGI:ParkinsonsUK-UCL.
GO; GO:1905477; P:positive regulation of protein localization to membrane; IMP:ParkinsonsUK-UCL.
GO; GO:1905281; P:positive regulation of retrograde transport, endosome to Golgi; NAS:ParkinsonsUK-UCL.
GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:ParkinsonsUK-UCL.
GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ParkinsonsUK-UCL.
GO; GO:0010498; P:proteasomal protein catabolic process; IMP:BHF-UCL.
GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL.
GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
GO; GO:0031648; P:protein destabilization; IDA:ParkinsonsUK-UCL.
GO; GO:0016579; P:protein deubiquitination; TAS:Reactome.
GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB.
GO; GO:0044314; P:protein K27-linked ubiquitination; TAS:ParkinsonsUK-UCL.
GO; GO:0035519; P:protein K29-linked ubiquitination; TAS:ParkinsonsUK-UCL.
GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
GO; GO:0085020; P:protein K6-linked ubiquitination; IDA:UniProtKB.
GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
GO; GO:0070585; P:protein localization to mitochondrion; IEA:Ensembl.
GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL.
GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB.
GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL.
GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:ParkinsonsUK-UCL.
GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:ParkinsonsUK-UCL.
GO; GO:0014059; P:regulation of dopamine secretion; TAS:ParkinsonsUK-UCL.
GO; GO:0010906; P:regulation of glucose metabolic process; TAS:ParkinsonsUK-UCL.
GO; GO:0032368; P:regulation of lipid transport; TAS:ParkinsonsUK-UCL.
GO; GO:0051881; P:regulation of mitochondrial membrane potential; IEA:Ensembl.
GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL.
GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL.
GO; GO:1903214; P:regulation of protein targeting to mitochondrion; NAS:ParkinsonsUK-UCL.
GO; GO:0031396; P:regulation of protein ubiquitination; IMP:ParkinsonsUK-UCL.
GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB.
GO; GO:1902803; P:regulation of synaptic vesicle transport; NAS:ParkinsonsUK-UCL.
GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
GO; GO:0006979; P:response to oxidative stress; ISS:ParkinsonsUK-UCL.
GO; GO:0001964; P:startle response; IEA:Ensembl.
GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
GO; GO:0055069; P:zinc ion homeostasis; ISS:ParkinsonsUK-UCL.
InterPro; IPR031127; E3_UB_ligase_RBR.
InterPro; IPR002867; IBR_dom.
InterPro; IPR003977; Parkin.
InterPro; IPR029071; Ubiquitin-rel_dom.
InterPro; IPR000626; Ubiquitin_dom.
PANTHER; PTHR11685; PTHR11685; 1.
Pfam; PF01485; IBR; 2.
Pfam; PF00240; ubiquitin; 1.
PIRSF; PIRSF037880; Parkin; 1.
PRINTS; PR01475; PARKIN.
SMART; SM00647; IBR; 2.
SMART; SM00213; UBQ; 1.
SUPFAM; SSF54236; SSF54236; 1.
PROSITE; PS50053; UBIQUITIN_2; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Autophagy; Complete proteome;
Cytoplasm; Disease mutation; Endoplasmic reticulum; Metal-binding;
Mitochondrion; Neurodegeneration; Nucleus; Parkinson disease;
Parkinsonism; Phosphoprotein; Polymorphism; Reference proteome;
Repeat; S-nitrosylation; Transcription; Transcription regulation;
Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc;
Zinc-finger.
CHAIN 1 465 E3 ubiquitin-protein ligase parkin.
/FTId=PRO_0000058576.
DOMAIN 1 76 Ubiquitin-like. {ECO:0000255|PROSITE-
ProRule:PRU00214}.
ZN_FING 141 225 RING-type 0; atypical.
ZN_FING 238 293 RING-type 1; atypical.
ZN_FING 313 377 IBR-type.
ZN_FING 418 449 RING-type 2.
REGION 204 238 SYT11 binding 1.
{ECO:0000269|PubMed:12925569}.
REGION 257 293 SYT11 binding 2.
{ECO:0000269|PubMed:12925569}.
REGION 378 410 REP. {ECO:0000250}.
ACT_SITE 431 431 {ECO:0000250|UniProtKB:Q9JK66}.
MOD_RES 65 65 Phosphoserine; by PINK1.
{ECO:0000269|PubMed:23754282,
ECO:0000269|PubMed:24660806,
ECO:0000269|PubMed:24784582}.
