id: Q86VP6 gene_symbol: CAND1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'CAND1 (Cullin-Associated and Neddylation-Dissociated 1; originally TIP120A) is a large HEAT-repeat protein that regulates the assembly and dynamic remodeling of cullin-RING E3 ubiquitin ligases (CRLs), most prominently SCF (SKP1-CUL1-F-box) complexes. CAND1 binds the unneddylated CUL1-RBX1 (ROC1) catalytic core and clamps around the cullin scaffold, with a beta-hairpin occupying the SKP1-adaptor binding site so that SKP1/F-box subunits cannot bind simultaneously. Rather than acting as a static inhibitor, CAND1 functions as a substrate-receptor (F-box protein) exchange factor: it accelerates dissociation of existing SCF complexes and promotes exchange of F-box receptors, allowing a common cullin-RBX1 core to be redistributed among many different substrate receptors. Its action is reciprocally coupled to the neddylation cycle - CUL1 neddylation (and binding of SKP1/F-box plus substrate) dissociates CAND1, while deneddylation regenerates the CAND1-bound state. Through this exchange activity CAND1 is a positive regulator of overall CRL activity in vivo and acts on cullins broadly, not just CUL1. CAND1 is predominantly cytoplasmic with nuclear pools, and it is a regulator/assembly factor rather than a catalytic ubiquitin-transfer enzyme.' alternative_products: - name: '1' id: Q86VP6-1 - name: '2' id: Q86VP6-2 sequence_note: VSP_013948 - name: '3' id: Q86VP6-3 sequence_note: VSP_013947, VSP_013949, VSP_013950 existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: CAND1 has nuclear pools (e.g., acting on nuclear CRL4) in addition to its predominant cytoplasmic localization; nuclear activity is supported. action: ACCEPT reason: CAND1 regulates nuclear CRLs and is detected in the nucleus; nuclear localization is well supported, though CAND1 is predominantly cytoplasmic. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0010265 label: SCF complex assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Regulation of SCF complex assembly via F-box exchange is the core biological process for CAND1 and is strongly supported experimentally. action: ACCEPT reason: CAND1 binds unneddylated CUL1-RBX1 and regulates SCF assembly/disassembly, promoting F-box receptor exchange; this is its defining role. supported_by: - reference_id: PMID:12504026 supporting_text: CAND1 regulates the formation of the SCF complex reference_section_type: ABSTRACT - reference_id: PMID:15537541 supporting_text: forms a tight complex with the Cul1-Roc1 reference_section_type: ABSTRACT - term: id: GO:0016567 label: protein ubiquitination evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: CAND1 is involved in (regulates) CRL-mediated protein ubiquitination as an assembly/exchange factor, not as a catalytic enzyme; involved_in is appropriate. action: ACCEPT reason: By controlling SCF/CRL assembly and F-box exchange, CAND1 modulates ubiquitination of CRL substrates; the regulatory involvement is well supported. supported_by: - reference_id: PMID:12609982 supporting_text: TIP120A greatly reduced the ubiquitination of phosphorylated reference_section_type: ABSTRACT - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Nuclear localization consistent with CAND1 regulating nuclear CRLs. action: ACCEPT reason: Nuclear pools of CAND1 are supported; localization annotation is appropriate. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: CAND1 is predominantly cytoplasmic, where most cullins reside; this is a core localization. action: ACCEPT reason: Directly supported - CAND1 is predominantly cytoplasmically localized with cullins as major interactors. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0010265 label: SCF complex assembly evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Same core process as the IBA annotation; CAND1 regulates SCF assembly via F-box exchange. action: ACCEPT reason: Strongly supported core function consistent with InterPro/experimental evidence. supported_by: - reference_id: PMID:12504026 supporting_text: CAND1 regulates the formation of the SCF complex reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12504026 qualifier: enables review: summary: The underlying interaction is CAND1 binding unneddylated CUL1, which is captured by the specific CRL-complex and SCF-assembly terms; bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic; CAND1-CUL1 binding is represented by more informative terms in this review. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12609982 qualifier: enables review: summary: The underlying interaction is CAND1 (TIP120A) with cullins/Rbx1; captured by specific CRL terms. Bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic; the cullin interactions are represented by specific terms. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15537541 qualifier: enables review: summary: The interaction is CAND1-CUL1-ROC1 (structural); captured by specific CRL/SCF terms. Bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic; the structural CAND1-CUL1-ROC1 interaction is represented by specific terms. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16861300 qualifier: enables review: summary: The interaction concerns the cullin-CAND1 complex and its dissociation; captured by specific CRL terms. Bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic for this CRL-regulatory interaction. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17290223 qualifier: enables review: summary: Generic protein-binding annotation; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding from a non-mechanistic interaction record is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21145461 qualifier: enables review: summary: From systematic CRL-network proteomics; the relevant CAND1 biology is captured by CRL-complex/SCF-assembly terms, so bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic; CRL-network membership is better represented by specific terms. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25435324 qualifier: enables review: summary: Generic protein-binding annotation from an importin-beta transport-mechanism study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: Generic protein-binding annotation from a quantitative interactome study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding from a high-throughput interactome is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30021884 qualifier: enables review: summary: Generic protein-binding annotation from a histone crosslinking-MS study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding from a high-throughput interactome is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34591642 qualifier: enables review: summary: Generic protein-binding annotation from a head-and-neck-cancer network map; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding from a high-throughput interactome is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Generic protein-binding annotation from a multimodal cell-map study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding from a high-throughput interactome is not informative. - term: id: GO:0017025 label: TBP-class protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: This derives from the historical TIP120A characterization as a TBP-interacting transcriptional regulator and predates the CRL-assembly paradigm; it is not the consensus core function of CAND1. action: MARK_AS_OVER_ANNOTATED reason: TBP binding reflects early TIP120A literature; the established CAND1 function is CRL/SCF assembly regulation, and TBP-class binding is not part of that core. supported_by: - reference_id: PMID:10581176 supporting_text: TBP-interacting protein 120A (TIP120A) is a novel eukaryotic transcriptional reference_section_type: ABSTRACT - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Transcriptional activation derives from the historical TIP120A work and is not the established core CAND1 function (CRL assembly regulation). action: MARK_AS_OVER_ANNOTATED reason: This is a historical/secondary TIP120A-era function and an indirect/broad effect, not the consensus CAND1 role. supported_by: - reference_id: PMID:10581176 supporting_text: differentiation-related gene expression reference_section_type: ABSTRACT - term: id: GO:0045899 label: positive regulation of RNA polymerase II transcription preinitiation complex assembly evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Derives from historical TIP120A transcription work; not the established core CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Historical/secondary TIP120A-era function, not the consensus CRL-assembly role. supported_by: - reference_id: PMID:10581176 supporting_text: TBP-interacting protein 120A (TIP120A) is a novel eukaryotic transcriptional reference_section_type: ABSTRACT - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Nucleoplasmic localization is consistent with CAND1 nuclear pools acting on nuclear CRLs. action: ACCEPT reason: Supported by immunofluorescence localization and consistent with CAND1's nuclear CRL-regulatory role. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Cytosolic localization is the predominant CAND1 localization and a core functional compartment. action: ACCEPT reason: Directly supported - CAND1 is predominantly cytoplasmic with cullins as major interactors. