CUL3 is a cullin scaffold protein that forms CUL3-RBX1 cullin-RING E3 ubiquitin ligase complexes (CRL3). It bridges the RBX1/E2 ubiquitin-conjugating machinery with BTB/POZ-domain substrate-adaptor proteins (such as KEAP1, the KLHL family, KCTD family, SPOP, and RhoBTB proteins), enabling ubiquitination of adaptor-recruited substrates and, in many cases, their proteasome-mediated degradation. CRL3 activity is regulated by reversible neddylation/deneddylation of CUL3 and by the CAND1 and COP9 signalosome exchange machinery. Through its different substrate adaptors, CRL3 acts in the NRF2/KEAP1 oxidative-stress response, WNK-kinase-dependent renal electrolyte and blood-pressure homeostasis, mitotic progression and cytokinesis, cytoskeletal regulation, and many other substrate-specific processes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: CUL3 has nuclear localization in some contexts. Reason: Nuclear localization is plausible for CUL3, but the review treats it as a broad compartment annotation rather than a pathway-specific function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0160072 ubiquitin ligase complex scaffold activity | IBA GO_REF:0000033 | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0031625 ubiquitin protein ligase binding | IBA GO_REF:0000033 | MODIFY | Summary: CUL3 is associated with ubiquitin ligase machinery, but the binding term is less informative than its scaffold activity. Reason: The evidence supports CUL3 as the scaffold component of CRL3 ligase complexes; ubiquitin protein ligase binding is a lower-information proxy. The CRL3 complex cellular-component annotation should be handled separately rather than used as an MF replacement. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0000209 protein polyubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: CUL3-containing CRL3 complexes can mediate protein polyubiquitination. Reason: Protein polyubiquitination is a proximal CRL3 output, while substrate-specific downstream effects should be curated separately. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output |
| GO:0000278 mitotic cell cycle | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0000922 spindle pole | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: CUL3 has nuclear localization in some contexts. Reason: Nuclear localization is plausible for CUL3, but the review treats it as a broad compartment annotation rather than a pathway-specific function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: CUL3 has cytoplasmic localization in some contexts. Reason: Cytoplasmic localization is compatible with CUL3 CRL scaffold function and should not be over-interpreted as a specific pathway output. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: A pool of CUL3 localizes to the Golgi in the RhoBTB3-CUL3 adaptor context, so this localization is adaptor-specific rather than a core CUL3 cellular component. Reason: Direct evidence (PMID:24145166) shows a RhoBTB3/CUL3/RBX1 ligase pool at the Golgi, so the Golgi annotation is retained as non-core and adaptor-specific, consistent with the IDA Golgi annotation for the same term. Supporting Evidence: PMID:24145166 a pool of CUL3 was detected on the Golgi, as previously shown (Singer et al., 1999), where it colocalizes with RhoBTB3 and GCC185 (Fig. 4 A). file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005819 spindle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0031461 cullin-RING ubiquitin ligase complex | IEA GO_REF:0000120 | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031514 motile cilium | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: This subcellular-location IEA annotation places CUL3 in the motile cilium, but this is not an established core CUL3 cellular component. Reason: CUL3 has a role in ciliogenesis through ubiquitin-proteasome control of axoneme extension (PMID:25270598), but a stable motile cilium localization is not supported as a core CUL3 cellular component. The Falcon synthesis cautions that specific organellar/cytoskeletal localizations require source-level confirmation before retention. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000002 | MODIFY | Summary: CUL3 is associated with ubiquitin ligase machinery, but the binding term is less informative than its scaffold activity. Reason: The evidence supports CUL3 as the scaffold component of CRL3 ligase complexes; ubiquitin protein ligase binding is a lower-information proxy. The CRL3 complex cellular-component annotation should be handled separately rather than used as an MF replacement. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0098794 postsynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: This inter-ontology IEA annotation places CUL3 at the postsynapse, paired with the postsynaptic protein-catabolism process annotation, but it is not a core CUL3 location. Reason: Postsynaptic localization is an adaptor/substrate-specific context (CRL3 contributes to postsynaptic protein turnover) rather than a core CUL3 cellular component. It may be valid in neuronal contexts but should not be promoted to a core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:12609982 TIP120A associates with cullins and modulates ubiquitin liga... