Parkin (ligase)

Parkin RBR E3 ubiquitin protein ligase
PDB rendering based on 1iyf.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1IYF​, 2JMO​, 4BM9​, 4I1F​, 4I1H​
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 • G-protein coupled receptor binding • actin binding • ubiquitin-protein transferase activity • protein binding • zinc ion binding • tubulin binding • ligase activity • SH3 domain binding • enzyme binding • kinase binding • protein kinase binding • PDZ domain binding • Hsp70 protein binding • heat shock protein binding • ubiquitin conjugating enzyme binding • ubiquitin protein ligase binding • identical protein binding • histone deacetylase binding • ubiquitin binding • phospholipase binding • chaperone binding • ubiquitin protein ligase activity • cullin family protein binding • ubiquitin-specific protease binding • F-box domain binding Cellular component • ubiquitin ligase complex • nucleus • cytoplasm • mitochondrion • endoplasmic reticulum • Golgi apparatus • cytosol • aggresome • SCF ubiquitin ligase complex • neuron projection • perinuclear region of cytoplasm • LUBAC complex • Lewy body • Parkin-FBXW7-Cul1 ubiquitin ligase complex Biological process • protein polyubiquitination • mitochondrial fission • mitochondrion degradation • negative regulation of protein phosphorylation • startle response • transcription, DNA-templated • protein monoubiquitination • response to oxidative stress • mitochondrion organization • central nervous system development • learning • adult locomotory behavior • proteasomal protein catabolic process • regulation of autophagy • positive regulation of gene expression • negative regulation of gene expression • positive regulation of mitochondrial fusion • negative regulation of mitochondrial fusion • regulation of mitochondrion organization • regulation of glucose metabolic process • regulation of dopamine secretion • protein ubiquitination • regulation of protein ubiquitination • negative regulation of actin filament bundle assembly • regulation of lipid transport • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • negative regulation of glucokinase activity • cellular response to unfolded protein • response to endoplasmic reticulum stress • synaptic transmission, glutamatergic • protein K29-linked ubiquitination • regulation of dopamine metabolic process • norepinephrine metabolic process • dopamine metabolic process • protein ubiquitination involved in ubiquitin-dependent protein catabolic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • proteasome-mediated ubiquitin-dependent protein catabolic process • positive regulation of DNA binding • negative regulation of neuron apoptotic process • cellular protein catabolic process • protein K27-linked ubiquitination • negative regulation by host of viral genome replication • positive regulation of transcription from RNA polymerase II promoter • negative regulation of JNK cascade • negative regulation of insulin secretion • protein stabilization • positive regulation of neurotransmitter uptake • dopamine uptake involved in synaptic transmission • protein autoubiquitination • regulation of mitochondrial membrane potential • zinc ion homeostasis • negative regulation of cell death • neuron cellular homeostasis • protein K63-linked ubiquitination • protein localization to mitochondrion • aggresome assembly • protein K48-linked ubiquitination • protein K11-linked ubiquitination • cellular response to manganese ion • protein K6-linked ubiquitination • positive regulation of mitochondrial fission • negative regulation of release of cytochrome c from mitochondria • cellular response to toxic substance • activation of mitophagy in response to mitochondrial depolarization • regulation of cellular response to oxidative stress • negative regulation of neuron death • positive regulation of proteasomal protein catabolic process • negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • negative regulation of primary amine oxidase activity • positive regulation of protein linear polyubiquitination • regulation of synaptic vesicle transport • regulation of mitochondrion degradation • negative regulation of oxidative stress-induced cell death • regulation of protein targeting to mitochondrion • positive regulation of tumor necrosis factor-mediated signaling pathway • cellular response to dopamine • negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway • positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway • negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway • positive regulation of dendrite extension • negative regulation of spontaneous neurotransmitter secretion • regulation of reactive oxygen species metabolic process • negative 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	Q9WVS6
RefSeq (mRNA)	NM_004562	NM_016694
RefSeq (protein)	NP_004553	NP_057903
Location (UCSC)	Chr 6: 161.35 – 162.73 Mb	Chr 17: 10.84 – 12.06 Mb
PubMed search

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. Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP). Moreover, Parkin is described to be necessary for mitophagy (autophagy of mitochondria).

However, 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:

• Alpha-synuclein,^[5][6]
• CASK,^[7]
• CUL1,^[8]
• FBXW7^[8] and
• GPR37,^[9][10]
• HSPA1A,^[9]
• HSPA8,^[9]
• Multisynthetase complex auxiliary component p38,^[11]
• PDCD2,^[12]
• SEPT5,^[13][14]
• SNCAIP,^[15]
• STUB1,^[9]
• SYT11,^[16] and
• Ubiquitin C.^[6][17]

