id: Q8NHY2 gene_symbol: COP1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: COP1 (also known as RFWD2; constitutive photomorphogenesis protein 1 homolog) is a RING-finger E3 ubiquitin-protein ligase (EC 2.3.2.27) that mediates ubiquitination and subsequent proteasomal degradation of substrate transcription factors and signaling proteins. Its domain architecture comprises an N-terminal C3HC4 RING-HC zinc finger (responsible for catalytic ubiquitin transfer and zinc binding), a central coiled-coil that mediates homodimerization, and a C-terminal seven-bladed WD40 beta-propeller that serves as the substrate-recognition module, binding short degron motifs in substrates. COP1 acts both as a stand-alone RING E3 and as the substrate-recognition subunit of a cullin-RING ligase (CRL4) module; in the DCX(DET1-COP1) complex (COP1, DET1, DDB1, CUL4A, RBX1) the catalytic RING is contributed by RBX1 while COP1 provides substrate recognition. Validated substrates include the AP-1 transcription factor c-Jun (JUN) and its relatives, the tumor suppressor p53 (TP53, with MTA1 co-regulation), the oncogenic ETS-family factors ETV1/ETV4/ETV5 and ETS1, the metastasis regulator MTA1, 14-3-3 sigma (SFN), C/EBPalpha (CEBPA, recruited via the pseudokinase adaptor TRIB1), and acetyl-CoA carboxylase 1 (ACACA). Substrate choice and ligase activity are regulated by the pseudokinase adaptors TRIB1/TRIB2, which bind the WD40 domain and compete with substrates. COP1 shuttles between nuclear speckles and the cytoplasm; ATM-dependent phosphorylation at Ser387 and 14-3-3 sigma binding drive its nuclear export and autoubiquitination upon DNA damage. Through degradation of these substrates, COP1 functions as a tumor suppressor in several contexts and contributes to control of lipogenesis. It autoubiquitinates and is stabilized by the COP9 signalosome subunit COPS6/CSN6. alternative_products: - name: '1' id: Q8NHY2-1 - name: 2 (delta24) id: Q8NHY2-2 sequence_note: VSP_012024, VSP_012025 - name: '3' id: Q8NHY2-3 sequence_note: VSP_012026, VSP_012027 - name: 4 (COP1D) id: Q8NHY2-4 sequence_note: VSP_012025 - name: 5 (E) id: Q8NHY2-5 sequence_note: VSP_055894, VSP_055895 existing_annotations: - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic (IBA) transfer of the well-supported role of COP1 in targeting substrates for proteasomal degradation. This is directly experimentally established for COP1 (c-Jun, p53, MTA1, ETS factors, 14-3-3sigma), so the term is appropriate and core. action: ACCEPT reason: COP1 is an E3 ligase whose central function is to mediate ubiquitin-dependent proteasomal degradation of its substrates, demonstrated experimentally in multiple studies. The IBA annotation correctly captures this core biological process. The falcon deep research consolidates this across substrates, scoped correctly to the human protein. supported_by: - reference_id: PMID:14739464 supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. - reference_id: file:human/COP1/COP1-deep-research-falcon.md supporting_text: COP1 catalyzes the transfer of ubiquitin from E2 enzymes to specific substrate proteins, marking them for proteasomal degradation. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cytoplasmic localization derived from the UniProt subcellular location vocabulary. COP1 is documented to shuttle between nuclear speckles and the cytoplasm, so this localization is supported, though it is a general parent term. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization is real (COP1 shuttles between nucleus and cytoplasm, and its nuclear export is regulated by 14-3-3 sigma after DNA damage), but the more informative location for its function is the nuclear speckle and the catalytic cytosol annotation; cytoplasm is a broad CC term retained as non-core. - term: id: GO:0016607 label: nuclear speck evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Nuclear speckle localization from UniProt subcellular location mapping. COP1 forms nuclear speckles, supported by experimental characterization of the human protein, and this is a more specific and informative location than bare cytoplasm. action: ACCEPT reason: COP1 is documented to localize to nuclear speckles ("In the nucleus, it forms nuclear speckles"), consistent with its role in nuclear ubiquitination of transcription factors such as p53 and ETS factors. This is an accurate and informative CC term. supported_by: - reference_id: file:human/COP1/COP1-uniprot.txt supporting_text: 'Nucleus speckle. Cytoplasm. Note=In the nucleus, it forms