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:17543862 A Cul3-based E3 ligase removes Aurora B from mitotic chromos... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:18850735 Characterization of the human COP9 signalosome complex using... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:19427028 Cullin3-based polyubiquitination and p62-dependent aggregati... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:19617556 The human Dcn1-like protein DCNL3 promotes Cul3 neddylation ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:20389280 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquiti... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:20554658 Kelch-like homologue 9 mutation is associated with an early ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:21577200 Tumor-suppressor role for the SPOP ubiquitin ligase in signa... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:21828050 Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuate... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:22466964 NEDD8 links cullin-RING ubiquitin ligase function to the p97... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:22542517 KBTBD13 interacts with Cullin 3 to form a functional ubiquit... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:22632832 Adaptor protein self-assembly drives the control of a cullin... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:23563313 CCDC22 deficiency in humans blunts activation of proinflamma... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:23665031 Disease-causing mutations in KLHL3 impair its effect on WNK4... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:25619834 KLHL39 suppresses colon cancer metastasis by blocking KLHL20... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:26949739 Identification of Human Neuronal Protein Complexes Reveals B... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:27152988 The BTB domains of the potassium channel tetramerization dom... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:30190310 Dimerization quality control ensures neuronal development an... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:31652307 Kelch-like protein 5-mediated ubiquitination of lysine 183 p... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:37788672 Cryo-EM structure of the KLHL22 E3 ligase bound to an oligom... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:38225382 Systematic discovery of protein interaction interfaces using... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0001822 kidney development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0006954 inflammatory response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0007229 integrin-mediated signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0017145 stem cell division | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0030163 protein catabolic process | IEA GO_REF:0000107 | MODIFY | Summary: CUL3 participates in ubiquitin-dependent substrate catabolism rather than generic protein catabolism. Reason: The more informative process term is ubiquitin-dependent or proteasome-mediated ubiquitin-dependent protein catabolism. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process ubiquitin-dependent protein catabolic process Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output |
| GO:0030332 cyclin binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This ortholog-transferred IEA annotation reflects CRL3-mediated targeting of cyclin E for ubiquitination, but direct cyclin binding by CUL3 itself is not established. Reason: Cyclin E is a CRL3 substrate (recruited via the RhoBTB3 adaptor at the Golgi; PMID:24145166 and PMID:10500095), but substrate recognition is mediated by the BTB adaptor rather than by direct CUL3 cyclin binding. Annotating CUL3 with cyclin binding over-attributes adaptor/substrate recognition to the scaffold. Supporting Evidence: PMID:24145166 RhoBTB3 is part of a CUL3–ubiquitin ligase complex on the Golgi that targets Cyclin E. |
| GO:0040016 embryonic cleavage | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CUL3 self-association is plausible because CRL3 complexes adopt dimeric (2:2) architectures driven by BTB-adaptor dimerization, but this is a low-information binding term. Reason: Structural studies show CRL3 complexes assemble as 2:2 dimers (a BTB-adaptor dimer recruiting two CUL3-RBX1 arms), so CUL3 molecules are present within a dimeric complex. However, identical protein binding is a generic term that does not capture the informative scaffold function and is retained only as non-core. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md structural/biochemical studies support **2:2 assemblies** (BTB dimer with two CUL3 arms) in CRL3 complexes |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0140252 regulation protein catabolic process at postsynapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:22542517 KBTBD13 interacts with Cullin 3 to form a functional ubiquit... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:22632832 Adaptor protein self-assembly drives the control of a cullin... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:26399832 Cell-fate determination by ubiquitin-dependent regulation of... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:29249570 Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mam... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation, but this PMID is a review article and the IDA evidence code should be checked. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. PMID:29249570 is a review article, so the process annotation can be retained but the IDA evidence code is suspicious and may represent an evidence-code mismatch with the accompanying NAS row. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:29249570 Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mam... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:31898230 CRL3s: The BTB-CUL3-RING E3 Ubiquitin Ligases. | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:37628845 The Role of PIK3R1 in Metabolic Function and Insulin Sensiti... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:37788672 Cryo-EM structure of the KLHL22 E3 ligase bound to an oligom... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: CUL3 has nucleoplasmic/nuclear localization in some contexts. Reason: Nucleoplasmic localization is treated as a cautious cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0015630 microtubule cytoskeleton | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005794 Golgi apparatus | IDA PMID:24145166 Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation... | KEEP AS NON CORE | Summary: Direct evidence places a RhoBTB3-CUL3 ubiquitin ligase pool at the Golgi, but this is adaptor-specific rather than a core CUL3 location. Reason: PMID:24145166 supports a Golgi-localized RhoBTB3/CUL3/RBX1 complex involved in Cyclin E regulation. Retain the direct IDA annotation as non-core and adaptor-specific rather than treating Golgi localization as a general CUL3 cellular component. Supporting Evidence: PMID:24145166 RhoBTB3 is part of a CUL3–ubiquitin ligase complex on the Golgi that targets Cyclin E. PMID:24145166 a pool of CUL3 was detected on the Golgi, as previously shown (Singer et al., 1999), where it colocalizes with RhoBTB3 and GCC185 (Fig. 4 A). file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:29769719 KLHL22 activates amino-acid-dependent mTORC1 signalling to p... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0005515 protein binding | IPI PMID:15107402 RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligas... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:23453970 Impaired KLHL3-mediated ubiquitination of WNK4 causes human ... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:35862218 ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocort... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:35687106 ARMC5 is part of an RPB1-specific ubiquitin ligase implicate... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:38225631 ARMC5 controls the degradation of most Pol II subunits, and ... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:39504960 Redundant pathways for removal of defective RNA polymerase I... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:39667934 CRL3(ARMC5) ubiquitin ligase and Integrator phosphatase form... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:35687106 ARMC5 is part of an RPB1-specific ubiquitin ligase implicate... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:38225631 ARMC5 controls the degradation of most Pol II subunits, and ... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:39504960 Redundant pathways for removal of defective RNA polymerase I... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:39667934 CRL3(ARMC5) ubiquitin ligase and Integrator phosphatase form... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0034599 cellular response to oxidative stress | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:15601839 BTB protein Keap1 targets antioxidant transcription factor N... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0071230 cellular response to amino acid stimulus | IDA PMID:29769719 KLHL22 activates amino-acid-dependent mTORC1 signalling to p... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:29769719 KLHL22 activates amino-acid-dependent mTORC1 signalling to p... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:29769719 KLHL22 activates amino-acid-dependent mTORC1 signalling to p... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:23453970 Impaired KLHL3-mediated ubiquitination of WNK4 causes human ... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0005737 cytoplasm | IDA PMID:27708159 Insulin resistance and diabetes caused by genetic or diet-in... | ACCEPT | Summary: CUL3 has cytoplasmic localization in some contexts. Reason: Cytoplasmic localization is compatible with CUL3 CRL scaffold function and should not be over-interpreted as a specific pathway output. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:27708159 Insulin resistance and diabetes caused by genetic or diet-in... | ACCEPT | Summary: CUL3 complexes can mediate K48-linked ubiquitination in specific substrate contexts. Reason: K48-linked ubiquitination is a supported CRL3 output when the source evidence demonstrates degradative ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:27708159 Insulin resistance and diabetes caused by genetic or diet-in... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:1900076 regulation of cellular response to insulin stimulus | IDA PMID:27708159 Insulin resistance and diabetes caused by genetic or diet-in... