Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: CAND1 has nuclear pools (e.g., acting on nuclear CRL4) in addition to its predominant cytoplasmic localization; nuclear activity is supported. Reason: CAND1 regulates nuclear CRLs and is detected in the nucleus; nuclear localization is well supported, though CAND1 is predominantly cytoplasmic. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0010265 SCF complex assembly	IBA GO_REF:0000033	ACCEPT	Summary: Regulation of SCF complex assembly via F-box exchange is the core biological process for CAND1 and is strongly supported experimentally. Reason: CAND1 binds unneddylated CUL1-RBX1 and regulates SCF assembly/disassembly, promoting F-box receptor exchange; this is its defining role. Supporting Evidence: PMID:12504026 CAND1 regulates the formation of the SCF complex PMID:15537541 forms a tight complex with the Cul1-Roc1
GO:0016567 protein ubiquitination	IBA GO_REF:0000033	ACCEPT	Summary: CAND1 is involved in (regulates) CRL-mediated protein ubiquitination as an assembly/exchange factor, not as a catalytic enzyme; involved_in is appropriate. Reason: By controlling SCF/CRL assembly and F-box exchange, CAND1 modulates ubiquitination of CRL substrates; the regulatory involvement is well supported. Supporting Evidence: PMID:12609982 TIP120A greatly reduced the ubiquitination of phosphorylated
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization consistent with CAND1 regulating nuclear CRLs. Reason: Nuclear pools of CAND1 are supported; localization annotation is appropriate. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: CAND1 is predominantly cytoplasmic, where most cullins reside; this is a core localization. Reason: Directly supported - CAND1 is predominantly cytoplasmically localized with cullins as major interactors. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0010265 SCF complex assembly	IEA GO_REF:0000002	ACCEPT	Summary: Same core process as the IBA annotation; CAND1 regulates SCF assembly via F-box exchange. Reason: Strongly supported core function consistent with InterPro/experimental evidence. Supporting Evidence: PMID:12504026 CAND1 regulates the formation of the SCF complex
GO:0005515 protein binding	IPI PMID:12504026 CAND1 binds to unneddylated CUL1 and regulates the formation...	MARK AS OVER ANNOTATED	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. Reason: protein binding is too generic; CAND1-CUL1 binding is represented by more informative terms in this review.
GO:0005515 protein binding	IPI PMID:12609982 TIP120A associates with cullins and modulates ubiquitin liga...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is CAND1 (TIP120A) with cullins/Rbx1; captured by specific CRL terms. Bare protein binding is uninformative. Reason: protein binding is too generic; the cullin interactions are represented by specific terms.
GO:0005515 protein binding	IPI PMID:15537541 Structure of the Cand1-Cul1-Roc1 complex reveals regulatory ...	MARK AS OVER ANNOTATED	Summary: The interaction is CAND1-CUL1-ROC1 (structural); captured by specific CRL/SCF terms. Bare protein binding is uninformative. Reason: protein binding is too generic; the structural CAND1-CUL1-ROC1 interaction is represented by specific terms.
GO:0005515 protein binding	IPI PMID:16861300 Regulation of neddylation and deneddylation of cullin1 in SC...	MARK AS OVER ANNOTATED	Summary: The interaction concerns the cullin-CAND1 complex and its dissociation; captured by specific CRL terms. Bare protein binding is uninformative. Reason: protein binding is too generic for this CRL-regulatory interaction.
GO:0005515 protein binding	IPI PMID:17290223 Impaired DNA damage checkpoint response in MIF-deficient mic...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation; uninformative for CAND1 function. Reason: Bare protein binding from a non-mechanistic interaction record is not informative.
GO:0005515 protein binding	IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by...	MARK AS OVER ANNOTATED	Summary: From systematic CRL-network proteomics; the relevant CAND1 biology is captured by CRL-complex/SCF-assembly terms, so bare protein binding is uninformative. Reason: protein binding is too generic; CRL-network membership is better represented by specific terms.