References

1. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (Apr 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 (Apr 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 (Aug 2004). "parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease". American Journal of Medical Genetics. Part A 129A (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 (Aug 2003). "How much phenotypic variation can be attributed to parkin genotype?". Annals of Neurology 54 (2): 176–185. doi:10.1002/ana.10613. PMID 12891670.
5. Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM, Wolozin B (Sep 2001). "Co-association of parkin and alpha-synuclein". NeuroReport 12 (13): 2839–43. doi:10.1097/00001756-200109170-00017. PMID 11588587.
6. Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E (Mar 2008). "alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease". The Journal of Biological Chemistry 283 (11): 6979–87. doi:10.1074/jbc.M710418200. PMID 18195004.
7. Fallon L, Moreau F, Croft BG, Labib N, Gu WJ, Fon EA (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". The Journal of Biological Chemistry 277 (1): 486–91. doi:10.1074/jbc.M109806200. PMID 11679592.
8. Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (Mar 2003). "Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity". Neuron 37 (5): 735–49. doi:10.1016/s0896-6273(03)00084-9. PMID 12628165.
9. Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R (Jul 2002). "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity". Molecular Cell 10 (1): 55–67. doi:10.1016/s1097-2765(02)00583-x. PMID 12150907.
10. 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 105 (7): 891–902. doi:10.1016/s0092-8674(01)00407-x. PMID 11439185.
11. Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, Prigent A, Robinson JC, Pradier L, Ruberg M, Mirande M, Hirsch E, Rooney T, Fournier A, Brice A (Jun 2003). "The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration". Human Molecular Genetics 12 (12): 1427–37. doi:10.1093/hmg/ddg159. PMID 12783850.
12. Fukae J, Sato S, Shiba K, Sato K, Mori H, Sharp PA, Mizuno Y, Hattori N (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 Letters 583 (3): 521–5. doi:10.1016/j.febslet.2008.12.055. PMID 19146857.
13. Choi P, Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung KK, Kehoe K, D'Adamio L, Lee JM, Cochran E, Bowser R, Dawson TM, Wolozin B (Oct 2003). "SEPT5_v2 is a parkin-binding protein". Brain Research. Molecular Brain Research 117 (2): 179–89. doi:10.1016/s0169-328x(03)00318-8. PMID 14559152.
14. Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M, Joshi HC, Zhou J (Dec 2008). "Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase". The Journal of Biological Chemistry 283 (51): 35783–8. doi:10.1074/jbc.M806860200. PMID 18845538.
15. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (Oct 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease". Nature Medicine 7 (10): 1144–50. doi:10.1038/nm1001-1144. PMID 11590439.
16. Huynh DP, Scoles DR, Nguyen D, Pulst SM (Oct 2003). "The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI". Human Molecular Genetics 12 (20): 2587–97. doi:10.1093/hmg/ddg269. PMID 12925569.
17. Yu F, Zhou J (Jul 2008). "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress". Neuroscience Letters 440 (1): 4–8. doi:10.1016/j.neulet.2008.05.052. PMID 18541373.

Further reading

• Saito M, Matsumine H, Tanaka H, Ishikawa A, Matsubayashi S, Hattori Y, Mizuno Y, Tsuji S (Jan 1997). "[Clinical characteristics and linkage analysis of autosomal recessive form of juvenile parkinsonism(AR-JP)]". Nihon Rinsho. Japanese Journal of Clinical Medicine 55 (1): 83–8. PMID 9014427.
• Fishman PS, Oyler GA (Jul 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 (Jun 2002). "[Function of Parkin]". Seikagaku. The Journal of Japanese Biochemical Society 74 (6): 471–6. PMID 12138708.
• West AB, Maidment NT (Mar 2004). "Genetics of parkin-linked disease". Human Genetics 114 (4): 327–336. doi:10.1007/s00439-003-1074-6. PMID 14727181.
• Mata IF, Lockhart PJ, Farrer MJ (Apr 2004). "Parkin genetics: one model for Parkinson's disease". Human Molecular Genetics. 13 Spec No 1 (90001): 127R–133. doi:10.1093/hmg/ddh089. PMID 14976155.
• Baptista MJ, Cookson MR, Miller DW (Feb 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 (Jul 2004). "How does parkin ligate ubiquitin to Parkinson's disease?". EMBO Reports 5 (7): 681–685. doi:10.1038/sj.embor.7400188. PMC 1299099. PMID 15229644.
• Pankratz N, Foroud T (Apr 2004). "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.
• Suzuki H (Sep 2006). "Protein-protein interactions in the mammalian brain". The Journal of Physiology 575 (Pt 2): 373–377. doi:10.1113/jphysiol.2006.115717. PMC 1819454. PMID 16840513.
• Hattori N, Machida Y, Sato S, Noda K, Iijima-Kitami M, Kubo S, Mizuno Y (2006). "Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins". Journal of Neural Transmission. Supplementum. 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, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schäffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y (Mar 1997). "Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27". American Journal of Human Genetics 60 (3): 588–96. PMC 1712507. PMID 9042918.
• Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (Apr 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, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (Apr 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, Abbas N, Bonifati V, De Michele G, Bonnet AM, Broussolle E, Pollak P, Vidailhet M, De Mari M, Marconi R, Medjbeur S, Filla A, Meco G, Agid Y, Brice A (Jul 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". American Journal of Human Genetics 63 (1): 88–94. doi:10.1086/301934. PMC 1377254. PMID 9634531.
• Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y (Aug 1998). "Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene". Biochemical and Biophysical Research Communications 249 (3): 754–8. doi:10.1006/bbrc.1998.9134. PMID 9731209.
• Lücking CB, Abbas N, Dürr A, Bonifati V, Bonnet AM, de Broucker T, De Michele G, Wood NW, Agid Y, Brice A (Oct 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, Dürr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Böhme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A (Apr 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". Human Molecular Genetics 8 (4): 567–574. doi:10.1093/hmg/8.4.567. PMID 10072423.
• Sunada Y, Saito F, Matsumura K, Shimizu T (Oct 1998). "Differential expression of the parkin gene in the human brain and peripheral leukocytes". Neuroscience Letters 254 (3): 180–182. doi:10.1016/S0304-3940(98)00697-1. PMID 10214987.
• Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y (May 1999). "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients". Annals of Neurology 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
• parkin protein at the US National Library of Medicine Medical Subject Headings (MeSH)