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0032480 negative regulation of type I interferon production | IDA PMID:36394357 XAF1 prevents hyperproduction of type I interferon upon vira... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0160072 ubiquitin ligase complex scaffold activity | IDA PMID:36394357 XAF1 prevents hyperproduction of type I interferon upon vira... | ACCEPT | Summary: CUL3 provides ubiquitin ligase complex scaffold activity in CRL3 complexes. Reason: This is the core molecular function of CUL3: it scaffolds RBX1/E2 catalytic machinery and BTB substrate adaptors rather than acting primarily as the catalytic transferase itself. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | ACCEPT | Summary: CUL3 complexes can mediate K48-linked ubiquitination in specific substrate contexts. Reason: K48-linked ubiquitination is a supported CRL3 output when the source evidence demonstrates degradative ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:25684205 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP ... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0005515 protein binding | IPI PMID:28169274 Armc5 deletion causes developmental defects and compromises ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005886 plasma membrane | IDA PMID:19617556 The human Dcn1-like protein DCNL3 promotes Cul3 neddylation ... | MARK AS OVER ANNOTATED | Summary: This localization is not established as a core CUL3 cellular component in this review. Reason: The synthesis supports CRL3 complex membership with cautious cytoplasm/nucleus localization; membrane, Golgi, exosome, sperm flagellum, or other specific locations require source-level confirmation before retention. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0005515 protein binding | IPI PMID:26906416 Characterization of the mammalian family of DCN-type NEDD8 E... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:24192928 Oncogenic function of SCCRO5/DCUN1D5 requires its Neddylatio... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0000209 protein polyubiquitination | IDA PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | ACCEPT | Summary: CUL3-containing CRL3 complexes can mediate protein polyubiquitination. Reason: Protein polyubiquitination is a proximal CRL3 output, while substrate-specific downstream effects should be curated separately. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output |
| GO:0005515 protein binding | IPI PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | MODIFY | Summary: CUL3 is associated with ubiquitin ligase machinery, but the binding term is less informative than its scaffold activity. Reason: The evidence supports CUL3 as the scaffold component of CRL3 ligase complexes; ubiquitin protein ligase binding is a lower-information proxy. The CRL3 complex cellular-component annotation should be handled separately rather than used as an MF replacement. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0051865 protein autoubiquitination | IDA PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | UNDECIDED | Summary: The source supports Cul3-dependent ubiquitination by assembled BTB-Cul3-Roc1 ligases, but it is unclear whether this row represents CUL3 autoubiquitination specifically. Reason: CUL3 is the scaffold in the tested ligase assemblies, while ubiquitin transfer is mediated by the assembled E3 complex. Source-level review is needed before retaining protein autoubiquitination as a direct CUL3 process annotation. Supporting Evidence: PMID:14528312 Here, we show that Cul3, but not other cullins, binds directly to multiple BTB domains through a conserved amino-terminal domain. PMID:14528312 In vitro, Cul3 promoted ubiquitination of Caenorhabditis elegans MEI-1, a katanin-like protein whose degradation requires the function of both Cul3 and BTB protein MEL-26. |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | MODIFY | Summary: The ubiquitin ligase activity belongs to the assembled CRL3 complex; CUL3 itself is best represented as the scaffold. Reason: For CUL3, ubiquitin ligase complex scaffold activity is the more accurate molecular function than a catalytic ubiquitin-protein transferase term. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0031208 POZ domain binding | IDA PMID:14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubi... | ACCEPT | Summary: CUL3 binds BTB/POZ-domain substrate adaptors in CRL3 complexes. Reason: POZ/BTB-domain adaptor binding is part of the core CRL3 scaffold architecture. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. |