GO:0005515 protein binding	IPI PMID:25435324 Structural mechanism of nuclear transport mediated by import...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from an importin-beta transport-mechanism study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a quantitative interactome study; uninformative for CAND1 function. Reason: Bare protein binding from a high-throughput interactome is not informative.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a histone crosslinking-MS study; uninformative for CAND1 function. Reason: Bare protein binding from a high-throughput interactome is not informative.
GO:0005515 protein binding	IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a head-and-neck-cancer network map; uninformative for CAND1 function. Reason: Bare protein binding from a high-throughput interactome is not informative.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a multimodal cell-map study; uninformative for CAND1 function. Reason: Bare protein binding from a high-throughput interactome is not informative.
GO:0017025 TBP-class protein binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:10581176 TBP-interacting protein 120A (TIP120A) is a novel eukaryotic transcriptional
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Transcriptional activation derives from the historical TIP120A work and is not the established core CAND1 function (CRL assembly regulation). Reason: This is a historical/secondary TIP120A-era function and an indirect/broad effect, not the consensus CAND1 role. Supporting Evidence: PMID:10581176 differentiation-related gene expression
GO:0045899 positive regulation of RNA polymerase II transcription preinitiation complex assembly	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Derives from historical TIP120A transcription work; not the established core CAND1 function. Reason: Historical/secondary TIP120A-era function, not the consensus CRL-assembly role. Supporting Evidence: PMID:10581176 TBP-interacting protein 120A (TIP120A) is a novel eukaryotic transcriptional
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nucleoplasmic localization is consistent with CAND1 nuclear pools acting on nuclear CRLs. Reason: Supported by immunofluorescence localization and consistent with CAND1's nuclear CRL-regulatory role. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization is the predominant CAND1 localization and a core functional compartment. Reason: Directly supported - CAND1 is predominantly cytoplasmic with cullins as major interactors. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005515 protein binding	IPI PMID:27542266 DCUN1D3 activates SCFSKP2 ubiquitin E3 ligase activity and c...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a DCUN1D3/SCF-SKP2 study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005515 protein binding	IPI PMID:26906416 Characterization of the mammalian family of DCN-type NEDD8 E...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a DCN-type NEDD8 E3 ligase study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005515 protein binding	IPI PMID:24192928 Oncogenic function of SCCRO5/DCUN1D5 requires its Neddylatio...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a SCCRO5/DCUN1D5 study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005515 protein binding	IPI PMID:26030138 Identification of Novel Proteins Co-Purifying with Cockayne ...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a CSB co-purification study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955245	ACCEPT	Summary: Nucleoplasmic localization (CAND1 binds nuclear CRL4) is consistent with CAND1 nuclear function. Reason: Supported by CAND1 regulation of nuclear CRLs (CRL4) per Reactome and consistent with nuclear pools. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955285	ACCEPT	Summary: Nucleoplasmic localization linked to displacement of CAND1 from nuclear CRL4; consistent with CAND1 nuclear function. Reason: Consistent with CAND1 acting on nuclear CRLs. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798748	MARK AS OVER ANNOTATED	Summary: Extracellular localization derives from a generic granule-exocytosis Reactome pathway and is not a functional site for this intracellular CRL-assembly factor. Reason: CAND1 is an intracellular cullin regulator; extracellular assignment reflects bulk granule/exocytosis pathway annotation, not biology.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800434	MARK AS OVER ANNOTATED	Summary: Extracellular localization from a generic granule-exocytosis Reactome pathway; not a functional site for CAND1. Reason: CAND1 is an intracellular cullin regulator; extracellular assignment is not biologically meaningful here.
