Parkin Protein
From Anvita Health Wiki
Contents |
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
- 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
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
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
More General Terms
Additional Terms
Internet Database
Entrez gene: 5071
Kegg: [1]
OMIM: 168600
OMIM: 600116
OMIM: 602544
Prosite: [2]
Prosite: [3]
Prosite: [4]
Prosite: [5]
UniProt: [6]
References
- UniProt [7]
- GeneReviews [8]
- Kitada T et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-8, 1998 PMID: [9]
- 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: [10]
- Chung KK et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304:1328-31, 2004 PMID: [11]
