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E3 ubiquitin-protein ligase parkin; EC=6.3.2.-; parkinson juvenile disease protein 2; parkinson disease protein 2 (PARK2 PRKN)

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; a) amount of STUB1 in the complex increases during ER stress b) STUB1 promotes dissociation of HSP70 from PARK2 & GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination c) HSP70 transiently associates with unfolded GPR37 & inhibits E3 activity of PARK2 d) 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

Related

alpha-synuclein; non-A beta component of AD amyloid; non-A4 component of amyloid; NACP (SNCA, NACP, PARK1) parkin gene

General

human longevity protein ring finger protein E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein

Properties

SIZE: entity length = 465 aa MW = 52 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: Ubiquitin-like {1-76} SYT11 binding 1 {204-238} RING-finger {238-293} MOTIF: SYT11 binding 2 {257-293} EFFECTOR-BOUND: Zn+2 FOR-BINDING-OF: DNA motif Zinc finger NAME: Zinc finger SITE: 313-377 EFFECTOR-BOUND: Zn+2 RING-finger {418-449} EFFECTOR-BOUND: Zn+2 FOR-BINDING-OF: DNA motif

Database Correlations

OMIM correlations MORBIDMAP 602544 UniProt O60260 PFAM correlations Entrez Gene 5071 Kegg hsa:5071

References

  1. UniProt :accession O60260
  2. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PARK2
  3. Kitada T et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-8, 1998 PMID: 9560156
  4. 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: 11431533
  5. Chung KK et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304:1328-31, 2004 PMID: 15105460
  6. 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: 23650379