GO:0005829 cytosol	TAS Reactome:R-HSA-5691131	ACCEPT	Summary: Cytosolic localization where CAND1 binds CUL1; a core compartment. Reason: Consistent with the predominant cytoplasmic localization of CAND1 and its cullin binding. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	ACCEPT	Summary: Cytosolic localization where CAND1 binds cytosolic CRL E3 ligases; core compartment. Reason: Consistent with CAND1's predominant cytoplasmic localization and CRL binding. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	ACCEPT	Summary: Cytosolic localization linked to displacement of CAND1 from cytosolic CRLs; core compartment. Reason: Consistent with CAND1's predominant cytoplasmic localization and CRL binding. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0034774 secretory granule lumen	TAS Reactome:R-HSA-6798748	MARK AS OVER ANNOTATED	Summary: Secretory granule lumen derives from a bulk granule-exocytosis Reactome pathway and is not a functional location for this cytosolic/nuclear CRL regulator. Reason: Not biologically meaningful for CAND1; reflects bulk pathway-level annotation.
GO:1904813 ficolin-1-rich granule lumen	TAS Reactome:R-HSA-6800434	MARK AS OVER ANNOTATED	Summary: Ficolin-1-rich granule lumen derives from a bulk granule-exocytosis Reactome pathway; not a functional location for CAND1. Reason: Not biologically meaningful for CAND1; reflects bulk pathway-level annotation.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Detection in exosome proteomics is a high-throughput finding and not a functional localization for this intracellular CRL regulator. Reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Generic membrane assignment from an NK-cell membrane-proteome survey; not a functional localization for the soluble cytosolic/nuclear CAND1. Reason: Bulk membrane-proteome detection is uninformative and likely co-isolation; CAND1 is not a membrane protein.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	ACCEPT	Summary: High-throughput sperm-nucleus proteomic detection; nuclear localization is independently supported for CAND1. Reason: Nuclear localization is genuine for CAND1 (nuclear CRL regulation); consistent with the other accepted nucleus annotations. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: Exosome proteomics detection; not a functional localization for CAND1. Reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	MARK AS OVER ANNOTATED	Summary: Exosome proteomics detection; not a functional localization for CAND1. Reason: Exosome detection in proteomic surveys does not reflect CAND1's site of action.
GO:0005634 nucleus	IDA PMID:21249194 Regulation of cullin RING E3 ubiquitin ligases by CAND1 in v...	ACCEPT	Summary: Nuclear localization is supported; CAND1 also has nuclear pools though it is predominantly cytoplasmic. Reason: Consistent with CAND1 acting on nuclear CRLs; nuclear localization is supported. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0005737 cytoplasm	IDA PMID:21249194 Regulation of cullin RING E3 ubiquitin ligases by CAND1 in v...	ACCEPT	Summary: Cytoplasmic localization is the predominant and core localization of CAND1. Reason: Directly demonstrated - CAND1 is predominantly cytoplasmically localized. Supporting Evidence: PMID:21249194 CAND1 is predominantly cytoplasmically localized
GO:0010265 SCF complex assembly	IDA PMID:15537541 Structure of the Cand1-Cul1-Roc1 complex reveals regulatory ...	ACCEPT	Summary: Structural study of CAND1-CUL1-ROC1 directly supports CAND1's role in regulating SCF complex assembly. Reason: The crystal structure shows CAND1 clamping CUL1 and blocking the adaptor site, mechanistically explaining its control of SCF assembly. Supporting Evidence: PMID:15537541 forms a tight complex with the Cul1-Roc1 PMID:15537541 occupies the adaptor binding site on
GO:0010265 SCF complex assembly	IDA PMID:21249194 Regulation of cullin RING E3 ubiquitin ligases by CAND1 in v...	ACCEPT	Summary: In vivo evidence that CAND1 regulates cullin-RING ligase assembly/activity by promoting substrate-receptor exchange. Reason: CAND1 functions as a positive regulator of CRL activity in vivo via F-box exchange, supporting its role in SCF assembly. Supporting Evidence: PMID:21249194 positive regulator of Cullin ligases in vivo
GO:0016567 protein ubiquitination	IDA PMID:15537541 Structure of the Cand1-Cul1-Roc1 complex reveals regulatory ...	ACCEPT	Summary: CAND1 regulates (is involved in) CRL-mediated ubiquitination as an assembly factor; involved_in is appropriate (CAND1 is not catalytic). Reason: Through control of SCF assembly CAND1 modulates substrate ubiquitination; the regulatory involvement is supported. Supporting Evidence: PMID:15537541 regulatory mechanisms for the