nuclear speckles.' - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: IEA assignment of ubiquitin protein ligase activity from InterPro/EC mapping (RING domain, EC 2.3.2.27). This is the core catalytic molecular function of COP1 and is independently supported by direct experimental evidence (EXP, IMP) in other annotations. action: ACCEPT reason: COP1 is a bona fide RING-finger E3 ubiquitin-protein ligase; the IEA inference from its RING domain and EC number is fully corroborated by experimental data. This is a core molecular function. supported_by: - reference_id: file:human/COP1/COP1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20843328 qualifier: enables review: summary: Generic "protein binding" (GO:0005515) from an IntAct interaction with 14-3-3 sigma/SFN. The interaction is real (SFN binds phospho-Ser387 COP1 and drives its nuclear export), but the bare protein binding term is uninformative per curation guidelines. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 protein binding does not convey a specific molecular function. The underlying COP1-SFN interaction is captured more informatively elsewhere (SFN is both a COP1 substrate and a regulator of COP1 nuclear export); the catalytic ligase activity is the relevant MF. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21572435 qualifier: enables review: summary: Generic "protein binding" from an IntAct interaction with ETV1, a substrate ETS transcription factor that COP1 ubiquitinates and degrades. The interaction is genuine but the bare term is uninformative. The COP1-ETV1 interaction reflects WD40-mediated degron recognition (VP/Val-Pro motif) rather than a non-specific binding event. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 is uninformative. The biologically meaningful relationship (COP1 recognizes and degrades ETV1/ETV4/ETV5) is better captured by the substrate-recognition and protein catabolic process annotations. supported_by: - reference_id: file:human/COP1/COP1-deep-research-falcon.md supporting_text: Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21625211 qualifier: enables review: summary: Generic "protein binding" from IntAct interactions reported in the COPS6/SFN study (interactors SFN and COPS6). COPS6/CSN6 binds and stabilizes COP1; SFN is a COP1 substrate. The interactions are real but the bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 protein binding conveys no specific function. The COP1-COPS6 and COP1-SFN interactions are better described by COP1's ligase activity (toward SFN) and its regulation/stabilization by the COP9 signalosome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25117710 qualifier: enables review: summary: Generic "protein binding" from IntAct interactions with ETS1 and ETS2, substrate ETS transcription factors. COP1 recognizes a phospho-degron on ETS1 (blocked by Src-family kinase phosphorylation). Real interactions, uninformative term. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 is uninformative. The functional relationship (COP1 phospho-degron recognition and degradation of ETS1/ETS2) is captured by the substrate-recognition and catabolic process annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: Generic "protein binding" from a high-throughput interactome study (interactor ETS2). Uninformative term derived from a proteome-scale screen. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 from a large-scale interactome screen does not convey a specific molecular function and provides no functional insight beyond what is already captured. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Generic "protein binding" from a high-throughput interactome study (interactors ETV5 and ETV1, both substrate ETS factors). Uninformative term. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 is uninformative. The ETV1/ETV5 interactions reflect COP1 substrate recognition, already captured by the catabolic-process and substrate-recognition annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35140242 qualifier: enables review: summary: Generic "protein binding" from a transcription-factor interaction network study (interactor ETV5, a substrate ETS factor). Uninformative term. