Parkin (ligase)

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For other uses, see Parkin (disambiguation).
Parkin RBR E3 ubiquitin protein ligase
Protein PARK2 PDB 1iyf.png
PDB rendering based on 1iyf.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PARK2 ; AR-JP; LPRS2; PDJ; PRKN
External IDs OMIM602544 MGI1355296 HomoloGene3355 GeneCards: PARK2 Gene
EC number 6.3.2.19
RNA expression pattern
PBB GE PARK2 207058 s at tn.png
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:
161.77 – 163.15 Mb
Chr 17:
11.07 – 11.64 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's disease (AR-JP).

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[edit]

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[edit]

Parkin (ligase) has been shown to interact with:

References[edit]

  1. ^ Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. (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 et al. (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 et al. (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 et al. (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 et al. (Sep 2001). "Co-association of parkin and alpha-synuclein". Neuroreport 12 (13): 2839–43. doi:10.1097/00001756-200109170-00017. PMID 11588587. 
  6. ^ a b Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H et al. (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. ^ a b 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. ^ a b c d Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI et al. (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 et al. (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. PMID 12783850. 
  12. ^ Fukae J, Sato S, Shiba K, Sato K, Mori H, Sharp PA et al. (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 et al. (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 et al. (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 et al. (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[edit]

External links[edit]