GO:0016567 protein ubiquitination	IDA PMID:21249194 Regulation of cullin RING E3 ubiquitin ligases by CAND1 in v...	ACCEPT	Summary: CAND1 regulates CRL-mediated ubiquitination in vivo via F-box exchange; involved_in is appropriate. Reason: CAND1 is a positive regulator of CRL ligase activity in vivo, modulating substrate ubiquitination. Supporting Evidence: PMID:21249194 positive regulator of Cullin ligases in vivo
GO:0031461 cullin-RING ubiquitin ligase complex	IDA PMID:15537541 Structure of the Cand1-Cul1-Roc1 complex reveals regulatory ...	ACCEPT	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. Reason: The CAND1-CUL1-ROC1 crystal structure directly demonstrates CAND1 as part of a cullin-RING complex. Supporting Evidence: PMID:15537541 forms a tight complex with the Cul1-Roc1
GO:0031461 cullin-RING ubiquitin ligase complex	IDA PMID:21249194 Regulation of cullin RING E3 ubiquitin ligases by CAND1 in v...	ACCEPT	Summary: CAND1 associates with cullin-RING complexes in vivo (binding unneddylated cullins); part_of is supported. Reason: Cullins are the major CAND1 interactors in cells, consistent with CAND1 being part of cullin-RING complexes. Supporting Evidence: PMID:21249194 cullins are the major
GO:0031461 cullin-RING ubiquitin ligase complex	IDA PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: CAND1 is part of cullin-RING ligase complexes; consistent with its broad cullin-binding and CRL-regulatory role. Reason: Supported as CAND1 being part of cullin-RING complexes. Supporting Evidence: PMID:21249194 cullins are the major
GO:0005515 protein binding	IPI PMID:18826954 SCCRO (DCUN1D1) is an essential component of the E3 complex ...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a DCUN1D1/neddylation E3 study; uninformative for CAND1 function. Reason: Bare protein binding is not informative.
GO:0005515 protein binding	IPI PMID:12504025 NEDD8 modification of CUL1 dissociates p120(CAND1), an inhib...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is CAND1 binding unneddylated CUL1; captured by specific CRL terms. Bare protein binding is uninformative. Reason: protein binding is too generic; the CAND1-CUL1 interaction is represented by specific terms.
GO:0005634 nucleus	IDA PMID:10581176 Induced expression, localization, and chromosome mapping of ...	ACCEPT	Summary: Nuclear (foci/speckle) localization reported in the historical TIP120A study; nuclear localization is independently supported. Reason: Nuclear localization is genuine for CAND1; this early study showed nuclear foci patterns. Supporting Evidence: PMID:10581176 nuclear localization
GO:0030154 cell differentiation	IDA PMID:10581176 Induced expression, localization, and chromosome mapping of ...	MARK AS OVER ANNOTATED	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. Reason: This reflects TIP120A-era expression correlations, not a direct mechanistic CAND1 role in differentiation. Supporting Evidence: PMID:10581176 differentiation-related gene expression
GO:0000151 ubiquitin ligase complex	IDA PMID:12609982 TIP120A associates with cullins and modulates ubiquitin liga...	ACCEPT	Summary: CAND1 (TIP120A) is part of cullin-containing ubiquitin ligase complexes; supported, though more specifically captured by cullin-RING ubiquitin ligase complex. Reason: CAND1 forms complexes with cullins/Rbx1; membership in a ubiquitin ligase complex is supported. Supporting Evidence: PMID:12609982 all cullins tested specifically interacted with TIP120A
GO:0016567 protein ubiquitination	IDA PMID:12609982 TIP120A associates with cullins and modulates ubiquitin liga...	ACCEPT	Summary: CAND1 (TIP120A) modulates SCF-mediated ubiquitination (reducing it by blocking Skp1/F-box binding); involved_in is appropriate. Reason: Direct evidence that CAND1 affects SCF ubiquitination of substrate; regulatory involvement is supported. Supporting Evidence: PMID:12609982 TIP120A greatly reduced the ubiquitination of phosphorylated
GO:0043086 negative regulation of catalytic activity	IDA PMID:12609982 TIP120A associates with cullins and modulates ubiquitin liga...	ACCEPT	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. Reason: CAND1 inhibits assembly of productive SCF complexes in vitro (negative regulation of the assembled ligase); a real, mechanistically supported activity. Supporting Evidence: PMID:12609982 negative regulator of SCF E3 ubiquitin ligases

