E3 Ubiquitin-Protein Ligase Parkin (PRKN) Human Recombinant Protein

The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PARK2: a component of a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'- linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Promotes the autophagic degradation of dysfunctional depolarized mitochondria. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). 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, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene. Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PARK2, CUL1 and FBXW7. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PARK2 and GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PARK2, whereas, STUB1 enhances the E3 activity of PARK2 through promotion of dissociation of HSP70 from PARK2-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING- type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. Highly expressed in the brain including the substantia nigra. Expressed in heart, testis and skeletal muscle. Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients. Overexpression protects dopamine neurons from kainate-mediated apoptosis. Found in serum. Belongs to the RBR family. Parkin subfamily. 6 isoforms of the human protein are produced by alternative splicing.

Protein type: EC 6.3.2.-; EC 6.3.2.19; Ligase; Ubiquitin conjugating system; Ubiquitin ligase

Chromosomal Location of Human Ortholog: 6q25.2-q27

Cellular Component: cytoplasm; cytosol; endoplasmic reticulum; Golgi apparatus; mitochondrion; neuron projection; nucleus; perinuclear region of cytoplasm; SCF ubiquitin ligase complex; ubiquitin ligase complex

Molecular Function: actin binding; beta-catenin binding; chaperone binding; enzyme binding; G-protein-coupled receptor binding; heat shock protein binding; histone deacetylase binding; Hsp70 protein binding; identical protein binding; kinase binding; PDZ domain binding; phospholipase binding; protein binding; protein kinase binding; SH3 domain binding; transcription factor activity; tubulin binding; ubiquitin binding; ubiquitin conjugating enzyme binding; ubiquitin protein ligase binding; ubiquitin-protein ligase activity; zinc ion binding

Biological Process: adult locomotory behavior; cellular protein catabolic process; cellular protein metabolic process; central nervous system development; dopamine metabolic process; macroautophagy; mitochondrial fission; mitochondrion degradation; mitochondrion organization and biogenesis; negative regulation of actin filament bundle formation; negative regulation of glucokinase activity; negative regulation of insulin secretion; negative regulation of JNK cascade; negative regulation of neuron apoptosis; negative regulation of protein amino acid phosphorylation; negative regulation of transcription from RNA polymerase II promoter; positive regulation of DNA binding; positive regulation of I-kappaB kinase/NF-kappaB cascade; positive regulation of neurotransmitter uptake; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; positive regulation of protein binding; positive regulation of protein catabolic process; positive regulation of transcription from RNA polymerase II promoter; proteasomal protein catabolic process; proteasomal ubiquitin-dependent protein catabolic process; protein autoubiquitination; protein destabilization; protein monoubiquitination; protein polyubiquitination; protein stabilization; protein ubiquitination; protein ubiquitination during ubiquitin-dependent protein catabolic process; regulation of autophagy; regulation of dopamine metabolic process; regulation of dopamine secretion; regulation of lipid transport; regulation of protein stability; regulation of protein ubiquitination; response to oxidative stress; zinc ion homeostasis

Disease: Leprosy, Susceptibility To, 2; Lung Cancer; Ovarian Cancer; Parkinson Disease 2, Autosomal Recessive Juvenile