Parkin (ligase)

From Wikipedia, the free encyclopedia

Parkinson disease (autosomal recessive, juvenile) 2, parkin

PDB rendering based on 1iyf.

Available structures: 1iyf, 2jmo

Identifiers

Symbol(s)

PARK2; AR-JP; LPRS2; PDJ; PRKN

External IDs

OMIM: 602544 MGI: 1355296 HomoloGene: 3355

EC number

6.3.2.19

Gene ontology
Molecular Function:	• ubiquitin-protein ligase activity • protein binding • zinc ion binding • ligase activity • metal ion binding
Cellular Component:	• nucleus • neuron projection
Biological Process:	• startle response • ubiquitin-dependent protein catabolic process • ubiquitin cycle • central nervous system development • learning • locomotory behavior • protein metabolic process • synaptic transmission, glutamatergic • norepinephrine metabolic process • dopamine metabolic process • regulation of neurotransmitter secretion • regulation of synaptic transmission • dopamine uptake

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

Refseq

NM_004562 (mRNA)
NP_004553 (protein)

NM_016694 (mRNA)
NP_057903 (protein)

Location

Chr 6: 161.69 - 163.07 Mb

Chr 17: 10.91 - 11.91 Mb

Pubmed search

[1]

[2]

For other uses, see Parkin (disambiguation).

Parkin is an E3 ligase in the ubiquitin-proteasome system which is encoded by the PARK2 gene. Many mutations in parkin have been associated with a familial form of Parkinson's disease termed autosomal recessive juvenile parkinsonism. How loss of function of parkin 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, CDC-rel2, cyclinE, p38 tRNA synthase, Pael-R, synaptotagmin XI, synphilin-1, 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.

1 Parkinson's disease
2 References
3 Further reading
4 External links

[edit] Parkinson's disease

The inheritance of the PARK2 mutation causing autosomal recessive juvenile parkinsonism

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.^[1] 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).^[2]

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.

[edit] References

^ 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.
^ 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): 176–85. doi:10.1002/ana.10613. PMID 12891670.

[edit] 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): 327-36. 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: R127-33. 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): 681-5. doi:10.1038/sj.embor.7400188. PMID 15229644.
Pankratz N, Foroud T (2005). "Genetics of Parkinson disease.". NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 1 (2): 235-42. PMID 15717024.
Suzuki H (2006). "Protein-protein interactions in the mammalian brain.". J. Physiol. (Lond.) 575 (Pt 2): 373-7. doi:10.1113/jphysiol.2006.115717. PMID 16840513.
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. (70): 205-8. 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. PMID 9042918.
Kitada T, Asakawa S, Hattori N, et al. (1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.". Nature 392 (6676): 605-8. 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): 143-6. 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. PMID 9634531.
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. 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. 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): 567-74. 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): 180-2. 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): 668-72. doi:10.1002/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z. PMID 10319893.