| GO:0000922 spindle pole | IDA PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005634 nucleus | IDA PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | ACCEPT | Summary: CUL3 has nuclear localization in some contexts. Reason: Nuclear localization is plausible for CUL3, but the review treats it as a broad compartment annotation rather than a pathway-specific function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005813 centrosome | IDA PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0016567 protein ubiquitination | IDA PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0072686 mitotic spindle | IDA PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:1901992 positive regulation of mitotic cell cycle phase transition | IMP PMID:23213400 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquityl... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:29276004 Missense Variants in RHOBTB2 Cause a Developmental and Epile... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005737 cytoplasm | IDA PMID:28395323 Defining the human sperm microtubulome: an integrated genomi... | ACCEPT | Summary: CUL3 has cytoplasmic localization in some contexts. Reason: Cytoplasmic localization is compatible with CUL3 CRL scaffold function and should not be over-interpreted as a specific pathway output. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0036126 sperm flagellum | IDA PMID:28395323 Defining the human sperm microtubulome: an integrated genomi... | MARK AS OVER ANNOTATED | Summary: This localization is not established as a core CUL3 cellular component in this review. Reason: The synthesis supports CRL3 complex membership with cautious cytoplasm/nucleus localization; membrane, Golgi, exosome, sperm flagellum, or other specific locations require source-level confirmation before retention. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0031398 positive regulation of protein ubiquitination | IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0031648 protein destabilization | IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:22748208 A homozygous mutation in KCTD7 links neuronal ceroid lipofus... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:23776465 Myeloma overexpressed 2 (Myeov2) regulates L11 subnuclear lo... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:26399832 Cell-fate determination by ubiquitin-dependent regulation of... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8932327 | ACCEPT | Summary: CUL3 can be represented in cytosolic CRL3 pathway contexts. Reason: Cytosolic localization is compatible with CUL3 scaffold biology, although repetitive Reactome cytosol rows are left mostly pending for source-level review. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952631 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9712274 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755505 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755507 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758090 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9759169 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9759172 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766645 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766656 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766677 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9766687 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005112 Notch binding | IPI PMID:25401743 KCTD10 is involved in the cardiovascular system and Notch si... | MARK AS OVER ANNOTATED | Summary: This annotation derives from a study of KCTD10 (a CUL3 BTB adaptor) in Notch signaling during embryonic development, but direct CUL3-Notch binding is not the core scaffold function. Reason: PMID:25401743 links the CUL3-KCTD10 module to Notch signaling, but substrate recognition is mediated by the KCTD10 adaptor rather than direct CUL3-Notch binding. Notch binding is a substrate-contextual, low-information MF that over-attributes adaptor/substrate recognition to the CUL3 scaffold. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:25401743 KCTD10 is involved in the cardiovascular system and Notch si... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0005515 protein binding | IPI PMID:26334369 Structural Insights into KCTD Protein Assembly and Cullin3 R... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:27561354 Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnov... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:27561354 Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnov... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0071630 nuclear protein quality control by the ubiquitin-proteasome system | IDA PMID:27561354 Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnov... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | IDA PMID:10500095 Cullin-3 targets cyclin E for ubiquitination and controls S ... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:25270598 Ubiquitin-proteasome system controls ciliogenesis at the ini... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005515 protein binding | IPI PMID:21778237 COMMD1 (copper metabolism MURR1 domain-containing protein 1)... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635854 | ACCEPT | Summary: CUL3 is represented as nucleoplasmic in Reactome GLI/Hedgehog CRL3 pathway reactions. Reason: Nuclear/nucleoplasmic localization is plausible for CUL3 in specific pathway contexts (e.g. SPOP-CUL3 acting on GLI transcription factors); this is treated as a cautious broad-compartment cellular component annotation consistent with the other accepted nucleus/nucleoplasm rows. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635855 | ACCEPT | Summary: CUL3 is represented as nucleoplasmic in Reactome GLI/Hedgehog CRL3 pathway reactions. Reason: Nuclear/nucleoplasmic localization is plausible for CUL3 in specific pathway contexts (e.g. SPOP-CUL3 acting on GLI transcription factors); this is treated as a cautious broad-compartment cellular component annotation consistent with the other accepted nucleus/nucleoplasm rows. