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.
Molecular Function: tubulin binding; identical protein binding; ubiquitin binding; zinc ion binding; histone deacetylase binding; ubiquitin-protein ligase activity; Hsp70 protein binding; actin binding; protein kinase binding; PDZ domain binding; protein binding; G-protein-coupled receptor binding; ubiquitin conjugating enzyme binding; heat shock protein binding; chaperone binding; ubiquitin protein ligase binding; SH3 domain binding; kinase binding; ligase activity
Biological Process: protein monoubiquitination; negative regulation of JNK cascade; proteasomal ubiquitin-dependent protein catabolic process; negative regulation of actin filament bundle formation; startle response; central nervous system development; protein polyubiquitination; regulation of protein ubiquitination; adult locomotory behavior; protein ubiquitination during ubiquitin-dependent protein catabolic process; regulation of neurotransmitter secretion; protein ubiquitination; mitochondrion localization; norepinephrine metabolic process; regulation of dopamine secretion; dopamine metabolic process; negative regulation of insulin secretion; negative regulation of glucokinase activity; zinc ion homeostasis; negative regulation of protein amino acid phosphorylation; regulation of lipid transport; dopamine uptake; negative regulation of neuron apoptosis; positive regulation of DNA binding; mitochondrion organization and biogenesis; mitochondrial fission; synaptic transmission, glutamatergic; protein autoubiquitination; positive regulation of I-kappaB kinase/NF-kappaB cascade; protein stabilization; transcription, DNA-dependent; learning; regulation of protein transport; cellular protein catabolic process; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; mitochondrion degradation; positive regulation of transcription from RNA polymerase II promoter; regulation of autophagy; response to oxidative stress
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.