DegronMD - O60260(PRKN)

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: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 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). {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11439185, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:25621951, ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:33499712}. 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GO - Biological processes (BP): adult locomotory behavior [GO:0008344]; aggresome assembly [GO:0070842]; amyloid fibril formation [GO:1990000]; autophagy of mitochondrion [GO:0000422]; cellular protein catabolic process [GO:0044257]; cellular response to dopamine [GO:1903351]; cellular response to manganese ion [GO:0071287]; cellular response to toxic substance [GO:0097237]; cellular response to unfolded protein [GO:0034620]; central nervous system development [GO:0007417]; dopamine metabolic process [GO:0042417]; dopamine uptake involved in synaptic transmission [GO:0051583]; ERAD pathway [GO:0036503]; free ubiquitin chain polymerization [GO:0010994]; learning [GO:0007612]; macroautophagy [GO:0016236]; mitochondrial fission [GO:0000266]; mitochondrion organization [GO:0007005]; mitochondrion to lysosome transport [GO:0099074]; mitophagy [GO:0000423]; negative regulation by host of viral genome replication [GO:0044828]; negative regulation of actin filament bundle assembly [GO:0032232]; negative regulation of canonical Wnt signaling pathway [GO:0090090]; negative regulation of cell death [GO:0060548]; negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway [GO:1902236]; negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway [GO:1903382]; negative regulation of exosomal secretion [GO:1903542]; negative regulation of gene expression [GO:0010629]; negative regulation of glucokinase activity [GO:0033132]; negative regulation of insulin secretion [GO:0046676]; negative regulation of intralumenal vesicle formation [GO:1905366]; negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator [GO:1902254]; negative regulation of JNK cascade [GO:0046329]; negative regulation of mitochondrial fusion [GO:0010637]; negative regulation of neuron apoptotic process [GO:0043524]; negative regulation of neuron death [GO:1901215]; negative regulation of oxidative stress-induced cell death [GO:1903202]; negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway [GO:1903377]; negative regulation of primary amine oxidase activity [GO:1902283]; negative regulation of protein phosphorylation [GO:0001933]; negative regulation of reactive oxygen species metabolic process [GO:2000378]; negative regulation of release of cytochrome c from mitochondria [GO:0090201]; negative regulation of spontaneous neurotransmitter secretion [GO:1904049]; negative regulation of transcription by RNA polymerase II [GO:0000122]; neuron cellular homeostasis [GO:0070050]; norepinephrine metabolic process [GO:0042415]; parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization [GO:0061734]; positive regulation of autophagy of mitochondrion [GO:1903599]; positive regulation of dendrite extension [GO:1903861]; positive regulation of DNA binding [GO:0043388]; positive regulation of gene expression [GO:0010628]; positive regulation of I-kappaB kinase/NF-kappaB signaling [GO:0043123]; positive regulation of mitochondrial fission [GO:0090141]; positive regulation of mitochondrial fusion [GO:0010636]; positive regulation of mitophagy in response to mitochondrial depolarization [GO:0098779]; positive regulation of neurotransmitter uptake [GO:0051582]; positive regulation of proteasomal protein catabolic process [GO:1901800]; positive regulation of proteasomal ubiquitin-dependent protein catabolic process [GO:0032436]; positive regulation of protein binding [GO:0032092]; positive regulation of protein catabolic process [GO:0045732]; positive regulation of protein linear polyubiquitination [GO:1902530]; positive regulation of protein localization to membrane [GO:1905477]; positive regulation of retrograde transport, endosome to Golgi [GO:1905281]; positive regulation of transcription by RNA polymerase II [GO:0045944]; positive regulation of tumor necrosis factor-mediated signaling pathway [GO:1903265]; proteasomal protein catabolic process [GO:0010498]; proteasome-mediated ubiquitin-dependent protein catabolic process [GO:0043161]; protein autoubiquitination [GO:0051865]; protein destabilization [GO:0031648]; protein deubiquitination [GO:0016579]; protein K11-linked ubiquitination [GO:0070979]; protein K27-linked ubiquitination [GO:0044314]; protein K29-linked ubiquitination [GO:0035519]; protein K48-linked ubiquitination [GO:0070936]; protein K63-linked ubiquitination [GO:0070534]; protein K6-linked ubiquitination [GO:0085020]; protein localization to mitochondrion [GO:0070585]; protein monoubiquitination [GO:0006513]; protein polyubiquitination [GO:0000209]; protein stabilization [GO:0050821]; protein ubiquitination [GO:0016567]; regulation of apoptotic process [GO:0042981]; regulation of autophagy [GO:0010506]; regulation of canonical Wnt signaling pathway [GO:0060828]; regulation of cellular response to oxidative stress [GO:1900407]; regulation of dopamine metabolic process [GO:0042053]; regulation of dopamine secretion [GO:0014059]; regulation of glucose metabolic process [GO:0010906]; regulation of lipid transport [GO:0032368]; regulation of mitochondrial membrane potential [GO:0051881]; regulation of mitochondrion organization [GO:0010821]; regulation of protein stability [GO:0031647]; regulation of protein targeting to mitochondrion [GO:1903214]; regulation of protein ubiquitination [GO:0031396]; regulation of reactive oxygen species metabolic process [GO:2000377]; regulation of synaptic vesicle transport [GO:1902803]; response to endoplasmic reticulum stress [GO:0034976]; response to oxidative stress [GO:0006979]; startle response [GO:0001964]; synaptic transmission, glutamatergic [GO:0035249]; ubiquitin-dependent protein catabolic process [GO:0006511]; zinc ion homeostasis [GO:0055069] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.A134V	SIDM02015	Colorectal Carcinoma	GDSC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.1111
p.P113T	SIDM00090	Ovarian Carcinoma	GDSC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.1111
p.P113T	OVCAR-8	ovary	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.1111
p.A120V	SIDM01106	Melanoma	GDSC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.3056
p.A120V	SK-MEL-24	skin	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.3056
p.D126E	SIDM01387	Small Cell Lung Carcinoma	GDSC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation altering degron motif	0.5647
p.E119G	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.2778
p.R123W	NAMALWA	haematopoietic and lymphoid tissue	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation altering degron motif	0.8634
p.I133V	JURL-MK1	haematopoietic and lymphoid tissue	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.1389
p.A117T	MEL-JUSO	skin	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.2222
p.C119S	NCI-H1781	lung	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation rewiring degron network	0.2778
p.R126Q	PF-382	haematopoietic and lymphoid tissue	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation altering degron motif	0.7329
p.R131C	KG-1	haematopoietic and lymphoid tissue	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation blocking phosphorylation signal	0.6389
p.R131H	HCT-15	large intestine	COSMIC	VILHTD	LIG_APCC_ABBA_1	121:126	Mutation blocking phosphorylation signal	0.6389

DegronMD: protein-targeted degradation, mutation and drug response to degrons

PRKN

UniProt ID: O60260

Entrez ID: 5071

Protein name: E3 ubiquitin-protein ligase parkin (Parkin) (EC 2.3.2.31) (Parkin RBR E3 ubiquitin-protein ligase) (Parkinson juvenile disease protein 2) (Parkinson disease protein 2)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for PRKN in