VAR_SEQ 1 191 Missing (in isoform 4).
{ECO:0000303|Ref.3}.
/FTId=VSP_011705.
VAR_SEQ 1 79 Missing (in isoform 3).
{ECO:0000303|Ref.3}.
/FTId=VSP_011706.
VAR_SEQ 58 206 Missing (in isoform 6). {ECO:0000305}.
/FTId=VSP_041563.
VAR_SEQ 179 206 Missing (in isoform 2 and isoform 7).
{ECO:0000303|PubMed:9560156,
ECO:0000303|Ref.4}.
/FTId=VSP_011707.
VAR_SEQ 290 290 V -> VGTGDTVVLRGALGGFRRGV (in isoform 5).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_011708.
VAR_SEQ 291 297 AGCPNSL -> VCLLPGM (in isoform 3).
{ECO:0000303|Ref.3}.
/FTId=VSP_011709.
VAR_SEQ 298 465 Missing (in isoform 3).
{ECO:0000303|Ref.3}.
/FTId=VSP_011710.
VAR_SEQ 312 361 Missing (in isoform 7 and isoform 8).
{ECO:0000303|Ref.4}.
/FTId=VSP_053651.
VAR_SEQ 362 368 FAFCREC -> YGQRRTK (in isoform 5).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_011711.
VAR_SEQ 369 465 Missing (in isoform 5).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_011712.
VARIANT 15 15 V -> M (in PARK2; dbSNP:rs532703934).
{ECO:0000269|PubMed:12397156}.
/FTId=VAR_019733.
VARIANT 33 33 R -> Q (in PARK2; dbSNP:rs147757966).
{ECO:0000269|PubMed:12730996}.
/FTId=VAR_019734.
VARIANT 37 37 P -> L (in PARK2; dbSNP:rs148990138).
{ECO:0000269|PubMed:12112109}.
/FTId=VAR_019735.
VARIANT 42 42 R -> P (in PARK2; induces a
conformational change in the PSMD4-
binding site of Ubl resulting in impaired
proteasomal binding; decreases
ubiquitination and degradation; increased
aggregation; dbSNP:rs368134308).
{ECO:0000269|PubMed:10888878,
ECO:0000269|PubMed:11431533,
ECO:0000269|PubMed:11971093,
ECO:0000269|PubMed:15584030,
ECO:0000269|PubMed:19229105,
ECO:0000269|PubMed:20889486}.
/FTId=VAR_019736.
VARIANT 46 46 A -> P (in PARK2).
{ECO:0000269|PubMed:12362318}.
/FTId=VAR_019737.
VARIANT 56 56 V -> E (in PARK2; dbSNP:rs137853059).
{ECO:0000269|PubMed:12056932}.
/FTId=VAR_070078.
VARIANT 82 82 A -> E (in PARK2; dbSNP:rs55774500).
{ECO:0000269|PubMed:11487568,
ECO:0000269|PubMed:12116199,
ECO:0000269|PubMed:12730996}.
/FTId=VAR_019738.
VARIANT 92 92 A -> V (in PARK2; dbSNP:rs566229879).
/FTId=VAR_019739.
VARIANT 100 100 Q -> H. {ECO:0000269|PubMed:12781599}.
/FTId=VAR_019740.
VARIANT 161 161 K -> N (in PARK2; severely compromises
the mitochondrial localization; fails to
stabilize BCL2; decreased binding to the
TP53 promoter; abolishes TP53
transcriptional repression;
dbSNP:rs137853057).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:19801972,
ECO:0000269|PubMed:20404107,
ECO:0000269|PubMed:20889974}.
/FTId=VAR_019741.
VARIANT 167 167 S -> N (in dbSNP:rs1801474).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10511432,
ECO:0000269|PubMed:10965160,
ECO:0000269|PubMed:12629236}.
/FTId=VAR_019742.
VARIANT 192 192 M -> L (in PARK2; unknown pathological
significance; dbSNP:rs9456735).
{ECO:0000269|PubMed:11971093}.
/FTId=VAR_054107.
VARIANT 192 192 M -> V (in PARK2; unknown pathological
significance; dbSNP:rs9456735).
{ECO:0000269|PubMed:12629236}.
/FTId=VAR_019743.
