Parkin (ligase)

For other uses, see Parkin (disambiguation).

Parkin RBR E3 ubiquitin protein ligase
250px 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
File: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: 161.35 – 162.73 Mb	Chr 17: 10.84 – 12.06 Mb
PubMed search	[1]	[2]

Parkin is a protein which in humans is encoded by the PARK2 gene. 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).

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. 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).

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,
• CASK,
• CUL1,
• FBXW7 and
• GPR37,
• HSPA1A,
• HSPA8,
• Multisynthetase complex auxiliary component p38,
• PDCD2,
• SEPT5,
• SNCAIP,
• STUB1,
• SYT11, and
• Ubiquitin C.

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)