PARK2
Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', '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 a 22 kDa O-linked glycosylated isoform 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 (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in the regulation of neuron death. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. 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. May represent a tumor suppressor gene. Belongs to the RBR family. Parkin subfamily. 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 (at protein level). 8 alternatively spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Molecular Function: actin binding; beta-catenin binding; cullin family protein binding; 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; metal ion binding; PDZ domain binding; phospholipase binding; protein binding; protein kinase binding; protein-containing complex binding; protein-folding chaperone binding; transcription corepressor activity; transferase activity; tubulin binding; ubiquitin binding; ubiquitin conjugating enzyme binding; ubiquitin protein ligase activity; ubiquitin protein ligase binding; ubiquitin-protein transferase activity; ubiquitin-specific protease binding
Biological Process: adult locomotory behavior; aggresome assembly; autophagy; autophagy of mitochondrion; cellular response to hydrogen sulfide; cellular response to L-glutamate; cellular response to toxic substance; dopamine metabolic process; dopamine uptake involved in synaptic transmission; free ubiquitin chain polymerization; learning; locomotory behavior; mitochondrial fragmentation involved in apoptotic process; mitochondrion localization; mitochondrion to lysosome transport; mitophagy; modulation of chemical synaptic transmission; negative regulation by host of viral genome replication; negative regulation of actin filament bundle assembly; negative regulation of canonical Wnt signaling pathway; negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; negative regulation of excitatory postsynaptic potential; negative regulation of exosomal secretion; 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 mitochondrial fission; negative regulation of neuron apoptotic process; negative regulation of neuron death; negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; negative regulation of primary amine oxidase activity; negative regulation of protein phosphorylation; negative regulation of reactive oxygen species biosynthetic process; 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 synaptic transmission, glutamatergic; negative regulation of transcription by RNA polymerase II; norepinephrine metabolic process; parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization; positive regulation of apoptotic process; positive regulation of ATP biosynthetic process; positive regulation of autophagy of mitochondrion; 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 insulin secretion involved in cellular response to glucose stimulus; positive regulation of mitochondrial fusion; positive regulation of mitochondrial membrane potential; positive regulation of mitophagy; positive regulation of mitophagy in response to mitochondrial depolarization; positive regulation of neurotransmitter uptake; positive regulation of proteasomal protein catabolic process; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; positive regulation of protein binding; positive regulation of protein linear polyubiquitination; positive regulation of protein localization to membrane; positive regulation of transcription by RNA polymerase II; positive regulation of tumor necrosis factor-mediated signaling pathway; proteasomal protein catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; protein autoubiquitination; protein catabolic process; protein destabilization; protein K11-linked ubiquitination; protein K48-linked ubiquitination; protein K6-linked ubiquitination; protein K63-linked ubiquitination; protein localization to mitochondrion; protein metabolic process; protein monoubiquitination; protein polyubiquitination; protein stabilization; protein ubiquitination; regulation of apoptotic process; regulation of autophagy; regulation of cellular response to oxidative stress; regulation of dopamine metabolic process; regulation of mitochondrial membrane potential; regulation of mitochondrion organization; regulation of neurotransmitter secretion; regulation of postsynaptic membrane neurotransmitter receptor levels; regulation of protein stability; regulation of protein ubiquitination; regulation of reactive oxygen species metabolic process; regulation of synaptic vesicle endocytosis; regulation protein catabolic process at presynapse; response to endoplasmic reticulum stress; startle response; synaptic transmission, dopaminergic; synaptic transmission, glutamatergic; ubiquitin-dependent protein catabolic process
