Parkin (protein)

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For other uses, see Parkin (disambiguation).
PRKN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPRKN, parkin RBR E3 ubiquitin protein ligase, AR-JP, LPRS2, PDJ, PARK2, Parkin
External IDsOMIM: 602544 MGI: 1355296 HomoloGene: 3355 GeneCards: PRKN
Orthologs
SpeciesHumanMouse
Entrez

5071

50873

Ensembl

ENSG00000185345

ENSMUSG00000023826

UniProt

O60260

Q9WVS6

RefSeq (mRNA)

NM_004562
NM_013987
NM_013988

NM_016694
NM_001317726

RefSeq (protein)

NP_004553
NP_054642
NP_054643

NP_001304655
NP_057903

Location (UCSC)Chr 6: 161.35 – 162.73 MbChr 17: 11.06 – 12.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Parkin is a protein which in humans is encoded by the PARK2 gene.[5][6] 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). 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.[7] 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).[8]

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:

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000185345 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023826 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ a b 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ 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.
  13. ^ a b c d 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ 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.
  20. ^ 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.
  21. ^ 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

External links

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