Core Functions

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:

SCF complex assembly protein ubiquitination

Cellular Locations:

cytosol nucleus

Supporting Evidence:

file:human/CAND1/CAND1-uniprot.txt
Acts as a F-box protein
PMID:12504026
CAND1 regulates the formation of the SCF complex
PMID:21249194
positive regulator of Cullin ligases in vivo

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:

SCF complex assembly

In Complex:

cullin-RING ubiquitin ligase complex

Supporting Evidence:

PMID:15537541
occupies the adaptor binding site on
PMID:12609982
negative regulator of SCF E3 ubiquitin ligases

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:10581176

Induced expression, localization, and chromosome mapping of a gene for the TBP-interacting protein 120A.

PMID:12504025

NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases.

PMID:12504026

CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex.

PMID:12609982

TIP120A associates with cullins and modulates ubiquitin ligase activity.

PMID:15537541

Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases.

PMID:16861300

Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate.

PMID:17290223

Impaired DNA damage checkpoint response in MIF-deficient mice.

PMID:18826954

SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:21145461

Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.

PMID:21249194

Regulation of cullin RING E3 ubiquitin ligases by CAND1 in vivo.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:22405651

The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:24192928

Oncogenic function of SCCRO5/DCUN1D5 requires its Neddylation E3 activity and nuclear localization.

PMID:25435324

Structural mechanism of nuclear transport mediated by importin β and flexible amphiphilic proteins.

PMID:26030138

Identification of Novel Proteins Co-Purifying with Cockayne Syndrome Group B (CSB) Reveals Potential Roles for CSB in RNA Metabolism and Chromatin Dynamics.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:26906416

Characterization of the mammalian family of DCN-type NEDD8 E3 ligases.

PMID:27542266

DCUN1D3 activates SCFSKP2 ubiquitin E3 ligase activity and cell cycle progression under UV damage.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:34591642

A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-5691131

CANDI binds CUL1

Reactome:R-HSA-6798748

Exocytosis of secretory granule lumen proteins

Reactome:R-HSA-6800434

Exocytosis of ficolin-rich granule lumen proteins

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955245

CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus

Reactome:R-HSA-8955285

COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

file:human/CAND1/CAND1-uniprot.txt

CAND1 UniProtKB record (Q86VP6)

file:human/CAND1/CAND1-notes.md

Manual CAND1 curation notes

Suggested Experiments

Experiment: 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.

Hypothesis: CAND1 accelerates F-box receptor exchange on cullin cores with rates that scale with neddylation/deneddylation cycling.

Type: in vitro single-molecule / kinetic exchange assay

Experiment: 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.

Hypothesis: CAND1 loss preferentially destabilizes low-abundance F-box receptors by impairing their cycling onto cullin cores.

Type: quantitative proteomics in CAND1-knockout cells

📚 Additional Documentation

Notes

(CAND1-notes.md)

CAND1 (Q86VP6) research notes

Identity / domain architecture

Cullin-associated NEDD8-dissociated protein 1 (CAND1), formerly TIP120A (TBP-interacting protein 120A). A ~120 kDa HEAT-repeat protein that clamps around the cullin scaffold. PMID:15537541

Core molecular function: SCF/CRL assembly factor & F-box (substrate-receptor) exchange factor

UniProt summary: key assembly factor of SCF E3 ligases that promotes exchange of the substrate-recognition F-box subunit; acts as an F-box protein exchange factor; activity coupled to neddylation cycles; in the deneddylated state cullin-binding CAND1 binds CUL1-RBX1, increasing SCF dissociation and promoting F-box exchange; probably similar role in other CRLs. [file:human/CAND1/CAND1-uniprot.txt "Key assembly factor of SCF (SKP1-CUL1-F-box protein) E3\nCC ubiquitin ligase complexes that promotes the exchange of the substrate-\nCC recognition F-box subunit"] [file:human/CAND1/CAND1-uniprot.txt "Acts as a F-box protein\nCC exchange factor."]
CAND1 binds unneddylated CUL1 and regulates SCF formation; dissociation of CAND1 promotes F-box incorporation. PMID:12504026
Neddylation of CUL1 (or SKP1+ATP) dissociates CAND1. PMID:12504026
CAND1 selectively binds unneddylated CUL1 and is dissociated by neddylation; forms CUL1-ROC1 ternary complex; regulates assembly of productive SCF ligases. PMID:12504025
Associates with all cullins tested; forms a complex with CUL1 and Rbx1 but interferes with Skp1/F-box binding; reduces SCF ubiquitination of substrate; "negative regulator of SCF E3 ubiquitin ligases." PMID:12609982

