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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. file:human/COP1/COP1-deep-research-falcon.md COP1 catalyzes the transfer of ubiquitin from E2 enzymes to specific substrate proteins, marking them for proteasomal degradation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | ACCEPT | 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. 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. Supporting Evidence: file:human/COP1/COP1-uniprot.txt Nucleus speckle. Cytoplasm. Note=In the nucleus, it forms nuclear speckles. |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: file:human/COP1/COP1-uniprot.txt E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. |
| GO:0005515 protein binding | IPI PMID:20843328 Nuclear export regulation of COP1 by 14-3-3Ο in response to ... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0005515 protein binding | IPI PMID:21572435 COP1 is a tumour suppressor that causes degradation of ETS t... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/COP1/COP1-deep-research-falcon.md Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets. |
| GO:0005515 protein binding | IPI PMID:21625211 COP9 signalosome subunit 6 stabilizes COP1, which functions ... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0005515 protein binding | IPI PMID:25117710 Phosphorylation of ETS1 by Src family kinases prevents its r... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: Generic "protein binding" from a high-throughput interactome study (interactor ETS2). Uninformative term derived from a proteome-scale screen. 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. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic "protein binding" from a high-throughput interactome study (interactors ETV5 and ETV1, both substrate ETS factors). Uninformative term. Reason: GO:0005515 is uninformative. The ETV1/ETV5 interactions reflect COP1 substrate recognition, already captured by the catabolic-process and substrate-recognition annotations. |
| GO:0005515 protein binding | IPI PMID:35140242 Human transcription factor protein interaction networks. | MARK AS OVER ANNOTATED | Summary: Generic "protein binding" from a transcription-factor interaction network study (interactor ETV5, a substrate ETS factor). Uninformative term. Reason: GO:0005515 conveys no specific molecular function; the ETV5 interaction reflects substrate recognition already captured elsewhere. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000107 | REMOVE | 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. 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. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | 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. Reason: COP1 directly mediates ubiquitination of multiple substrates (JUN, p53, MTA1, SFN, ETS factors, ACC1); protein ubiquitination is a core BP for this gene. Supporting Evidence: file:human/COP1/COP1-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:12615916 Characterization of human constitutive photomorphogenesis pr... | ACCEPT | 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. Reason: Direct in vitro demonstration of RING-dependent ubiquitin ligase activity firmly establishes GO:0061630 as a core molecular function of COP1. Supporting Evidence: PMID:12615916 The RING domain of huCOP1 displays ubiquitin ligase activity in an autoubiquitination assay in vitro |
| GO:0005737 cytoplasm | IC PMID:39920308 Mutations in the kinesin KIF12 promote MASH in humans and mi... | ACCEPT | 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. 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. Supporting Evidence: PMID:39920308 lipogenic enzyme turnover |
| GO:0006511 ubiquitin-dependent protein catabolic process | IMP PMID:39920308 Mutations in the kinesin KIF12 promote MASH in humans and mi... | ACCEPT | 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. 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. Supporting Evidence: PMID:39920308 lipogenic enzyme turnover |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IMP PMID:39920308 Mutations in the kinesin KIF12 promote MASH in humans and mi... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:39920308 lipogenic enzyme turnover |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-264444 | ACCEPT | 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). 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. Supporting Evidence: file:human/COP1/COP1-uniprot.txt EC=2.3.2.27 |
| GO:0005515 protein binding | IPI PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | IDA PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... | ACCEPT | 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. 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. Supporting Evidence: PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... | ACCEPT | 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. Reason: Experimentally demonstrated that COP1 (within the CUL4A complex) targets c-Jun for proteasomal degradation; this is a core biological process for COP1. Supporting Evidence: PMID:14739464 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. |
| GO:0005515 protein binding | IPI PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functio... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0010212 response to ionizing radiation | IDA PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functio... | KEEP AS NON CORE | 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. 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. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functio... | ACCEPT | Summary: IMP evidence that COP1 promotes proteasomal degradation of MTA1 (and itself via autoubiquitination). Captures COP1's positive role in proteasomal protein catabolism. Reason: As an E3 ligase, COP1 positively drives proteasomal degradation of its substrates; this is well supported and consistent with its core function. Supporting Evidence: PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. |
| GO:0061630 ubiquitin protein ligase activity | IMP PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functio... | ACCEPT | 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. Reason: Mutagenesis-supported demonstration of RING-dependent ubiquitin ligase activity toward a substrate firmly supports GO:0061630 as a core molecular function. Supporting Evidence: PMID:19805145 E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-264418 | KEEP AS NON CORE | Summary: Cytosol localization from Reactome (TAS), modeling COP1 nucleus-to-cytoplasm translocation. Consistent with the documented cytoplasmic pool of COP1. 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. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-264444 | KEEP AS NON CORE | Summary: Cytosol localization from Reactome (TAS), modeling COP1 autoubiquitination of phospho-COP1(Ser387). Consistent with the cytoplasmic pool of COP1. Reason: Supported general cytosolic localization; retained as non-core in favor of the more informative nuclear speckle and complex-membership annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-264458 | KEEP AS NON CORE | Summary: Cytosol localization from Reactome (TAS), modeling proteasome-mediated degradation of COP1. Consistent with the cytoplasmic pool of COP1. Reason: Supported general cytosolic localization; retained as non-core in favor of more functionally informative location annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-264418 | KEEP AS NON CORE | Summary: Nucleoplasm localization from Reactome (TAS), modeling COP1 nuclear-to-cytoplasmic translocation. Consistent with COP1's documented nuclear pool and nuclear-speckle localization. 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. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-264435 | KEEP AS NON CORE | Summary: Nucleoplasm localization from Reactome (TAS), modeling dissociation of the COP1-p53 complex. Consistent with COP1's nuclear pool where it regulates p53. Reason: Supported nuclear localization; nucleoplasm is a general location retained as non-core, with nuclear speck preferred as the specific informative term. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-349444 | KEEP AS NON CORE | 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. Reason: Supported nuclear localization; nucleoplasm is general and retained as non-core, with nuclear speck preferred as the specific informative term. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952638 | KEEP AS NON CORE | 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. Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is a general CC term retained as non-core, with nuclear speck preferred. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952639 | KEEP AS NON CORE | Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle (NEDD8:UBE2M binding the CRL4 complex). Consistent with COP1's nuclear CRL4 pool. Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8955245 | KEEP AS NON CORE | Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (CAND1 binding the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool. Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8955285 | KEEP AS NON CORE | 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. Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8956045 | KEEP AS NON CORE | 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. Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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