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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. Note: This description may include information from UniProtKB.
Protein type: EC 6.3.2.-; EC; Ligase; Translation; Translation regulation; Ubiquitin conjugating system; Ubiquitin ligase
Chromosomal Location of Human Ortholog: 6q26
Cellular Component: aggresome; cytoplasm; cytosol; endoplasmic reticulum; Golgi apparatus; LUBAC complex; mitochondrion; mitochondrion-derived vesicle; neuron projection; nucleus; Parkin-FBXW7-Cul1 ubiquitin ligase complex; perinuclear region of cytoplasm; presynapse; protein complex; SCF ubiquitin ligase complex; ubiquitin ligase complex
Molecular Function: actin binding; beta-catenin binding; chaperone binding; DNA binding transcription factor activity; enzyme binding; F-box domain 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; tubulin binding; ubiquitin binding; ubiquitin conjugating enzyme binding; ubiquitin protein ligase activity involved in ERAD pathway; ubiquitin protein ligase binding; ubiquitin-protein transferase activity; ubiquitin-specific protease binding; zinc ion binding
Biological Process: adult locomotory behavior; cellular protein catabolic process; cellular protein metabolic process; cellular response to manganese ion; cellular response to unfolded protein; central nervous system development; dopamine metabolic process; dopamine uptake; ER-associated protein catabolic process; ERAD pathway; free ubiquitin chain polymerization; learning; macroautophagy; macromitophagy; mitochondrial fission; mitochondrion degradation; mitochondrion organization; mitochondrion to lysosome transport; negative regulation of actin filament bundle formation; negative regulation of canonical Wnt signaling pathway; negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; negative regulation of gene expression; negative regulation of glucokinase activity; negative regulation of insulin secretion; negative regulation of intralumenal vesicle formation; negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; negative regulation of JNK cascade; negative regulation of mitochondrial fusion; negative regulation of neuron apoptosis; negative regulation of neuron death; negative regulation of primary amine oxidase activity; negative regulation of protein phosphorylation; negative regulation of reactive oxygen species metabolic process; negative regulation of release of cytochrome c from mitochondria; negative regulation of spontaneous neurotransmitter secretion; negative regulation of transcription from RNA polymerase II promoter; norepinephrine metabolic process; parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; positive regulation of dendrite extension; positive regulation of DNA binding; positive regulation of gene expression; positive regulation of I-kappaB kinase/NF-kappaB signaling; positive regulation of mitochondrial fission; positive regulation of mitochondrial fusion; positive regulation of mitophagy in response to mitochondrial depolarization; 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 protein linear polyubiquitination; positive regulation of protein localization to membrane; positive regulation of retrograde transport, endosome to Golgi; positive regulation of transcription from RNA polymerase II promoter; proteasomal protein catabolic process; proteasomal ubiquitin-dependent protein catabolic process; protein autoubiquitination; protein destabilization; protein deubiquitination; protein K11-linked ubiquitination; protein K27-linked ubiquitination; protein K48-linked ubiquitination; protein K6-linked ubiquitination; protein monoubiquitination; protein polyubiquitination; protein stabilization; protein ubiquitination; protein ubiquitination involved in ubiquitin-dependent protein catabolic process; regulation of autophagy; regulation of cellular response to oxidative stress; regulation of dopamine metabolic process; regulation of dopamine secretion; regulation of glucose metabolic process; regulation of lipid transport; regulation of mitochondrial membrane potential; regulation of mitochondrion organization; regulation of protein stability; regulation of protein ubiquitination; regulation of reactive oxygen species metabolic process; regulation of synaptic vesicle transport; response to oxidative stress; startle response; synaptic transmission, glutamatergic; transcription, DNA-dependent; zinc ion homeostasis
Disease: Leprosy, Susceptibility To, 2; Lung Cancer; Ovarian Cancer; Parkinson Disease 2, Autosomal Recessive Juvenile
Reference #:  O60260 (UniProtKB)
Alt. Names/Synonyms: AR-JP; E3 ubiquitin-protein ligase parkin; LPRS2; PARK2; parkin; parkin 2; Parkinson disease (autosomal recessive, juvenile) 2, parkin; Parkinson disease protein 2; Parkinson juvenile disease protein 2; PDJ; PRKN; PRKN2
Gene Symbols: PRKN
Molecular weight: 51,641 Da
Basal Isoelectric point: 6.71  Predict pI for various phosphorylation states
CST Pathways:  Parkinson's Disease
Protein-Specific Antibodies or siRNAs from Cell Signaling Technology® Total Proteins
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