Structural mechanism

Crystal structure of Cand1-Cul1-Roc1: Cand1 superhelix clamps Cul1; a beta-hairpin occupies the adaptor (Skp1) binding site; HEAT repeats bury the Cul1 lysine whose neddylation blocks Cand1 association. PMID:15537541

In vivo dynamics / regulation

Although early biochemistry framed CAND1 as an inhibitor/sequester, in vivo it is a positive regulator of CRL activity that promotes substrate-receptor exchange (dynamic recycling). PMID:21249194
In mammalian cells CAND1 is predominantly cytoplasmic and cullins are its major interactors; only small amounts bind Cul1 at steady state (consistent with transient exchange-factor action). PMID:21249194
F-box protein + substrate promote dissociation of the cullin-CAND1 complex, coupling assembly to substrate availability and neddylation. PMID:16861300

Localization

Predominantly cytoplasmic/cytosolic, with nuclear pools (CRL4 in nucleus per Reactome). Cytosol and nucleus are both supported. Exosome/membrane/secretory-granule/ficolin-granule annotations are high-throughput proteomic (HDA) or Reactome "exocytosis" assignments and are best treated as over-annotations / contaminant-type localizations rather than functional sites.

Historical TIP120A / transcription annotations

CAND1 was originally described as TIP120A, a TBP-interacting transcriptional regulator. PMID:10581176
The TBP-class protein binding (GO:0017025), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of RNA pol II PIC assembly (GO:0045899), and cell differentiation (GO:0030154, from PMID:10581176) annotations derive from this early work. They predate the CRL-assembly paradigm and are not the consensus core function; treat as non-core / over-annotated.

Synthesis of core vs non-core

CORE: F-box/substrate-receptor exchange factor & SCF/CRL assembly regulation (GO:0010265 SCF complex assembly; involvement in protein ubiquitination GO:0016567 as a regulator, not catalyst); binding to / being part of cullin-RING ligase complex (GO:0031461) in its unneddylated/exchange state; negative regulation of (premature/unproductive) CRL catalytic activity (GO:0043086); cytosol & nucleus localization.
NON-CORE / historical: TBP-class binding and transcription-regulation terms, cell differentiation (TIP120A era).
OVER-ANNOTATED / uninformative: many high-throughput "protein binding" (GO:0005515) IPI hits; extracellular region, secretory granule lumen, ficolin-1-rich granule lumen, extracellular exosome, membrane (HDA/Reactome contaminant-type localizations).
NOTE: CAND1 is a regulator/assembly factor, NOT a catalytic E3 or a ubiquitin-transfer enzyme; protein ubiquitination annotations are "involved_in" (regulatory) and should be read as such.

Pn Notes

(CAND1-pn-notes.md)

CAND1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q86VP6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CAND1/CAND1-ai-review.yaml
AIGR review HTML: present - genes/human/CAND1/CAND1-ai-review.html
Gene notes: present - genes/human/CAND1/CAND1-notes.md
GOA TSV: present - genes/human/CAND1/CAND1-goa.tsv
UniProt record: present - genes/human/CAND1/CAND1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CAND1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CAND1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 27; MARK_AS_OVER_ANNOTATED: 29

PN Consistency Summary

Consistency: Consistent. PN, review, notes and (no separate deep-research file; review references serve) all describe CAND1 as the CUL1-RBX1-binding F-box/substrate-receptor exchange factor that remodels SCF/CRL complexes and is a positive regulator of CRL activity in vivo (PMID:12504026, 15537541, 21249194). PN's "F-box exchange factor / Armadillo-like (HEAT-repeat)" matches the review's mechanism exactly.
PN story / NEW pressure: PN projects GO:1990757 "ubiquitin ligase activator activity" (verified real; def "binds to and increases the activity of a ubiquitin ligase"). This aligns with the review's conclusion that CAND1 is an in-vivo positive regulator of CRL activity and is genuinely NEW to GOA (current GOA carries SCF assembly / part-of CRL, not an activator MF). It is defensible as ADD. Separately, the review independently proposes a finer NEW term "cullin-RING ligase substrate-receptor exchange factor activity" — I verified via OLS that NO such GO term exists (candidate, correctly flagged as new). So GO:1990757 is the best existing real term and is a sound PN-node addition; the review's bespoke term is a legitimate future request.
Evidence alignment: PN row cites reference 23453757 (title not resolved in dossier). Review supports activator/exchange role via PMID:12504026, 15537541, 21249194, 12609982. Overlap is thematic (CRL assembly regulation); the PN-cited 23453757 is not in the review's reference list — minor divergence worth noting.
Verdict: Consistent and the strongest ADD case of the six — GO:1990757 (real) is a defensible new MF for CAND1, matching both PN and the review's positive-regulator framing. Recommended edits: [YAML] consider adding GO:1990757 ubiquitin ligase activator activity to CAND1 existing/core (currently only proposed as a bespoke new term); [REF] confirm PN reference 23453757 and add to the review if it supports the activator role.