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27542266 qualifier: enables review: summary: Generic protein-binding annotation from a DCUN1D3/SCF-SKP2 study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26906416 qualifier: enables review: summary: Generic protein-binding annotation from a DCN-type NEDD8 E3 ligase study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24192928 qualifier: enables review: summary: Generic protein-binding annotation from a SCCRO5/DCUN1D5 study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26030138 qualifier: enables review: summary: Generic protein-binding annotation from a CSB co-purification study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8955245 qualifier: located_in review: summary: Nucleoplasmic localization (CAND1 binds nuclear CRL4) is consistent with CAND1 nuclear function. action: ACCEPT reason: Supported by CAND1 regulation of nuclear CRLs (CRL4) per Reactome and consistent with nuclear pools. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8955285 qualifier: located_in review: summary: Nucleoplasmic localization linked to displacement of CAND1 from nuclear CRL4; consistent with CAND1 nuclear function. action: ACCEPT reason: Consistent with CAND1 acting on nuclear CRLs. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-6798748 qualifier: located_in review: summary: Extracellular localization derives from a generic granule-exocytosis Reactome pathway and is not a functional site for this intracellular CRL-assembly factor. action: MARK_AS_OVER_ANNOTATED reason: CAND1 is an intracellular cullin regulator; extracellular assignment reflects bulk granule/exocytosis pathway annotation, not biology. - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-6800434 qualifier: located_in review: summary: Extracellular localization from a generic granule-exocytosis Reactome pathway; not a functional site for CAND1. action: MARK_AS_OVER_ANNOTATED reason: CAND1 is an intracellular cullin regulator; extracellular assignment is not biologically meaningful here. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5691131 qualifier: located_in review: summary: Cytosolic localization where CAND1 binds CUL1; a core compartment. action: ACCEPT reason: Consistent with the predominant cytoplasmic localization of CAND1 and its cullin binding. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Cytosolic localization where CAND1 binds cytosolic CRL E3 ligases; core compartment. action: ACCEPT reason: Consistent with CAND1's predominant cytoplasmic localization and CRL binding. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Cytosolic localization linked to displacement of CAND1 from cytosolic CRLs; core compartment. action: ACCEPT reason: Consistent with CAND1's predominant cytoplasmic localization and CRL binding. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0034774 label: secretory granule lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-6798748 qualifier: located_in review: summary: Secretory granule lumen derives from a bulk granule-exocytosis Reactome pathway and is not a functional location for this cytosolic/nuclear CRL regulator. action: MARK_AS_OVER_ANNOTATED reason: Not biologically meaningful for CAND1; reflects bulk pathway-level annotation. - term: id: GO:1904813 label: ficolin-1-rich granule lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-6800434 qualifier: located_in review: summary: Ficolin-1-rich granule lumen derives from a bulk granule-exocytosis Reactome pathway; not a functional location for CAND1. action: MARK_AS_OVER_ANNOTATED reason: Not biologically meaningful for CAND1; reflects bulk pathway-level annotation. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: Detection in exosome proteomics is a high-throughput finding and not a functional localization for this intracellular CRL regulator. action: MARK_AS_OVER_ANNOTATED reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action. - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: Generic membrane assignment from an NK-cell membrane-proteome survey; not a functional localization for the soluble cytosolic/nuclear CAND1. action: MARK_AS_OVER_ANNOTATED reason: Bulk membrane-proteome detection is uninformative and likely co-isolation; CAND1 is not a membrane protein. - term: id: GO:0005634 label: nucleus evidence_type: HDA original_reference_id: PMID:21630459 qualifier: located_in review: summary: High-throughput sperm-nucleus proteomic detection; nuclear localization is independently supported for CAND1. action: ACCEPT reason: Nuclear localization is genuine for CAND1 (nuclear CRL regulation); consistent with the other accepted nucleus annotations. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Exosome proteomics detection; not a functional localization for CAND1. action: MARK_AS_OVER_ANNOTATED reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:20458337 qualifier: located_in review: summary: Exosome proteomics detection; not a functional localization for CAND1. action: MARK_AS_OVER_ANNOTATED reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:21249194 qualifier: located_in review: summary: Nuclear localization is supported; CAND1 also has nuclear pools though it is predominantly cytoplasmic. action: ACCEPT reason: Consistent with CAND1 acting on nuclear CRLs; nuclear localization is supported. