Human Gene PRKN (ENST00000338468.7) Description and Page Index
Description: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as '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 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. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. 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. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene. (from UniProt O60260) RefSeq Summary (NM_004562): The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]. Gencode Transcript: ENST00000338468.7 Gencode Gene: ENSG00000185345.21 Transcript (Including UTRs) Position: hg38 chr6:161,350,099-162,727,668 Size: 1,377,570 Total Exon Count: 11 Strand: - Coding Region Position: hg38 chr6:161,350,099-162,054,135 Size: 704,037 Coding Exon Count: 8
ID:PRKN2_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase parkin; EC=6.3.2.-; AltName: Full=Parkinson juvenile disease protein 2; Short=Parkinson disease protein 2; FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as '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 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. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. 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. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PARK2, CUL1 and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains of SYT11. Interacts and regulates the turnover of SEPT5. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PARK2 and GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PARK2, whereas, STUB1 enhances the E3 activity of PARK2 through promotion of dissociation of HSP70 from PARK2-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING- type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. INTERACTION: Q5S007:LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863; P49792:RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138; Q8IXI2:RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430; Q9Z2Q6:Sept5 (xeno); NbExp=2; IntAct=EBI-716346, EBI-772125; Q15645:TRIP13; NbExp=3; IntAct=EBI-716346, EBI-358993; Q6NUN9:ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525; SUBCELLULAR LOCATION: Cytoplasm, cytosol. Nucleus. Endoplasmic reticulum. Mitochondrion. Note=Mainly localizes in the cytosol. Co-localizes with SYT11 in neutrites. Co-localizes with SNCAIP in brainstem Lewy bodies. Relocates to dysfunctional mitochondria that have lost the mitochondrial membrane potential; recruitment to mitochondria is PINK1-dependent. TISSUE SPECIFICITY: 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). DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes. PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation. PTM: S-nitrosylated. The inhibition of PARK2 ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PARK2 substrates. DISEASE: Defects in PARK2 are a cause of Parkinson disease (PARK) [MIM:168600]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early- onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. DISEASE: Defects in PARK2 are the cause of Parkinson disease type 2 (PARK2) [MIM:600116]; also known as early-onset parkinsonism with diurnal fluctuation (EPDF) or autosomal recessive juvenile Parkinson disease (PDJ). A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually befor 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper- reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent. DISEASE: Note=Defects in PARK2 may be involved in the development and/or progression of ovarian cancer. MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable and lies within FRA6E, the third most common fragile site in tumor tissue. MISCELLANEOUS: 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 (PubMed:21532592). SIMILARITY: Belongs to the RBR family. Parkin subfamily. SIMILARITY: Contains 1 IBR-type zinc finger. SIMILARITY: Contains 2 RING-type zinc fingers. SIMILARITY: Contains 1 ubiquitin-like domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PARK2"; WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue 131 of September 2011; URL="http://www.expasy.org/spotlight/back_issues/sptlt131.shtml";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O60260
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000209 protein polyubiquitination GO:0000266 mitochondrial fission GO:0000422 mitophagy GO:0000423 macromitophagy GO:0001933 negative regulation of protein phosphorylation GO:0001963 synaptic transmission, dopaminergic GO:0001964 startle response GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006511 ubiquitin-dependent protein catabolic process GO:0006513 protein monoubiquitination GO:0006914 autophagy GO:0006979 response to oxidative stress GO:0007005 mitochondrion organization GO:0007417 central nervous system development GO:0007612 learning GO:0007626 locomotory behavior GO:0008344 adult locomotory behavior GO:0010498 proteasomal protein catabolic process GO:0010506 regulation of autophagy GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0010636 positive regulation of mitochondrial fusion GO:0010637 negative regulation of mitochondrial fusion GO:0010821 regulation of mitochondrion organization GO:0010906 regulation of glucose metabolic process GO:0010994 free ubiquitin chain polymerization GO:0014059 regulation of dopamine secretion GO:0016236 macroautophagy GO:0016567 protein ubiquitination GO:0016579 protein deubiquitination GO:0019538 protein metabolic process GO:0031396 regulation of protein ubiquitination GO:0031647 regulation of protein stability GO:0031648 protein destabilization GO:0032092 positive regulation of protein binding GO:0032232 negative regulation of actin filament bundle assembly GO:0032368 regulation of lipid transport GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0033132 negative regulation of glucokinase activity GO:0034620 cellular response to unfolded protein GO:0034976 response to endoplasmic reticulum stress GO:0035249 synaptic transmission, glutamatergic GO:0035519 protein K29-linked ubiquitination GO:0036503 ERAD pathway GO:0042053 regulation of dopamine metabolic process GO:0042415 norepinephrine metabolic process GO:0042417 dopamine metabolic process GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043388 positive regulation of DNA binding GO:0043524 negative regulation of neuron apoptotic process GO:0044257 cellular protein catabolic process GO:0044267 cellular protein metabolic process GO:0044314 protein K27-linked ubiquitination GO:0044828 negative regulation by host of viral genome replication GO:0045732 positive regulation of protein catabolic process GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0046329 negative regulation of JNK cascade GO:0046676 negative regulation of insulin secretion GO:0046928 regulation of neurotransmitter secretion GO:0050804 modulation of synaptic transmission GO:0050821 protein stabilization GO:0051582 positive regulation of neurotransmitter uptake GO:0051583 dopamine uptake involved in synaptic transmission GO:0051865 protein autoubiquitination GO:0051881 regulation of mitochondrial membrane potential GO:0055069 zinc ion homeostasis GO:0060548 negative regulation of cell death GO:0060828 regulation of canonical Wnt signaling pathway GO:0061734 parkin-mediated mitophagy in response to mitochondrial depolarization GO:0070050 neuron cellular homeostasis GO:0070534 protein K63-linked ubiquitination GO:0070585 protein localization to mitochondrion GO:0070842 aggresome assembly GO:0070936 protein K48-linked ubiquitination GO:0070979 protein K11-linked ubiquitination GO:0071287 cellular response to manganese ion GO:0085020 protein K6-linked ubiquitination GO:0090090 negative regulation of canonical Wnt signaling pathway GO:0090141 positive regulation of mitochondrial fission GO:0090201 negative regulation of release of cytochrome c from mitochondria GO:0097237 cellular response to toxic substance GO:0098779 mitophagy in response to mitochondrial depolarization GO:0099074 mitochondrion to lysosome transport GO:1900407 regulation of cellular response to oxidative stress GO:1901215 negative regulation of neuron death GO:1901800 positive regulation of proteasomal protein catabolic process GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway GO:1902254 negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator GO:1902283 negative regulation of primary amine oxidase activity GO:1902530 positive regulation of protein linear polyubiquitination GO:1902803 regulation of synaptic vesicle transport GO:1903202 negative regulation of oxidative stress-induced cell death GO:1903214 regulation of protein targeting to mitochondrion GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway GO:1903351 cellular response to dopamine GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway GO:1903382 negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway GO:1903542 negative regulation of exosomal secretion GO:1903599 positive regulation of mitophagy GO:1903861 positive regulation of dendrite extension GO:1904049 negative regulation of spontaneous neurotransmitter secretion GO:1905281 positive regulation of retrograde transport, endosome to Golgi GO:1905366 negative regulation of intralumenal vesicle formation GO:1905477 positive regulation of protein localization to membrane GO:2000377 regulation of reactive oxygen species metabolic process GO:2000378 negative regulation of reactive oxygen species metabolic process