VARIANT 211 211 K -> N (in PARK2; severely compromises
the mitochondrial localization; fails to
stabilize BCL2; dbSNP:rs137853060).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:11179010,
ECO:0000269|PubMed:12114481,
ECO:0000269|PubMed:12629236,
ECO:0000269|PubMed:20404107}.
/FTId=VAR_019744.
VARIANT 212 212 C -> Y (in PARK2; dbSNP:rs137853058).
{ECO:0000269|PubMed:11163284,
ECO:0000269|PubMed:12056932}.
/FTId=VAR_019746.
VARIANT 240 240 T -> M (in PARK2; dbSNP:rs137853054).
{ECO:0000269|PubMed:12629236}.
/FTId=VAR_019747.
VARIANT 240 240 T -> R (in PARK2; impairs the ability to
ubiquitinate SNCAIP and BCL2; loss of
UBE2L3 binding; severely compromises the
mitochondrial localization;
dbSNP:rs137853054).
{ECO:0000269|PubMed:10888878,
ECO:0000269|PubMed:11431533,
ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:20404107,
ECO:0000269|PubMed:20889974,
ECO:0000269|PubMed:9731209}.
/FTId=VAR_019748.
VARIANT 253 253 C -> Y (in PARK; late onset;
dbSNP:rs747427602).
{ECO:0000269|PubMed:12730996}.
/FTId=VAR_019749.
VARIANT 256 256 R -> C (in PARK2 and PARK; at
heterozygosity it is associated with late
onset Parkinson disease; impairs the
ability to ubiquitinate SNCAIP and
ZNF746; decreased binding to the TP53
promoter; abolishes TP53 transcriptional
repression; dbSNP:rs150562946).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:11971093,
ECO:0000269|PubMed:12116199,
ECO:0000269|PubMed:12730996,
ECO:0000269|PubMed:19801972}.
/FTId=VAR_019750.
VARIANT 271 271 R -> S. {ECO:0000269|PubMed:12781599}.
/FTId=VAR_019751.
VARIANT 275 275 R -> W (in PARK2 and PARK; at
heterozygosity it is associated with late
onset Parkinson disease; impairs the
ability to ubiquitinate SNCAIP; abolishes
p53/TP53 transcriptional repression;
dbSNP:rs34424986).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:11179010,
ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:11971093,
ECO:0000269|PubMed:12114481,
ECO:0000269|PubMed:12116199,
ECO:0000269|PubMed:12730996,
ECO:0000269|PubMed:19801972,
ECO:0000269|PubMed:21376232,
ECO:0000269|PubMed:22956510}.
/FTId=VAR_019752.
VARIANT 280 280 D -> N (in PARK; does not affect PINK-1
dependent localization to depolarized
mitochondria; dbSNP:rs72480422).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:12730996,
ECO:0000269|PubMed:20404107}.
/FTId=VAR_019753.
VARIANT 284 284 G -> R (in PARK2; dbSNP:rs751037529).
/FTId=VAR_019754.
VARIANT 289 289 C -> G (in PARK2; increased aggregation;
fails to ubiquitinate SYT11; loses
ability to bind SYT11; impaired
relocalization to damaged mitochondria;
loss of function in mitophagy;
dbSNP:rs55961220).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:12925569,
ECO:0000269|PubMed:20889486}.
/FTId=VAR_019755.
VARIANT 311 311 Q -> R (in a patient with Parkinson
disease; unknown pathological
significance).
{ECO:0000269|PubMed:19501131}.
/FTId=VAR_062672.
VARIANT 328 328 G -> E (in PARK2; does not affect PINK-1
dependent localization to depolarized
mitochondria).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:12116199,
ECO:0000269|PubMed:20404107}.
/FTId=VAR_019756.
VARIANT 334 334 R -> C (in dbSNP:rs199657839).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:27535533}.
/FTId=VAR_019757.
VARIANT 339 339 A -> S. {ECO:0000269|PubMed:12781599}.
/FTId=VAR_019758.
VARIANT 351 351 T -> P (in PARK2; impairs folding of IBR
domain). {ECO:0000269|PubMed:12112109,
ECO:0000269|PubMed:17360614}.
/FTId=VAR_019759.
VARIANT 366 366 R -> W (in dbSNP:rs56092260).
{ECO:0000269|PubMed:10965160}.
/FTId=VAR_019760.
VARIANT 371 371 A -> T (in a patient with Parkinson
disease; unknown pathological
significance).
{ECO:0000269|PubMed:19501131}.
/FTId=VAR_062673.