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21249194 qualifier: located_in review: summary: Cytoplasmic localization is the predominant and core localization of CAND1. action: ACCEPT reason: Directly demonstrated - CAND1 is predominantly cytoplasmically localized. supported_by: - reference_id: PMID:21249194 supporting_text: CAND1 is predominantly cytoplasmically localized reference_section_type: ABSTRACT - term: id: GO:0010265 label: SCF complex assembly evidence_type: IDA original_reference_id: PMID:15537541 qualifier: involved_in review: summary: Structural study of CAND1-CUL1-ROC1 directly supports CAND1's role in regulating SCF complex assembly. action: ACCEPT reason: The crystal structure shows CAND1 clamping CUL1 and blocking the adaptor site, mechanistically explaining its control of SCF assembly. supported_by: - reference_id: PMID:15537541 supporting_text: forms a tight complex with the Cul1-Roc1 reference_section_type: ABSTRACT - reference_id: PMID:15537541 supporting_text: occupies the adaptor binding site on reference_section_type: ABSTRACT - term: id: GO:0010265 label: SCF complex assembly evidence_type: IDA original_reference_id: PMID:21249194 qualifier: involved_in review: summary: In vivo evidence that CAND1 regulates cullin-RING ligase assembly/activity by promoting substrate-receptor exchange. action: ACCEPT reason: CAND1 functions as a positive regulator of CRL activity in vivo via F-box exchange, supporting its role in SCF assembly. supported_by: - reference_id: PMID:21249194 supporting_text: positive regulator of Cullin ligases in vivo reference_section_type: ABSTRACT - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:15537541 qualifier: involved_in review: summary: CAND1 regulates (is involved in) CRL-mediated ubiquitination as an assembly factor; involved_in is appropriate (CAND1 is not catalytic). action: ACCEPT reason: Through control of SCF assembly CAND1 modulates substrate ubiquitination; the regulatory involvement is supported. supported_by: - reference_id: PMID:15537541 supporting_text: regulatory mechanisms for the reference_section_type: ABSTRACT - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:21249194 qualifier: involved_in review: summary: CAND1 regulates CRL-mediated ubiquitination in vivo via F-box exchange; involved_in is appropriate. action: ACCEPT reason: CAND1 is a positive regulator of CRL ligase activity in vivo, modulating substrate ubiquitination. supported_by: - reference_id: PMID:21249194 supporting_text: positive regulator of Cullin ligases in vivo reference_section_type: ABSTRACT - term: id: GO:0031461 label: cullin-RING ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:15537541 qualifier: part_of review: summary: CAND1 forms a defined complex with the CUL1-ROC1 (RBX1) cullin-RING core; part_of the CRL complex (in its unneddylated/exchange-competent state) is supported. action: ACCEPT reason: The CAND1-CUL1-ROC1 crystal structure directly demonstrates CAND1 as part of a cullin-RING complex. supported_by: - reference_id: PMID:15537541 supporting_text: forms a tight complex with the Cul1-Roc1 reference_section_type: ABSTRACT - term: id: GO:0031461 label: cullin-RING ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:21249194 qualifier: part_of review: summary: CAND1 associates with cullin-RING complexes in vivo (binding unneddylated cullins); part_of is supported. action: ACCEPT reason: Cullins are the major CAND1 interactors in cells, consistent with CAND1 being part of cullin-RING complexes. supported_by: - reference_id: PMID:21249194 supporting_text: cullins are the major reference_section_type: ABSTRACT - term: id: GO:0031461 label: cullin-RING ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:22405651 qualifier: part_of review: summary: CAND1 is part of cullin-RING ligase complexes; consistent with its broad cullin-binding and CRL-regulatory role. action: ACCEPT reason: Supported as CAND1 being part of cullin-RING complexes. supported_by: - reference_id: PMID:21249194 supporting_text: cullins are the major reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18826954 qualifier: enables review: summary: Generic protein-binding annotation from a DCUN1D1/neddylation E3 study; uninformative for CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: Bare protein binding is not informative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12504025 qualifier: enables review: summary: The underlying interaction is CAND1 binding unneddylated CUL1; captured by specific CRL terms. Bare protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: protein binding is too generic; the CAND1-CUL1 interaction is represented by specific terms. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:10581176 qualifier: located_in review: summary: Nuclear (foci/speckle) localization reported in the historical TIP120A study; nuclear localization is independently supported. action: ACCEPT reason: Nuclear localization is genuine for CAND1; this early study showed nuclear foci patterns. supported_by: - reference_id: PMID:10581176 supporting_text: nuclear localization reference_section_type: ABSTRACT - term: id: GO:0030154 label: cell differentiation evidence_type: IDA original_reference_id: PMID:10581176 qualifier: involved_in review: summary: Cell differentiation derives from the historical TIP120A work (expression changes upon differentiation) and is an indirect/correlative association, not the established core CAND1 function. action: MARK_AS_OVER_ANNOTATED reason: This reflects TIP120A-era expression correlations, not a direct mechanistic CAND1 role in differentiation. supported_by: - reference_id: PMID:10581176 supporting_text: differentiation-related gene expression reference_section_type: ABSTRACT - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:12609982 qualifier: part_of review: summary: CAND1 (TIP120A) is part of cullin-containing ubiquitin ligase complexes; supported, though more specifically captured by cullin-RING ubiquitin ligase complex. action: ACCEPT reason: CAND1 forms complexes with cullins/Rbx1; membership in a ubiquitin ligase complex is supported. supported_by: - reference_id: PMID:12609982 supporting_text: all cullins tested specifically interacted with TIP120A reference_section_type: ABSTRACT - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:12609982 qualifier: involved_in review: summary: CAND1 (TIP120A) modulates SCF-mediated ubiquitination (reducing it by blocking Skp1/F-box binding); involved_in is appropriate. action: ACCEPT reason: Direct evidence that CAND1 affects SCF ubiquitination of substrate; regulatory involvement is supported. supported_by: - reference_id: PMID:12609982 supporting_text: TIP120A greatly reduced the ubiquitination of phosphorylated reference_section_type: ABSTRACT - term: id: GO:0043086 label: negative regulation of catalytic activity evidence_type: IDA original_reference_id: PMID:12609982 qualifier: involved_in review: summary: In its CUL1-bound (unneddylated) state CAND1 negatively regulates SCF catalytic activity by blocking productive assembly; supported, though in vivo CAND1 is a positive regulator of overall CRL activity through exchange. action: ACCEPT reason: CAND1 inhibits assembly of productive SCF complexes in vitro (negative regulation of the assembled ligase); a real, mechanistically supported activity. supported_by: - reference_id: PMID:12609982 supporting_text: negative regulator of SCF E3 ubiquitin ligases reference_section_type: ABSTRACT references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:10581176 title: Induced expression, localization, and chromosome mapping of a gene for the TBP-interacting protein 120A. findings: [] - id: PMID:12504025 title: NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. findings: [] - id: PMID:12504026 title: CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. findings: [] - id: PMID:12609982 title: TIP120A associates with cullins and modulates ubiquitin ligase activity. findings: [] - id: PMID:15537541 title: Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. findings: [] - id: PMID:16861300 title: Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. findings: [] - id: PMID:17290223 title: Impaired DNA damage checkpoint response in MIF-deficient mice. findings: [] - id: PMID:18826954 title: SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:20458337 title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. findings: [] - id: PMID:21145461 title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. findings: [] - id: PMID:21249194 title: Regulation of cullin RING E3 ubiquitin ligases by CAND1 in vivo. findings: [] - id: PMID:21630459 title: Proteomic characterization of the human sperm nucleus. findings: [] - id: PMID:22405651 title: The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. findings: [] - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: [] - id: PMID:24192928 title: Oncogenic function of SCCRO5/DCUN1D5 requires its Neddylation E3 activity and nuclear localization. findings: [] - id: PMID:25435324 title: Structural mechanism of nuclear transport mediated by importin β and flexible amphiphilic proteins. findings: [] - id: PMID:26030138 title: Identification of Novel Proteins Co-Purifying with Cockayne Syndrome Group B (CSB) Reveals Potential Roles for CSB in RNA Metabolism and Chromatin Dynamics. findings: [] - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] - id: PMID:26906416 title: