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Prkn

Developmental stage

In late 10 dpc weakly expressed in postmitotic neurons in the mantle layer of the developing nervous system (at protein level). Expression increased at 11-12 dpc (at protein level). At 15-16 dpc, as more specialized neurons and nonneural cells are formed, expression is more tissue specific (at protein level). Expression was highest in the neurites, moderate levels were observed in the migrating postmitotic neurons in the intermediate and neopallial layers (at protein level). In the diencephalon and other CNS regions, while the weakest level of expression was observed in the cell bodies (at protein level). In nonneural tissues, high levels of expression were found in the muscle walls of the intestine, the blood vessels and the dermis (at protein level).

Domain

The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes.

The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription.

Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain.

Function

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:29311685, PubMed:32047033). Substrates include SYT11 and VDAC1 (PubMed:29311685, PubMed:32047033). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2 (By similarity). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:25474007, PubMed:32047033). 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 (By similarity). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (By similarity). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (By similarity). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:22082830, PubMed:24898855, PubMed:25474007, PubMed:32047033). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:22082830, PubMed:24898855, PubMed:32047033). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin (PubMed:25474007). After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30 (PubMed:21753002). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy (By similarity). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:24192653). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (By similarity). Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (By similarity). Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A (By similarity). Limits the production of reactive oxygen species (ROS) (By similarity). Regulates cyclin-E during neuronal apoptosis (By similarity). In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (By similarity). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene (By similarity).

Pathway

Protein modification; protein ubiquitination.

Post-translational modifications

Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation.

S-nitrosylated.

Phosphorylated. Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin. Phosphorylation at Thr-174 by PINK1 and at Thr-216 is important for mitochondrial localization.

Sequence Similarities

Belongs to the RBR family. Parkin subfamily.

Tissue Specificity

Expressed in all subdivisions of the brain (at protein level) (PubMed:11675120). Highly expressed in brainstem, cranial nerve, pontine, cerebellar nuclei, indusium griseum, nuclei reticularis, strata oriens and laccunosum moleculare of the hippocampal CA2 region (PubMed:11122330). Low levels were found in the telencephalon and diencephalon (PubMed:11122330). Expressed in heart, liver, skeletal muscle, kidney and testis (PubMed:10818204).

Cellular localization

Alternative names

Park2, E3 ubiquitin-protein ligase parkin, Parkin RBR E3 ubiquitin-protein ligase

swissprot:Q9WVS6