VARIANT 380 380 V -> L (in dbSNP:rs1801582).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10965160,
ECO:0000269|PubMed:12397156,
ECO:0000269|PubMed:12730996}.
/FTId=VAR_019761.
VARIANT 394 394 D -> N (in dbSNP:rs1801334).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:12397156,
ECO:0000269|PubMed:12730996}.
/FTId=VAR_019762.
VARIANT 402 402 R -> C (in PARK2; dbSNP:rs55830907).
{ECO:0000269|PubMed:15584030}.
/FTId=VAR_070079.
VARIANT 415 415 T -> N (in PARK2; impairs the ability to
ubiquitinate SNCAIP; does not affect
turnover of CDCRE1; impairs PINK1-
dependent localization to dysfunctional
depolarized mitochondria;
dbSNP:rs778125254).
{ECO:0000269|PubMed:10072423,
ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:15584030,
ECO:0000269|PubMed:19966284}.
/FTId=VAR_019763.
VARIANT 418 418 C -> R (in PARK2; decreased binding to
the TP53 promoter; abolishes TP53
transcriptional repression; fails to
ubiquitinate SYT11 but does not loose
ability to bind SYT11).
{ECO:0000269|PubMed:12925569,
ECO:0000269|PubMed:15584030,
ECO:0000269|PubMed:19801972}.
/FTId=VAR_070080.
VARIANT 430 430 G -> D (in PARK2; impairs PINK1-dependent
localization to dysfunctional depolarized
mitochondria; impaired E3 ubiquitin-
protein ligase toward ZNF746;
dbSNP:rs191486604).
{ECO:0000269|PubMed:10824074,
ECO:0000269|PubMed:11179010,
ECO:0000269|PubMed:11971093,
ECO:0000269|PubMed:12114481,
ECO:0000269|PubMed:12730996,
ECO:0000269|PubMed:19966284,
ECO:0000269|PubMed:21376232}.
/FTId=VAR_019764.
VARIANT 431 431 C -> F (in PARK2; impaired E3 ubiquitin-
protein ligase toward ZNF746 and BCL2;
dbSNP:rs397514694).
{ECO:0000269|PubMed:10939576,
ECO:0000269|PubMed:20889974,
ECO:0000269|PubMed:21376232}.
/FTId=VAR_019765.
VARIANT 437 437 P -> L (in PARK2; impaired E3 ubiquitin-
protein ligase toward BCL2;
dbSNP:rs149953814).
{ECO:0000269|PubMed:11971093,
ECO:0000269|PubMed:12114481,
ECO:0000269|PubMed:12629236,
ECO:0000269|PubMed:12730996,
ECO:0000269|PubMed:20889974}.
/FTId=VAR_019766.
VARIANT 441 441 C -> R (in PARK2; decreased binding to
the TP53 promoter; abolishes TP53
transcriptional repression;
dbSNP:rs778305273).
{ECO:0000269|PubMed:12116199,
ECO:0000269|PubMed:19801972}.
/FTId=VAR_019767.
MUTAGEN 65 65 S->E: Phosphomimetic mutant; still
requires PINK1 for activation. PRKN is
activated in presence of phosphorylated
ubiquitin. {ECO:0000269|PubMed:24660806,
ECO:0000269|PubMed:24784582}.
MUTAGEN 332 332 C->S: Impairs folding of IBR domain.
{ECO:0000269|PubMed:17360614}.
MUTAGEN 337 337 C->A: Impairs the ability to ubiquitinate
SNCAIP. {ECO:0000269|PubMed:11590439}.
MUTAGEN 365 365 C->S: Impairs protein folding.
{ECO:0000269|PubMed:17360614}.
MUTAGEN 403 403 W->A: Decreased autoinhibition and
increased E3 activity.
{ECO:0000269|PubMed:24784582}.
MUTAGEN 421 421 C->A: Impairs the ability of self-
ubiquitination and to ubiquitinate
SNCAIP. {ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:18541373}.
MUTAGEN 431 431 C->S: Impairs the ability to ubiquitinate
target proteins.
{ECO:0000269|PubMed:11590439,
ECO:0000269|PubMed:23727886,
ECO:0000269|PubMed:23770887}.
MUTAGEN 433 433 H->N,A: Impaired activity.
{ECO:0000269|PubMed:23727886,
ECO:0000269|PubMed:23770887}.
MUTAGEN 444 444 E->Q,A: Impaired activity.
