E3 ubiquitin-protein ligase parkin; EC=6.3.2.-; parkinson juvenile disease protein 2; parkinson disease protein 2 (PARK2 PRKN)
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Function
- functions within a multiprotein E3 ubiquitin ligase complex, catalyzing covalent attachment of ubiquitin moieties onto substrate proteins
- substrates include SYT11, CCNE1, GPR37, STUB1, a 22 kD O-linked glycosylated isoform of SNCAIP, SEPT5 & AIMP2
- may play a more general role in the ubiquitin proteasomal pathway by participating in the removal &/or detoxification of abnormally folded or damaged protein
- may play a role in removal of damaged mitochondria[6]
- loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2
- may protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, & kainate- induced excitotoxicity
- may play a role in controlling neurotransmitter trafficking at the presynaptic terminal & in Ca+2-dependent exocytosis
- regulates cyclin E during neuronal apoptosis
- may represent a tumor suppressor gene protein ubiquitination
- auto-ubiquitinates (E2-dependent) leading to its own degradation
- S-nitrosylated: inhibition of PARK2 ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in Parkinson's disease by impairing the ubiquitination of PARK2 substrates
- forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6
- part of a SCF-like complex, consisting of PARK2, CUL1 & FBXW7
- interacts with SNCAIP
- binds to the C2A & C2B domains of SYT11
- interacts & regulates the turnover of SEPT5
- part of a complex, including STUB1, HSP70 & GPR37;
- amount of STUB1 in the complex increases during ER stress
- STUB1 promotes dissociation of HSP70 from PARK2 & GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination
- HSP70 transiently associates with unfolded GPR37 & inhibits E3 activity of PARK2
- STUB1 enhances E3 activity of PARK2 by enhancing dissociation of HSP70 from PARK2-GPR37 complexes
- interacts with PSMD4 & PACRG
- interacts with LRRK2.
- interacts with RANBP2
- interacts with SUMO1 but not SUMO2, which promotes nuclear localization & autoubiquitination
- interacts (via first RING-type domain) with AIMP2 (via N-terminus)
- interacts with PSMA7
Structure
- ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes
- belongs to the RBR family, parkin subfamily
- contains 1 IBR-type Zn+2 finger
- contains 2 RING-type Zn+2 fingers
- contains 1 ubiquitin-like domain
Compartment
- cytoplasm, nucleus
- co-localizes with SYT11 in neutrites
- co-localizes with SNCAIP in brainstem Lewy bodies
Alternative splicing
named isoforms=5
Expression
- highly expressed in brain including substantia nigra
- expressed in heart, testis & skeletal muscle
- expression is down-regulated or absent in tumor biopsies, & absent in the brain of PARK2 patients.
- overexpression protects dopamine neurons from kainate- mediated apoptosis
- found in plasma (at protein level)
Pathology
- defects in PARK2 are a cause of Parkinson's disease
- defects in PARK2 are the cause of autosomal recessive early-onset Parkinson's disease type 2
- defects in PARK2 may be involved in the development &/or progression of ovarian cancer
- S-nitrosylated parkin is also increased in affected areas of post-mortem brains in Parkinson's disease & Lewy body dementia[3].
Notes
- the parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable & lies within FRA6E, the 3rd most common fragile site in tumor tissue
More general terms
Additional terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/O60260.html
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PARK2
- ↑ 3.0 3.1 Kitada T et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-8, 1998 PMID: https://www.ncbi.nlm.nih.gov/pubmed/9560156
- ↑ Journal Watch 22(1):8, 2002 Shimura H et al Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11431533
- ↑ Chung KK et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304:1328-31, 2004 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15105460
- ↑ 6.0 6.1 Rana A, Rera M, Walker DW. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci U S A. 2013 May 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23650379
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5071
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5071
- OMIM: https://mirror.omim.org/entry/168600
- OMIM: https://mirror.omim.org/entry/600116
- OMIM: https://mirror.omim.org/entry/602544
- UniProt: http://www.uniprot.org/uniprot/O60260.html