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 conveys no specific molecular function; the ETV5 interaction reflects substrate recognition already captured elsewhere. - term: id: GO:0000139 label: Golgi membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Golgi membrane localization transferred by Ensembl Compara from a rat ortholog. This is not supported by the human COP1 literature, which describes nuclear-speckle and cytoplasmic/cytosolic localization. Likely an erroneous ortholog transfer. action: REMOVE reason: There is no experimental support in human (or convincing functional rationale) for COP1 acting at the Golgi membrane. The annotation derives solely from automatic transfer (GO_REF:0000107) from a rat protein and conflicts with the well-documented nuclear/cytoplasmic localization of COP1. - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: Protein ubiquitination assigned via UniPathway mapping. This is the core biological process catalyzed by COP1 as a RING E3 ligase and is well supported experimentally. action: ACCEPT reason: COP1 directly mediates ubiquitination of multiple substrates (JUN, p53, MTA1, SFN, ETS factors, ACC1); protein ubiquitination is a core BP for this gene. supported_by: - reference_id: file:human/COP1/COP1-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: EXP original_reference_id: PMID:12615916 qualifier: enables review: summary: Experimental (EXP) demonstration that the COP1 RING domain has ubiquitin ligase activity in an in vitro autoubiquitination assay. This is the strongest evidence for the core catalytic molecular function of COP1. action: ACCEPT reason: Direct in vitro demonstration of RING-dependent ubiquitin ligase activity firmly establishes GO:0061630 as a core molecular function of COP1. supported_by: - reference_id: PMID:12615916 supporting_text: The RING domain of huCOP1 displays ubiquitin ligase activity in an autoubiquitination assay in vitro - term: id: GO:0005737 label: cytoplasm evidence_type: IC original_reference_id: PMID:39920308 qualifier: is_active_in review: summary: Curator-inferred (IC) "is_active_in cytoplasm", from the KIF12/ACC1 study where COP1 ubiquitinates the cytoplasmic enzyme acetyl-CoA carboxylase 1. The is_active_in qualifier appropriately marks the cytoplasm as a site of COP1 catalytic activity. action: ACCEPT reason: COP1 acts in the cytoplasm to ubiquitinate cytoplasmic substrates such as ACC1; the is_active_in qualifier captures functional cytoplasmic activity, which is more meaningful than the bare located_in cytoplasm annotation. supported_by: - reference_id: PMID:39920308 supporting_text: lipogenic enzyme turnover - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:39920308 qualifier: involved_in review: summary: IMP evidence that COP1 drives ubiquitin-dependent turnover of the lipogenic enzyme ACC1/ACACA. Supports COP1's core role in ubiquitin-dependent protein catabolism. action: ACCEPT reason: COP1 mediates ubiquitin-dependent degradation of ACC1 (and many other substrates); this is a core biological process. The more specific proteasome-mediated term is also annotated and preferred for the core synthesis, but this parent term is correct. supported_by: - reference_id: PMID:39920308 supporting_text: lipogenic enzyme turnover - term: id: GO:0045717 label: negative regulation of fatty acid biosynthetic process evidence_type: IMP original_reference_id: PMID:39920308 qualifier: involved_in review: summary: IMP evidence that COP1-mediated degradation of acetyl-CoA carboxylase 1 (ACC1), enhanced by KIF12, suppresses lipogenesis; loss promotes MASH/steatohepatitis. This is a downstream physiological consequence of COP1's catalytic activity. action: KEEP_AS_NON_CORE reason: The link between COP1 and fatty acid biosynthesis is genuine but is a tissue-/ substrate-specific physiological outcome (ACC1 turnover in liver) rather than the core molecular/biological role of COP1, which is general substrate ubiquitination and degradation. Retained as a non-core process annotation. supported_by: - reference_id: PMID:39920308 supporting_text: lipogenic enzyme turnover - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-264444 qualifier: enables review: summary: TAS (Reactome) assignment of ubiquitin-protein transferase activity, capturing COP1 autoubiquitination. This is a correct molecular-function term for COP1's E3 ligase activity (a parent/sibling of GO:0061630). action: ACCEPT reason: COP1's catalytic activity (EC 2.3.2.27) is ubiquitin-protein transferase activity; the term is accurate and supported by Reactome's modeling of COP1 autoubiquitination and by experimental data. supported_by: - reference_id: file:human/COP1/COP1-uniprot.txt supporting_text: 'EC=2.3.2.27' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14739464 qualifier: enables review: summary: Generic "protein binding" from the