Parkin (ligase)

For other uses, see Parkin (disambiguation).

Parkinson protein 2, E3 ubiquitin protein ligase (parkin)
PDB rendering based on 1iyf.
Available structures PDB 1IYF, 2JMO
Identifiers
Symbols	PARK2; AR-JP; LPRS2; PDJ; PRKN
External IDs	OMIM: 602544 MGI: 1355296 HomoloGene: 3355 GeneCards: PARK2 Gene
EC number	6.3.2.19
Gene Ontology Molecular function • ubiquitin-protein ligase activity • protein binding • zinc ion binding • ligase activity • acid-amino acid ligase activity • kinase binding • protein kinase binding • PDZ domain binding • ubiquitin protein ligase binding • metal ion binding • chaperone binding Cellular component • nucleus • cytoplasm • mitochondrion • mitochondrion • endoplasmic reticulum • Golgi apparatus • cytosol • aggresome • neuron projection • protein complex • perinuclear region of cytoplasm Biological process • protein polyubiquitination • mitochondrion degradation • negative regulation of protein phosphorylation • startle response • ubiquitin-dependent protein catabolic process • protein monoubiquitination • central nervous system development • learning • cell death • adult locomotory behavior • regulation of autophagy • protein metabolic process • negative regulation of actin filament bundle assembly • synaptic transmission, glutamatergic • norepinephrine metabolic process • dopamine metabolic process • protein ubiquitination involved in ubiquitin-dependent protein catabolic process • positive regulation of I-kappaB kinase/NF-kappaB cascade • regulation of neurotransmitter secretion • dopamine uptake • protein autoubiquitination • negative regulation of cell death • protein K63-linked ubiquitination • aggresome assembly • protein K48-linked ubiquitination • neuron death • negative regulation of release of cytochrome c from mitochondria • regulation of reactive oxygen species metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5071	50873
Ensembl	ENSG00000185345	ENSMUSG00000023826
UniProt	O60260	Q2KHJ9
RefSeq (mRNA)	NM_004562.2	NM_016694.3
RefSeq (protein)	NP_004553.2	NP_057903.1
Location (UCSC)	Chr 6: 161.77 – 163.15 Mb	Chr 17: 11.26 – 12.25 Mb
PubMed search	[1]	[2]

Parkin is a protein which in humans is encoded by the PARK2 gene.^[1][2] The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation^{[citation needed]}. Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson disease.

How loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include synphilin-1, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R, synaptotagmin XI, sp22 and parkin itself (see also ubiquitin ligase). Additionally, Parkin contains a C-terminal motif that binds PDZ domains. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1.

Parkinson's disease

PARK2 (OMIM *602544) is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease (OMIM 600116) due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset Parkinson disease. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% homozygous mutations.^[3] Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).^[4]

Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.

Interactions

Parkin (ligase) has been shown to interact with STUB1,^[5] SEPT5,^[6][7] Alpha-synuclein,^[8][9] SNCAIP,^[10] SYT11,^[11] HSPA1A,^[5] Multisynthetase complex auxiliary component p38,^[12] CASK,^[13] CUL1,^[14] PDCD2,^[15] HSPA8,^[5] GPR37,^[5][16] FBXW7^[14] and Ubiquitin C.^[9][17]