Full Consistency Review

UniProt: Q86VP6 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE
PN placement: Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor|Armadillo-like ; PN-node mapping: F-box-exchange-factor type/subtype → mapped/ok_for_propagation GO:1990757 ubiquitin ligase activator activity (new_to_goa); CRL-regulator group → context_only/too_broad GO:1904666; E3-ligases class → context_only GO:0061630.
Consistency: Consistent. PN, review, notes and (no separate deep-research file; review references serve) all describe CAND1 as the CUL1-RBX1-binding F-box/substrate-receptor exchange factor that remodels SCF/CRL complexes and is a positive regulator of CRL activity in vivo (PMID:12504026, 15537541, 21249194). PN's "F-box exchange factor / Armadillo-like (HEAT-repeat)" matches the review's mechanism exactly.
PN story / NEW pressure: PN projects GO:1990757 "ubiquitin ligase activator activity" (verified real; def "binds to and increases the activity of a ubiquitin ligase"). This aligns with the review's conclusion that CAND1 is an in-vivo positive regulator of CRL activity and is genuinely NEW to GOA (current GOA carries SCF assembly / part-of CRL, not an activator MF). It is defensible as ADD. Separately, the review independently proposes a finer NEW term "cullin-RING ligase substrate-receptor exchange factor activity" — I verified via OLS that NO such GO term exists (candidate, correctly flagged as new). So GO:1990757 is the best existing real term and is a sound PN-node addition; the review's bespoke term is a legitimate future request.
Mapping strategy: Type/subtype projection of GO:1990757 onto CAND1 is appropriate and adds value over current GOA. The group/class context_only (too_broad) calls are correct (CRL-regulator descendants mix inhibitors and activators; E3 class mixes catalytic/scaffold/adaptor). No precedent-style over-broadening here.
Evidence alignment: PN row cites reference 23453757 (title not resolved in dossier). Review supports activator/exchange role via PMID:12504026, 15537541, 21249194, 12609982. Overlap is thematic (CRL assembly regulation); the PN-cited 23453757 is not in the review's reference list — minor divergence worth noting.
Verdict: Consistent and the strongest ADD case of the six — GO:1990757 (real) is a defensible new MF for CAND1, matching both PN and the review's positive-regulator framing. Recommended edits: [YAML] consider adding GO:1990757 ubiquitin ligase activator activity to CAND1 existing/core (currently only proposed as a bespoke new term); [REF] confirm PN reference 23453757 and add to the review if it supports the activator role.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CAND1/CAND1-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | CRL regulator | F-box exchange factor | Armadillo-like

UniProt: Q86VP6
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR011989
PN references (titles):
- 23453757
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor|Armadillo-like
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990757 ubiquitin ligase activator activity]
  rationale: This PN type captures CAND-family exchange factors that activate/remodel cullin-RING ligase assemblies. The closest shared GO activity is ubiquitin ligase activator activity.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990757 ubiquitin ligase activator activity]
  rationale: This PN type captures CAND-family exchange factors that activate/remodel cullin-RING ligase assemblies. The closest shared GO activity is ubiquitin ligase activator activity.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator
  status=context_only scope=too_broad_to_propagate GO=[GO:1904666 regulation of ubiquitin protein ligase activity]
  rationale: This PN group records regulation of cullin-RING ligase systems, but the members include inhibitors, exchange factors, and modulators with different directionality. It is context only.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:1990757 ubiquitin ligase activator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor
GO:1990757 ubiquitin ligase activator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor|Armadillo-like

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

CAND1

Gene Description

Proposed New Ontology Terms

cullin-RING ubiquitin ligase substrate receptor exchange factor activity