Characterization of the mammalian family of DCN-type NEDD8 E3 ligases. findings: [] - id: PMID:27542266 title: DCUN1D3 activates SCFSKP2 ubiquitin E3 ligase activity and cell cycle progression under UV damage. findings: [] - id: PMID:30021884 title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. findings: [] - id: PMID:34591642 title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: Reactome:R-HSA-5691131 title: CANDI binds CUL1 findings: [] - id: Reactome:R-HSA-6798748 title: Exocytosis of secretory granule lumen proteins findings: [] - id: Reactome:R-HSA-6800434 title: Exocytosis of ficolin-rich granule lumen proteins findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955245 title: CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus findings: [] - id: Reactome:R-HSA-8955285 title: COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: file:human/CAND1/CAND1-uniprot.txt title: CAND1 UniProtKB record (Q86VP6) findings: [] - id: file:human/CAND1/CAND1-notes.md title: Manual CAND1 curation notes findings: [] core_functions: - description: CAND1 binds the unneddylated CUL1-RBX1 (ROC1) cullin core and acts as a substrate-receptor (F-box protein) exchange factor, promoting dissociation of existing SCF complexes and exchange of F-box receptors to remodel the cellular repertoire of SCF complexes. directly_involved_in: - id: GO:0010265 label: SCF complex assembly - id: GO:0016567 label: protein ubiquitination locations: - id: GO:0005829 label: cytosol - id: GO:0005634 label: nucleus supported_by: - reference_id: file:human/CAND1/CAND1-uniprot.txt supporting_text: Acts as a F-box protein reference_section_type: DATABASE_ENTRY - reference_id: PMID:12504026 supporting_text: CAND1 regulates the formation of the SCF complex reference_section_type: ABSTRACT - reference_id: PMID:21249194 supporting_text: positive regulator of Cullin ligases in vivo reference_section_type: ABSTRACT - description: CAND1 clamps around the cullin scaffold and, in the unneddylated state, blocks the SKP1/F-box adaptor binding site; its binding is reciprocally regulated by the neddylation cycle, making CAND1 a regulator of cullin-RING ligase activity rather than a catalytic enzyme. directly_involved_in: - id: GO:0010265 label: SCF complex assembly in_complex: id: GO:0031461 label: cullin-RING ubiquitin ligase complex supported_by: - reference_id: PMID:15537541 supporting_text: occupies the adaptor binding site on reference_section_type: ABSTRACT - reference_id: PMID:12609982 supporting_text: negative regulator of SCF E3 ubiquitin ligases reference_section_type: ABSTRACT proposed_new_terms: - proposed_name: cullin-RING ubiquitin ligase substrate receptor exchange factor activity proposed_definition: A molecular function in which a protein binds an unneddylated cullin-RING ligase (CRL) core and catalyzes the dissociation and exchange of substrate-receptor (e.g. F-box) modules, thereby remodeling the repertoire of assembled CRL complexes. Distinct from a simple adaptor/binding activity in that it actively accelerates receptor cycling. justification: CAND1's defining, conserved mechanistic role is acting as a substrate-receptor exchange factor for cullin-RING ligases (clamping the unneddylated CUL1-RBX1 core and accelerating F-box receptor exchange). No existing GO molecular function term captures this exchange-factor activity; the closest existing terms (molecular adaptor activity, SCF complex assembly) understate the active, catalytic exchange mechanism. This gap is why no molecular_function is asserted in core_functions. suggested_questions: - question: How is the apparently contradictory in vitro inhibitory versus in vivo positive (exchange-promoting) role of CAND1 on CRL activity reconciled at the level of individual cullin-RING ligases and substrate receptors? experts: - Deshaies RJ - Zheng N - question: To what extent does CAND1 act equivalently across all cullins (CUL1-CUL5) versus having cullin- or receptor-specific exchange preferences? experts: - Xiong Y suggested_experiments: - hypothesis: CAND1 accelerates F-box receptor exchange on cullin cores with rates that scale with neddylation/deneddylation cycling. description: Use single-molecule or stopped-flow kinetics with purified CUL1-RBX1, CAND1, and competing fluorescently labeled F-box-SKP1 modules (with and without NEDD8) to measure exchange rates directly. experiment_type: in vitro single-molecule / kinetic exchange assay - hypothesis: CAND1 loss preferentially destabilizes low-abundance F-box receptors by impairing their cycling onto cullin cores. description: Quantify the F-box/substrate-receptor proteome and CRL substrate levels by mass spectrometry in CAND1-knockout versus wild-type cells, testing the predicted collapse of receptor diversity. experiment_type: quantitative proteomics in CAND1-knockout cells