DET1/CUL4A study (interactor DET1, UniProtKB Q7L5Y6). COP1 is a component of the DCX(DET1-COP1) complex; the DET1 interaction is real but the bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 conveys no specific function. The COP1-DET1 interaction is captured by the Cul4A-RING E3 ligase complex membership annotation, which is far more informative. - term: id: GO:0031464 label: Cul4A-RING E3 ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:14739464 qualifier: part_of review: summary: IDA evidence that COP1 is a component of the DCX(DET1-COP1) CUL4A-based E3 ligase complex (with DET1, DDB1, CUL4A, RBX1) that ubiquitinates c-Jun. Well-supported complex membership and a core cellular component for COP1's adaptor function. action: ACCEPT reason: COP1 is directly demonstrated to assemble into a CUL4A-RING ligase complex, where it serves as the substrate-recognition subunit. This is an accurate and informative CC annotation central to COP1 biology. supported_by: - reference_id: PMID:14739464 supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:14739464 qualifier: involved_in review: summary: IMP evidence that the DET1-COP1 complex drives c-Jun ubiquitination and proteasomal degradation. Directly supports COP1's core role in proteasome-mediated protein catabolism. action: ACCEPT reason: Experimentally demonstrated that COP1 (within the CUL4A complex) targets c-Jun for proteasomal degradation; this is a core biological process for COP1. supported_by: - reference_id: PMID:14739464 supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19805145 qualifier: enables review: summary: Generic "protein binding" from the MTA1 study (interactor MTA1, UniProtKB Q13330), a COP1 substrate. The interaction is real but the bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: GO:0005515 is uninformative. The COP1-MTA1 interaction (COP1 ubiquitinates MTA1; MTA1 reciprocally promotes COP1 autoubiquitination) is captured by the catalytic and regulatory annotations. - term: id: GO:0010212 label: response to ionizing radiation evidence_type: IDA original_reference_id: PMID:19805145 qualifier: involved_in review: summary: IDA evidence that ionizing radiation modulates COP1-mediated MTA1 proteolysis (radiation stabilizes MTA1 by disrupting COP1 function). This is a contextual/stimulus response rather than a core function of COP1. action: KEEP_AS_NON_CORE reason: COP1's involvement in the ionizing-radiation/DNA-damage response (via MTA1 and p53 regulation) is a real but context-specific physiological role, not the core ligase function. Retained as a non-core process annotation. - term: id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:19805145 qualifier: involved_in review: summary: IMP evidence that COP1 promotes proteasomal degradation of MTA1 (and itself via autoubiquitination). Captures COP1's positive role in proteasomal protein catabolism. action: ACCEPT reason: As an E3 ligase, COP1 positively drives proteasomal degradation of its substrates; this is well supported and consistent with its core function. supported_by: - reference_id: PMID:19805145 supporting_text: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IMP original_reference_id: PMID:19805145 qualifier: enables review: summary: IMP evidence for COP1 ubiquitin protein ligase activity toward MTA1, with RING mutants (C156S/C159S, C136S/C139S) abolishing MTA1 ubiquitination. Reinforces the core catalytic MF. action: ACCEPT reason: Mutagenesis-supported demonstration of RING-dependent ubiquitin ligase activity toward a substrate firmly supports GO:0061630 as a core molecular function. supported_by: - reference_id: PMID:19805145 supporting_text: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-264418 qualifier: located_in review: summary: Cytosol localization from Reactome (TAS), modeling COP1 nucleus-to-cytoplasm translocation. Consistent with the documented cytoplasmic pool of COP1. action: KEEP_AS_NON_CORE reason: Cytosolic localization is supported and COP1 acts in the cytoplasm on substrates like ACC1, but cytosol is a general location captured non-core; the nuclear speckle and CUL4A complex annotations are more functionally informative. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-264444 qualifier: located_in review: summary: Cytosol localization from Reactome (TAS), modeling COP1 autoubiquitination of phospho-COP1(Ser387). Consistent with the cytoplasmic pool of COP1. action: KEEP_AS_NON_CORE reason: Supported general cytosolic localization; retained as non-core in favor of the more informative nuclear speckle and complex-membership annotations. