Recombinant Human Parkin protein (denatured)

Specifications

Form

Liquid

Additional notes

ab177625 was purified using anion-exchange chromatography (DEAE sepharose resin) and gel-filtration chromatography (Sephacryl S-200) with 20mM Tris pH 7.5, 2mM EDTA.

General info

Function

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 : 22396657, PubMed : 23620051, PubMed : 23754282, PubMed : 24660806, PubMed : 24751536, 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 (PubMed : 10888878, PubMed : 10973942, PubMed : 11431533, PubMed : 12150907, PubMed : 12628165, PubMed : 15105460, PubMed : 16135753, PubMed : 21376232, PubMed : 21532592, PubMed : 22396657, PubMed : 23620051, PubMed : 23754282, PubMed : 24660806, PubMed : 24751536). 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 : 25474007, PubMed : 25621951, 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 (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 : 15728840, PubMed : 19229105). 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 : 11439185, PubMed : 18957282, PubMed : 19029340, PubMed : 19966284, PubMed : 21376232, PubMed : 22082830, PubMed : 22396657, PubMed : 23620051, PubMed : 23933751, PubMed : 24660806, PubMed : 24784582, PubMed : 24896179, PubMed : 25474007, PubMed : 25527291, 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 : 11439185, PubMed : 19029340, PubMed : 19801972, PubMed : 19966284, PubMed : 21376232, PubMed : 22082830, PubMed : 22396657, PubMed : 23620051, PubMed : 23685073, PubMed : 23933751, PubMed : 24896179, PubMed : 25527291, PubMed : 32047033, 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 : 24784582, PubMed : 25474007, 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 : 27534820, 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 : 22396657, PubMed : 23620051, PubMed : 23685073, PubMed : 23933751, PubMed : 24896179, PubMed : 25527291). 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 the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed : 23620051). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed : 23620051). 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 (PubMed : 22396657). 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 (PubMed : 21376232). Limits the production of reactive oxygen species (ROS) (PubMed : 18541373). Regulates cyclin-E during neuronal apoptosis (PubMed : 12628165). 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 (PubMed : 11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene (PubMed : 12719539).

Sequence similarities

Belongs to the RBR family. Parkin subfamily.

Post-translational modifications

ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation positively regulates its E3 ligase activity.. Auto-ubiquitinates in an E2-dependent manner leading to its own degradation (PubMed:19229105, PubMed:23770917, PubMed:25474007). Also polyubiquitinated by RNF41 for proteasomal degradation (PubMed:19229105).. S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PRKN substrates.. Phosphorylated (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, PubMed:25474007). Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is important for mitochondrial localization (PubMed:18957282).

Subcellular localisation

Nucleus