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635856 | ACCEPT | Summary: CUL3 is represented as nucleoplasmic in Reactome GLI/Hedgehog CRL3 pathway reactions. Reason: Nuclear/nucleoplasmic localization is plausible for CUL3 in specific pathway contexts (e.g. SPOP-CUL3 acting on GLI transcription factors); this is treated as a cautious broad-compartment cellular component annotation consistent with the other accepted nucleus/nucleoplasm rows. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0007080 mitotic metaphase chromosome alignment | IMP PMID:17543862 A Cul3-based E3 ligase removes Aurora B from mitotic chromos... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0007080 mitotic metaphase chromosome alignment | IMP PMID:19995937 The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midz... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0045842 positive regulation of mitotic metaphase/anaphase transition | IMP PMID:17543862 A Cul3-based E3 ligase removes Aurora B from mitotic chromos... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:24768539 K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ub... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: This localization is not established as a core CUL3 cellular component in this review. Reason: The synthesis supports CRL3 complex membership with cautious cytoplasm/nucleus localization; membrane, Golgi, exosome, sperm flagellum, or other specific locations require source-level confirmation before retention. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: This localization is not established as a core CUL3 cellular component in this review. Reason: The synthesis supports CRL3 complex membership with cautious cytoplasm/nucleus localization; membrane, Golgi, exosome, sperm flagellum, or other specific locations require source-level confirmation before retention. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:19158078 Control of rapsyn stability by the CUL-3-containing E3 ligas... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:22578813 Translational homeostasis via the mRNA cap-binding protein, ... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:23453970 Impaired KLHL3-mediated ubiquitination of WNK4 causes human ... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:23576762 Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis v... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0005515 protein binding | IPI PMID:18397884 Regulation of TIP60 by ATF2 modulates ATM activation. | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1504190 | ACCEPT | Summary: CUL3 can be represented in cytosolic CRL3 pathway contexts. Reason: Cytosolic localization is compatible with CUL3 scaffold biology, although repetitive Reactome cytosol rows are left mostly pending for source-level review. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1504193 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1504213 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5658424 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952630 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018778 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018787 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9706390 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9929484 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9929486 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9929490 | ACCEPT | Summary: CUL3 is represented as cytosolic in Reactome CRL3 pathway reactions. Reason: Cytosolic localization is compatible with CUL3 CRL3 scaffold function; this is a broad-compartment cellular component annotation consistent with the other accepted cytosol/cytoplasm rows for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Cytosol/cytoplasm and nucleus (plausible but evidence here is limited):** |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:23455478 Ubiquitylation-dependent localization of PLK1 in mitosis. | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0000209 protein polyubiquitination | IDA PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | ACCEPT | Summary: CUL3-containing CRL3 complexes can mediate protein polyubiquitination. Reason: Protein polyubiquitination is a proximal CRL3 output, while substrate-specific downstream effects should be curated separately. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | MODIFY | Summary: The ubiquitin ligase activity belongs to the assembled CRL3 complex; CUL3 itself is best represented as the scaffold. Reason: For CUL3, ubiquitin ligase complex scaffold activity is the more accurate molecular function than a catalytic ubiquitin-protein transferase term. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0005515 protein binding | IPI PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0031208 POZ domain binding | IDA PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | ACCEPT | Summary: CUL3 binds BTB/POZ-domain substrate adaptors in CRL3 complexes. Reason: POZ/BTB-domain adaptor binding is part of the core CRL3 scaffold architecture. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0032467 positive regulation of cytokinesis | IMP PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:19261606 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is requi... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | MODIFY | Summary: The ubiquitin ligase activity belongs to the assembled CRL3 complex; CUL3 itself is best represented as the scaffold. Reason: For CUL3, ubiquitin ligase complex scaffold activity is the more accurate molecular function than a catalytic ubiquitin-protein transferase term. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:15983046 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor prote... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0006513 protein monoubiquitination | IDA PMID:22358839 Ubiquitin-dependent regulation of COPII coat size and functi... | KEEP AS NON CORE | Summary: Some CUL3-adaptor complexes mediate monoubiquitination rather than degradative polyubiquitination. Reason: Protein monoubiquitination is a valid adaptor/substrate-specific CUL3 output, but it is not the main degradative CRL3 process summarized as core. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IDA PMID:22358839 Ubiquitin-dependent regulation of COPII coat size and functi... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0007229 integrin-mediated signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0017145 stem cell division | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:22358839 Ubiquitin-dependent regulation of COPII coat size and functi... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0040016 embryonic cleavage | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: This automated or broad pathway annotation is downstream of CUL3-adaptor substrate biology rather than a core CUL3 function. Reason: The Falcon synthesis warns against promoting broad pathway, development, disease, or phenotype terms to core CUL3 annotations without direct mechanistic evidence at the annotated pathway node. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0048208 COPII vesicle coating | IMP PMID:22358839 Ubiquitin-dependent regulation of COPII coat size and functi... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0005515 protein binding | IPI PMID:18826954 SCCRO (DCUN1D1) is an essential component of the E3 complex ... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | MODIFY | Summary: The ubiquitin ligase activity belongs to the assembled CRL3 complex; CUL3 itself is best represented as the scaffold. Reason: For CUL3, ubiquitin ligase complex scaffold activity is the more accurate molecular function than a catalytic ubiquitin-protein transferase term. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0016477 cell migration | IMP PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0016567 protein ubiquitination | IDA PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0035024 negative regulation of Rho protein signal transduction | IMP PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043149 stress fiber assembly | IMP PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:19782033 Cullin mediates degradation of RhoA through evolutionarily c... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:20389280 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquiti... | ACCEPT | Summary: CUL3-containing CRL3 complexes support ubiquitin-dependent proteasomal substrate degradation. Reason: Proteasome-mediated ubiquitin-dependent catabolism is a canonical proximal output for many CRL3 substrate-adaptor complexes, while non-degradative ubiquitination remains a caveat for some substrates. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Proteasomal targeting is a canonical outcome for many CRLs, and reviews explicitly describe substrate ubiquitination “for proteasomal degradation” as a CRL3 output file:human/CUL3/CUL3-deep-research-falcon.md not all CUL3-dependent ubiquitination is degradative |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:20389280 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquiti... | MODIFY | Summary: The ubiquitin ligase activity belongs to the assembled CRL3 complex; CUL3 itself is best represented as the scaffold. Reason: For CUL3, ubiquitin ligase complex scaffold activity is the more accurate molecular function than a catalytic ubiquitin-protein transferase term. Proposed replacements: ubiquitin ligase complex scaffold activity Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md evidence best supports a CUL3 annotation consistent with **“ubiquitin ligase complex scaffold activity”** / **E3 ligase scaffold** rather than “ubiquitin-protein transferase activity” (which is catalytic and typically attributed to the E2/E3 catalytic machinery rather than the scaffold) |