References

1. ^ Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature 392 (6676): 605–608. doi:10.1038/33416. PMID 9560156. 
2. ^ Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143–146. doi:10.1006/geno.1997.5196. PMID 9570960. 
3. ^ Poorkaj P, Nutt JG, James D, Gancher S, Bird TD, Steinbart E, Schellenberg GD, Payami H (2004). "parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease". Am. J. Med. Genet. A 129 (1): 44–50. doi:10.1002/ajmg.a.30157. PMID 15266615. 
4. ^ Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destée A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A (2003). "How much phenotypic variation can be attributed to parkin genotype?". Ann. Neurol. 54 (2): 176–185. doi:10.1002/ana.10613. PMID 12891670. 
5. ^ ^{a b c d} Imai, Yuzuru; Soda Mariko, Hatakeyama Shigetsugu, Akagi Takumi, Hashikawa Tsutomu, Nakayama Kei Ichi, Takahashi Ryosuke (Jul. 2002). "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity". Mol. Cell (United States) 10 (1): 55–67. doi:10.1016/S1097-2765(02)00583-X. ISSN 1097-2765. PMID 12150907. 
6. ^ Choi, P; Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung K K K, Kehoe K, D'Adamio L, Lee J M, Cochran E, Bowser R, Dawson T M, Wolozin B (Oct. 2003). "SEPT5_v2 is a parkin-binding protein". Brain Res. Mol. Brain Res. (Netherlands) 117 (2): 179–189. doi:10.1016/S0169-328X(03)00318-8. ISSN 0169-328X. PMID 14559152. 
7. ^ Liu, Min; Aneja Ritu, Sun Xiaodong, Xie Songbo, Wang Hongxia, Wu Xiaojing, Dong Jin-Tang, Li Minggang, Joshi Harish C, Zhou Jun (Dec. 2008). "Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase". J. Biol. Chem. (United States) 283 (51): 35783–35788. doi:10.1074/jbc.M806860200. ISSN 0021-9258. PMID 18845538. 
8. ^ Choi, P; Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee J M, Wolozin B (Sep. 2001). "Co-association of parkin and alpha-synuclein". Neuroreport (England) 12 (13): 2839–43. ISSN 0959-4965. PMID 11588587. 
9. ^ ^{a b} Kawahara, Kohichi; Hashimoto Makoto, Bar-On Pazit, Ho Gilbert J, Crews Leslie, Mizuno Hideya, Rockenstein Edward, Imam Syed Z, Masliah Eliezer (Mar. 2008). "alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease". J. Biol. Chem. (United States) 283 (11): 6979–6987. doi:10.1074/jbc.M710418200. ISSN 0021-9258. PMID 18195004. 
10. ^ Chung, K K; Zhang Y, Lim K L, Tanaka Y, Huang H, Gao J, Ross C A, Dawson V L, Dawson T M (Oct. 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nat. Med. (United States) 7 (10): 1144–1150. doi:10.1038/nm1001-1144. ISSN 1078-8956. PMID 11590439. 
11. ^ Huynh, Duong P; Scoles Daniel R, Nguyen Dung, Pulst Stefan M (Oct. 2003). "The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI". Hum. Mol. Genet. (England) 12 (20): 2587–2597. doi:10.1093/hmg/ddg269. ISSN 0964-6906. PMID 12925569. 
12. ^ Corti, Olga; Hampe Cornelia, Koutnikova Hana, Darios Frédéric, Jacquier Sandrine, Prigent Annick, Robinson Jean-Charles, Pradier Laurent, Ruberg Merle, Mirande Marc, Hirsch Etienne, Rooney Thomas, Fournier Alain, Brice Alexis (Jun. 2003). "The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration". Hum. Mol. Genet. (England) 12 (12): 1427–1437. doi:10.1093/hmg/ddg159. ISSN 0964-6906. PMID 12783850. 
13. ^ Fallon, Lara; Moreau France, Croft Benjamin G, Labib Noura, Gu Wen-Jie, Fon Edward A (Jan. 2002). "Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain". J. Biol. Chem. (United States) 277 (1): 486–491. doi:10.1074/jbc.M109806200. ISSN 0021-9258. PMID 11679592. 
14. ^ ^{a b} Staropoli, John F; McDermott Caroline, Martinat Cécile, Schulman Brenda, Demireva Elena, Abeliovich Asa (Mar. 2003). "Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity". Neuron (United States) 37 (5): 735–749. doi:10.1016/S0896-6273(03)00084-9. ISSN 0896-6273. PMID 12628165. 
15. ^ Fukae, Jiro; Sato Shigeto, Shiba Kahori, Sato Ken-ichi, Mori Hideo, Sharp Philip A, Mizuno Yoshikuni, Hattori Nobutaka (Feb. 2009). "Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease". FEBS Lett. (Netherlands) 583 (3): 521–525. doi:10.1016/j.febslet.2008.12.055. PMID 19146857. 
16. ^ Imai, Y; Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (Jun. 2001). "An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin". Cell (United States) 105 (7): 891–902. doi:10.1016/S0092-8674(01)00407-X. ISSN 0092-8674. PMID 11439185. 
17. ^ Yu, Furong; Zhou Jianhua (Jul. 2008). "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress". Neurosci. Lett. (Ireland) 440 (1): 4–8. doi:10.1016/j.neulet.2008.05.052. ISSN 0304-3940. PMID 18541373. 