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-264458 qualifier: located_in review: summary: Cytosol localization from Reactome (TAS), modeling proteasome-mediated degradation of COP1. Consistent with the cytoplasmic pool of COP1. action: KEEP_AS_NON_CORE reason: Supported general cytosolic localization; retained as non-core in favor of more functionally informative location annotations. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-264418 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS), modeling COP1 nuclear-to-cytoplasmic translocation. Consistent with COP1's documented nuclear pool and nuclear-speckle localization. action: KEEP_AS_NON_CORE reason: COP1 is present in the nucleus; nucleoplasm is supported but is a general location. The nuclear speck annotation is the more specific and informative CC term for COP1. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-264435 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS), modeling dissociation of the COP1-p53 complex. Consistent with COP1's nuclear pool where it regulates p53. action: KEEP_AS_NON_CORE reason: Supported nuclear localization; nucleoplasm is a general location retained as non-core, with nuclear speck preferred as the specific informative term. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-349444 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS), modeling ATM phosphorylation of COP1 at Ser387 in the nucleus following DNA damage. Consistent with COP1's nuclear pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization; nucleoplasm is general and retained as non-core, with nuclear speck preferred as the specific informative term. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8952638 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle (NEDD8 transfer to the CRL4 complex). Consistent with COP1's nuclear CRL4-associated pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is a general CC term retained as non-core, with nuclear speck preferred. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8952639 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle (NEDD8:UBE2M binding the CRL4 complex). Consistent with COP1's nuclear CRL4 pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8955245 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (CAND1 binding the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8955285 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (COMMDs displacing CAND1 from the CRL4 complex). Consistent with COP1's nuclear CRL4 pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8956045 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (COP9 signalosome deneddylation of the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool. action: KEEP_AS_NON_CORE reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. core_functions: - description: RING-type E3 ubiquitin-protein ligase activity. COP1 transfers ubiquitin from an E2 conjugating enzyme to substrate lysines (EC 2.3.2.27), either as a stand-alone RING ligase or as part of a CUL4A-based cullin-RING ligase, driving substrate ubiquitination. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity directly_involved_in: - id: GO:0016567 label: protein ubiquitination locations: - id: GO:0016607 label: nuclear speck - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:12615916 supporting_text: The RING domain of huCOP1 displays ubiquitin ligase activity in an autoubiquitination assay in vitro - description: Substrate-recognition adaptor of a CUL4A-RING ubiquitin ligase. Via its C-terminal WD40 beta-propeller, COP1 binds degron motifs in substrate transcription factors and signaling proteins and recruits them to the DCX(DET1-COP1) CUL4A ligase for ubiquitination and proteasomal degradation; substrate selection is regulated by the pseudokinase adaptors TRIB1/TRIB2. