FEATURES

FAMILY

DESCRIPTION

Also known as PRKN_HUMAN, PRKN, PARK2. Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:32047033, PubMed:29311685, PubMed:22396657). Substrates include SYT11 and VDAC1 (PubMed:32047033, PubMed:29311685). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, PubMed:21376232, PubMed:21532592, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536, PubMed:22396657). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951, PubMed:32047033, PubMed:25474007). 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 (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:19229105, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). 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:32047033, PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:18957282, PubMed:21376232, PubMed:22396657, PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:11439185, PubMed:22082830, PubMed:23933751). 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:32047033, PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:21376232, PubMed:22396657, PubMed:11439185, PubMed:22082830, PubMed:23933751, PubMed:33499712). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin (PubMed:24660806, PubMed:25474007, PubMed:24784582, PubMed:25527291). 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:19029340, PubMed:19966284, PubMed:21753002, PubMed:23620051, PubMed:24896179, PubMed:25527291, PubMed:22396657, PubMed:23933751). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes th Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 (PubMed:21532592, PubMed:11078524). Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the complex increases during ER stress (PubMed:12150907). STUB1 promotes the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PRKN, whereas, STUB1 enhances the E3 activity of PRKN through promotion of dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination (PubMed:16955485). Interacts (via first RING-type domain) with AIMP2 (via N-terminus) (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, PubMed:18541373). Interacts with PINK1 (PubMed:19966284, PubMed:20798600). Forms a complex with PINK1 and PARK7 (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 may facilitate PRKN transport into the mitochondria (PubMed:22082830). Interacts with MFN2 (phosphorylated), promotes PRKN localization in dysfunctional depolarized mitochondria (PubMed:23620051). Interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria (PubMed:23933751). Interacts with ZNF746 (PubMed:21376232). Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria (PubMed:24270810). Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria (PubMed:24270810). Forms a complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 (By similarity).

EXTERNAL LINKS

PRKN

E3 ubiquitin-protein ligase parkin

PRKN

Molecular Synopsis