{ECO:0000269|PubMed:23727886,
ECO:0000269|PubMed:23770887}.
CONFLICT 223 223 S -> P (in Ref. 1; BAA25751 and 3;
AAM21458/AAM21457). {ECO:0000305}.
CONFLICT 289 290 CV -> MI (in Ref. 2; AAM21461).
{ECO:0000305}.
CONFLICT 339 339 A -> V (in Ref. 9; AAS88422).
{ECO:0000305}.
STRAND 2 11 {ECO:0000244|PDB:5C1Z}.
STRAND 13 16 {ECO:0000244|PDB:5C1Z}.
STRAND 19 21 {ECO:0000244|PDB:1IYF}.
HELIX 23 34 {ECO:0000244|PDB:5C1Z}.
HELIX 38 40 {ECO:0000244|PDB:5C1Z}.
STRAND 41 45 {ECO:0000244|PDB:5C1Z}.
STRAND 48 50 {ECO:0000244|PDB:5C1Z}.
TURN 52 55 {ECO:0000244|PDB:1IYF}.
HELIX 56 59 {ECO:0000244|PDB:5C1Z}.
TURN 62 64 {ECO:0000244|PDB:5N2W}.
STRAND 66 71 {ECO:0000244|PDB:5C1Z}.
STRAND 147 150 {ECO:0000244|PDB:4I1F}.
TURN 152 154 {ECO:0000244|PDB:4I1F}.
STRAND 156 166 {ECO:0000244|PDB:4I1F}.
TURN 167 169 {ECO:0000244|PDB:4I1F}.
STRAND 174 178 {ECO:0000244|PDB:4I1F}.
HELIX 183 187 {ECO:0000244|PDB:4I1F}.
STRAND 192 196 {ECO:0000244|PDB:4I1F}.
STRAND 198 200 {ECO:0000244|PDB:5N38}.
STRAND 205 212 {ECO:0000244|PDB:4I1F}.
STRAND 223 225 {ECO:0000244|PDB:4I1H}.
TURN 239 241 {ECO:0000244|PDB:4I1F}.
STRAND 246 250 {ECO:0000244|PDB:4I1F}.
STRAND 257 260 {ECO:0000244|PDB:4I1F}.
HELIX 261 273 {ECO:0000244|PDB:4I1F}.
STRAND 278 280 {ECO:0000244|PDB:4I1F}.
TURN 281 283 {ECO:0000244|PDB:4I1F}.
STRAND 284 286 {ECO:0000244|PDB:4I1F}.
HELIX 301 307 {ECO:0000244|PDB:4I1F}.
HELIX 309 326 {ECO:0000244|PDB:4I1F}.
TURN 335 337 {ECO:0000244|PDB:4I1F}.
STRAND 340 343 {ECO:0000244|PDB:5N38}.
STRAND 348 351 {ECO:0000244|PDB:4I1F}.
STRAND 355 358 {ECO:0000244|PDB:5N38}.
STRAND 363 365 {ECO:0000244|PDB:4I1F}.
TURN 366 368 {ECO:0000244|PDB:4I1F}.
STRAND 374 376 {ECO:0000244|PDB:4I1H}.
HELIX 379 381 {ECO:0000244|PDB:4BM9}.
HELIX 395 400 {ECO:0000244|PDB:4I1F}.
STRAND 401 403 {ECO:0000244|PDB:5N38}.
STRAND 414 417 {ECO:0000244|PDB:4I1F}.
TURN 419 421 {ECO:0000244|PDB:4I1F}.
STRAND 424 426 {ECO:0000244|PDB:4I1F}.
STRAND 429 431 {ECO:0000244|PDB:4I1F}.
STRAND 433 435 {ECO:0000244|PDB:4I1F}.
TURN 439 441 {ECO:0000244|PDB:4I1F}.
STRAND 444 446 {ECO:0000244|PDB:4I1F}.
TURN 447 449 {ECO:0000244|PDB:4I1F}.
HELIX 455 461 {ECO:0000244|PDB:4I1F}.
SEQUENCE 465 AA; 51641 MW; 9A8BB802A3FC84C3 CRC64;
MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD
LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA
VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP
SCWDDVLIPN RMSGECQSPH CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT
CTDVRSPVLV FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE
LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV TCEGGNGLGC
GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ ARWEAASKET IKKTTKPCPR
CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG CEWNRVCMGD HWFDV


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