Further reading

• Saito M, Matsumine H, Tanaka H et al. (1997). "[Clinical characteristics and linkage analysis of autosomal recessive form of juvenile parkinsonism(AR-JP)]". Nippon Rinsho 55 (1): 83–8. PMID 9014427. 
• Fishman PS, Oyler GA (2002). "Significance of the parkin gene and protein in understanding Parkinson's disease". Current neurology and neuroscience reports 2 (4): 296–302. doi:10.1007/s11910-002-0004-7. PMID 12044248. 
• Takahashi R (2002). "[Function of Parkin]". Seikagaku 74 (6): 471–6. PMID 12138708. 
• West AB, Maidment NT (2004). "Genetics of parkin-linked disease". Hum. Genet. 114 (4): 327–336. doi:10.1007/s00439-003-1074-6. PMID 14727181. 
• Mata IF, Lockhart PJ, Farrer MJ (2004). "Parkin genetics: one model for Parkinson's disease". Hum. Mol. Genet. 13 Spec No 1 (90001): 127R–133. doi:10.1093/hmg/ddh089. PMID 14976155. 
• Baptista MJ, Cookson MR, Miller DW (2004). "Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease". The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 10 (1): 63–72. doi:10.1177/1073858403260392. PMID 14987449. 
• Kahle PJ, Haass C (2005). "How does parkin ligate ubiquitin to Parkinson's disease?". EMBO Rep. 5 (7): 681–685. doi:10.1038/sj.embor.7400188. PMC 1299099. PMID 15229644. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1299099. 
• Pankratz N, Foroud T (2005). "Genetics of Parkinson disease". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 1 (2): 235–242. doi:10.1602/neurorx.1.2.235. PMC 534935. PMID 15717024. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=534935. 
• Suzuki H (2006). "Protein-protein interactions in the mammalian brain". J. Physiol. (Lond.) 575 (Pt 2): 373–377. doi:10.1113/jphysiol.2006.115717. PMC 1819454. PMID 16840513. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1819454. 
• Hattori N, Machida Y, Sato S et al. (2006). "Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins". J. Neural Transm. Suppl.. Journal of Neural Transmission. Supplementa 70 (70): 205–208. doi:10.1007/978-3-211-45295-0_31. ISBN 978-3-211-28927-3. PMID 17017530. 
• Matsumine H, Saito M, Shimoda-Matsubayashi S et al. (1997). "Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27". Am. J. Hum. Genet. 60 (3): 588–96. PMC 1712507. PMID 9042918. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1712507. 
• Kitada T, Asakawa S, Hattori N et al. (1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature 392 (6676): 605–608. doi:10.1038/33416. PMID 9560156. 
• Matsumine H, Yamamura Y, Hattori N et al. (1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143–146. doi:10.1006/geno.1997.5196. PMID 9570960. 
• Tassin J, Dürr A, de Broucker T et al. (1998). "Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson's Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson's Disease". Am. J. Hum. Genet. 63 (1): 88–94. doi:10.1086/301934. PMC 1377254. PMID 9634531. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1377254. 
• Hattori N, Matsumine H, Asakawa S et al. (1998). "Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene". Biochem. Biophys. Res. Commun. 249 (3): 754–8. doi:10.1006/bbrc.1998.9134. PMID 9731209. 
• Lücking CB, Abbas N, Dürr A et al. (1998). "Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group". Lancet 352 (9137): 1355–6. doi:10.1016/S0140-6736(05)60746-5. PMID 9802278. 
• Abbas N, Lücking CB, Ricard S et al. (1999). "A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease". Hum. Mol. Genet. 8 (4): 567–574. doi:10.1093/hmg/8.4.567. PMID 10072423. 
• Sunada Y, Saito F, Matsumura K, Shimizu T (1999). "Differential expression of the parkin gene in the human brain and peripheral leukocytes". Neurosci. Lett. 254 (3): 180–182. doi:10.1016/S0304-3940(98)00697-1. PMID 10214987. 
• Shimura H, Hattori N, Kubo S et al. (1999). "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients". Ann. Neurol. 45 (5): 668–672. doi:10.1002/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z. PMID 10319893. 

External links

• GeneReviews/NCBI/NIH/UW entry on Parkin Type of Juvenile Parkinson Disease
• MeSH parkin+protein