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity directly_involved_in: - id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process - id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process locations: - id: GO:0016607 label: nuclear speck substrates: - id: UniProtKB:P05412 label: JUN - id: UniProtKB:P04637 label: TP53 - id: UniProtKB:P50549 label: ETV1 - id: UniProtKB:P31947 label: SFN in_complex: id: GO:0031464 label: Cul4A-RING E3 ubiquitin ligase complex supported_by: - reference_id: PMID:14739464 supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. - reference_id: PMID:21572435 supporting_text: COP1 is a tumour suppressor that causes degradation of ETS transcription factors. - reference_id: file:human/COP1/COP1-deep-research-falcon.md supporting_text: Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets. proposed_new_terms: [] suggested_questions: - question: Does COP1 possess intrinsic, stand-alone E3 ligase activity toward all of its reported substrates, or is its physiological activity primarily channeled through the CUL4A-RING (DCX DET1-COP1) module in which RBX1 is the catalytic RING? - question: How is COP1 substrate choice partitioned in vivo between its canonical WD40 degron binding and the TRIB1/TRIB2-mediated recruitment of non-canonical substrates such as C/EBPalpha? - question: Which COP1 substrates are physiologically dominant in specific tissues (e.g., ETS factors in prostate, ACC1 in liver, c-Jun/p53 broadly), and does this explain its context-dependent tumor-suppressor versus other roles? suggested_experiments: - description: Define the COP1 ubiquitinome in cells with degron-binding-deficient WD40 mutants versus RING-catalytic mutants (e.g., quantitative diGly/ubiquitin-remnant proteomics) to separate substrate-recognition from catalytic contributions. - description: Reconstitute the DCX(DET1-COP1) CUL4A-RBX1 complex in vitro and compare ubiquitination kinetics of c-Jun, p53, ETV1, SFN and ACC1 with and without TRIB1/TRIB2 to map the rules of substrate selectivity and adaptor competition. - description: Use structure-guided degron mutagenesis of individual substrates (and the COP1 WD40 pocket) combined with cellular stability assays to validate which proteins are direct COP1 substrates versus indirect. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:12615916 title: Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity. findings: [] - id: PMID:14739464 title: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. findings: [] - id: PMID:19805145 title: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. findings: [] - id: PMID:20843328 title: Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage. findings: [] - id: PMID:21572435 title: COP1 is a tumour suppressor that causes degradation of ETS transcription factors. findings: [] - id: PMID:21625211 title: COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ. findings: [] - id: PMID:25117710 title: Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. findings: [] - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35140242 title: Human transcription factor protein interaction networks. findings: [] - id: PMID:39920308 title: Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover. findings: [] - id: Reactome:R-HSA-264418 title: Translocation of COP1 from the nucleus to the cytoplasm findings: [] - id: Reactome:R-HSA-264435 title: Dissociation of the COP1-p53 complex findings: [] - id: Reactome:R-HSA-264444 title: Autoubiquitination of phospho-COP1(Ser-387 ) findings: [] - id: Reactome:R-HSA-264458 title: Proteasome mediated degradation of COP1 findings: [] - id: Reactome:R-HSA-349444 title: Phosphorylation of COP1 at Ser-387 by ATM findings: [] - id: Reactome:R-HSA-8952638 title: AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952639 title: NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955245 title: CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus findings: [] - id: Reactome:R-HSA-8955285 title: COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8956045 title: COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex findings: [] - id: file:human/COP1/COP1-deep-research-falcon.md title: Falcon deep research report for COP1 reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: "LLM-synthesized deep-research report (Edison/Falcon). Correctly scopes to human COP1/RFWD2 (Q8NHY2) and does NOT conflate it with plant Arabidopsis COP1; the MANDATORY VERIFICATION preamble appears heeded. Usefully consolidates the WD40 VP (Val-Pro) degron mechanism, the CRL4(COP1/DET1) substrate-receptor architecture, and ERK1/2-regulated nucleus/nuclear-envelope redistribution (Ouyang 2020). Treat substrate table skeptically: it mixes well-established substrates (p53, c-Jun, ETS factors, C/EBPalpha) with newer single-study or review-sourced claims (ACSL4, LUZP1, UTX/KDM6A, P57Kip2/CDKN1C, CDH18) and a c/EBPbeta-in-microglia claim (Ndoja 2020) that are not in the current GOA; these are not used to add or remove annotations here without primary verification. Primary PMIDs for the cited works were not all resolvable from the cache, so correctness is left UNVERIFIED pending PubMed checks."