| GO:0005827 polar microtubule | IDA PMID:19995937 The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midz... | KEEP AS NON CORE | Summary: This cytoskeleton/centrosome/spindle localization is likely context-specific for CUL3-adaptor biology. Reason: Centrosome, spindle, and cytoskeletal annotations may be valid in specific mitotic or adaptor contexts but are not the core CUL3 location. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md **Membrane/centrosome/cytoskeleton claims require caution:** file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0016567 protein ubiquitination | IDA PMID:17543862 A Cul3-based E3 ligase removes Aurora B from mitotic chromos... | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0016567 protein ubiquitination | IDA PMID:19995937 The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midz... | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0016567 protein ubiquitination | IDA PMID:20389280 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquiti... | ACCEPT | Summary: CUL3-containing CRL3 complexes mediate protein ubiquitination. Reason: Protein ubiquitination is the proximal biological process output of CUL3 scaffold function in CRL3 E3 ligase complexes. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md Multiple CRL3 systems demonstrate ubiquitination output; for example, CRL3^KLHL22 assays support ubiquitination activity dependence on CUL3 structural motifs |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:17543862 A Cul3-based E3 ligase removes Aurora B from mitotic chromos... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:19995937 The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midz... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:20389280 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquiti... | ACCEPT | Summary: CUL3 is a core component of Cul3-RING ubiquitin ligase complexes. Reason: CRL3 complex membership is a core cellular component annotation for CUL3. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md CUL3 is the **central scaffold** of CRL3 ubiquitin ligases, bridging (i) a **RING protein (RBX1)** that recruits E2~ubiquitin and (ii) **BTB-domain substrate adaptor/receptor proteins** that recruit specific substrates. file:human/CUL3/CUL3-deep-research-falcon.md direct structural evidence places CUL3 in CRL3 assemblies containing RBX1 and BTB adaptors |
| GO:0005515 protein binding | IPI PMID:18573101 KCTD5, a putative substrate adaptor for cullin3 ubiquitin li... | MARK AS OVER ANNOTATED | Summary: This is a generic protein binding annotation supported by a pairwise or high-throughput interaction; the informative CUL3 interactions (BTB/POZ adaptor binding, RBX1, regulators) are captured by more specific terms. Reason: Bare protein binding (GO:0005515) is low-information and should not be retained as a core CUL3 molecular function. CUL3's biologically meaningful interactions with BTB/POZ-domain substrate adaptors are already captured by POZ domain binding (GO:0031208), and its scaffold role by ubiquitin ligase complex scaffold activity (GO:0160072). Many of these rows derive from large-scale interactome or affinity screens and capture adaptor, substrate, or non-specific partners rather than a distinct CUL3 function. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md Avoid annotating CUL3 with generic “protein binding” or “ubiquitin protein ligase binding” unless the evidence is specifically required for MF, because these terms are often **low-information** and may reflect experimental detection rather than biological specificity. |
| GO:0000082 G1/S transition of mitotic cell cycle | TAS PMID:8681378 cul-1 is required for cell cycle exit in C. elegans and iden... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0008284 positive regulation of cell population proliferation | TAS PMID:9733711 Cloning and expression analysis of a novel salicylate suppre... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
| GO:0097193 intrinsic apoptotic signaling pathway | TAS PMID:8681378 cul-1 is required for cell cycle exit in C. elegans and iden... | KEEP AS NON CORE | Summary: This is a substrate-, adaptor-, or phenotype-specific downstream process for CUL3. Reason: The process can be retained as non-core where source evidence supports a specific CUL3-adaptor substrate context, but the core CUL3 function remains CRL3 scaffold-mediated ubiquitination. Supporting Evidence: file:human/CUL3/CUL3-deep-research-falcon.md oxidative stress response, blood pressure/electrolyte phenotypes, neurodevelopmental phenotypes, or cancer-associated phenotypes can be downstream of CUL3-dependent substrate regulation. These should not be treated as core CUL3 BP terms without direct mechanistic evidence that CUL3’s scaffold activity is required in the specific pathway node being annotated. |
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Download this section (compressed HTML)Q: Which generic protein-binding rows correspond to direct CUL3-BTB adaptor, RBX1, substrate, or regulator interactions that should be converted to more informative terms?
Q: Which substrate-specific pathway and phenotype annotations have direct CUL3 scaffold-dependent evidence rather than adaptor/substrate or disease-context inference?
Q: Which annotations should distinguish CUL3's core scaffold activity from CRL3 regulation by neddylation, deneddylation, CSN, and CAND1-mediated adaptor exchange?
Experiment: Review CRL3 adaptor modules one at a time, separating CUL3 scaffold activity from adaptor-specific substrate recognition and downstream pathway outputs.
Experiment: Prioritize source-level review of membrane, Golgi, centrosome, spindle, cytoskeleton, and synaptic localization claims before retaining them as CUL3 cellular component annotations.
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