Parkin (ligase)

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Parkinson protein 2, E3 ubiquitin protein ligase (parkin)

PDB rendering based on 1iyf.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsPARK2; AR-JP; LPRS2; PDJ; PRKN
External IDsOMIM: 602544 MGI: 1355296 HomoloGene: 3355 GeneCards: PARK2 Gene
EC number6.3.2.19
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez507150873
EnsemblENSG00000185345ENSMUSG00000023826
UniProtO60260Q9WVS6
RefSeq (mRNA)NM_004562NM_016694
RefSeq (protein)NP_004553NP_057903
Location (UCSC)Chr 6:
161.77 – 163.15 Mb		Chr 17:
11.07 – 11.64 Mb
PubMed search
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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's disease (AR-JP).

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. ↑ 5.0 5.1 5.2 5.3 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. ↑ 9.0 9.1 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.  Unknown parameter |unused_data= ignored (help);
  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. ↑ 14.0 14.1 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

External links

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