CAND2 (Cullin-associated NEDD8-dissociated protein 2; also TIP120B, TBP-interacting protein of 120 kDa B) is a large (~1236 aa) HEAT-repeat (alpha-solenoid) protein and the paralog of CAND1. Like CAND1, it functions as a regulator of cullin-RING ubiquitin ligase (CRL/SCF) assembly rather than as a ligase itself: it binds unneddylated, substrate-receptor-free cullin-RBX cores (CAND-bound cullins cannot be neddylated, and neddylated cullins do not stably bind CAND) and acts as an F-box-protein exchange factor, sequestering cullins and accelerating the dissociation/exchange of F-box (and other substrate-recognition) modules to dynamically reshape the cellular repertoire of active CRL complexes within the NEDD8/COP9-signalosome remodeling cycle. CAND2 has no catalytic ubiquitin-ligase activity of its own. Biochemically it binds the CUL1-RBX1 core comparably to CAND1 but catalyzes SCF disassembly with lower efficiency (higher KM, faster koff), and CAND1 and CAND2 can act nonredundantly to support optimal activity of specific SCF ligases (e.g. SCF(FBXL5)-mediated IRP2 turnover). It was originally identified as a TBP-interacting protein expressed preferentially in muscle and induced during myogenesis, where it binds CUL1 and suppresses SCF-dependent ubiquitination of the differentiation factor myogenin to accelerate myogenic differentiation; it also interacts with the transcription-related factors TBP and CNOT3/NOT3, and is a specific in vitro substrate of the HECT E3 ligase UBE3C/KIAA10, which targets it for proteasomal degradation. CAND2 is enriched in skeletal and cardiac muscle and is also found in epididymis; subcellular pools are reported in both the nucleus and the cytosol. Common variation at the CAND2 locus (rs4642101) is associated with atrial fibrillation risk.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of nuclear localization, consistent with UniProt's reported nuclear localization and the TBP-interaction history. Reason: Plausible localization (UniProt lists Nucleus), but a cytosolic pool is also reported (IDA) and the CRL-assembly regulator function is not restricted to the nucleus; non-core. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0010265 SCF complex assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in SCF complex assembly, the core function of the CAND family as CRL substrate-receptor exchange factors. Core process, now supported by direct human CAND2 biochemistry (F-box exchange-factor activity on the CUL1-RBX1 core) and the muscle myogenin/CUL1 study. Reason: Core biological process; CAND2, like CAND1, promotes exchange of the F-box substrate-recognition subunit in SCF complexes, regulating CRL assembly. Human CAND2 binds the CUL1-RBX1 core and acts as an F-box exchange factor (less efficient than CAND1), and in muscle it binds CUL1 to modulate SCF-dependent turnover of myogenin. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt promotes the exchange of the substrate-recognition F-box subunit in SCF complexes, thereby playing a key role in the cellular repertoire of SCF complexes file:human/CAND2/CAND2-deep-research-falcon.md CAND-family proteins (classically CAND1, by inference also CAND2) preferentially associate with **unneddylated** cullins; structural/mechanistic work emphasizes that **CAND-bound cullins cannot be neddylated**, and **neddylated cullins do not stably bind CAND** |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic assignment of involvement in protein ubiquitination. CAND2 has no ligase activity; it regulates CRL assembly, indirectly affecting ubiquitination flux. Reason: CAND2 is a CRL assembly regulator/exchange factor, not a ubiquitin ligase or conjugation enzyme. It does not itself ubiquitinate substrates; an involved_in protein ubiquitination annotation overstates a direct catalytic/process role. Its effect on ubiquitination is indirect via SCF complex assembly. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated electronic assignment of nuclear localization, transferred from the UniProt subcellular location / mouse ortholog. Reason: Plausible localization redundant with the IBA nucleus annotation; a cytosolic pool also exists, and localization is non-core relative to the CRL-assembly function. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0010265 SCF complex assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment (CAND1/CAND2 family signature IPR039852) of involvement in SCF complex assembly. Core process. Reason: Core biological process; redundant with the IBA assignment and consistent with the CAND family's exchange-factor role. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt promotes the exchange of the substrate-recognition F-box subunit in SCF complexes, thereby playing a key role in the cellular repertoire of SCF complexes |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | KEEP AS NON CORE | Summary: Membrane yeast two-hybrid interaction with the GLP-1 receptor (GLP1R) from a screen for GLP-1R interactors. Bare protein binding is uninformative. Reason: High-throughput interaction screen; bare protein binding is uninformative per curation guidelines and the GLP1R interaction is peripheral to CAND2's CRL-assembly function. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt O75155; P43220: GLP1R; NbExp=2; IntAct=EBI-5656182, EBI-7466542; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map interactions (e.g. SYP, FHL2, CIDEB). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt O75155; P08247: SYP; NbExp=3; IntAct=EBI-5656182, EBI-9071725; |
| GO:0017025 TBP-class protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of TBP-class protein binding, reflecting the original identification of TIP120B as a TBP-interacting protein. Reason: Consistent with the TIP120B naming and the TBP-affinity origin (UniProt SUBUNIT lists TBP binding), but this transcription-related interaction is a historical/secondary aspect distinct from the core CRL-assembly function and is only an electronic ortholog transfer. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt SUBUNIT: Binds TBP, CNOT3 and UBE3C. |
| GO:0005829 cytosol | IDA PMID:12692129 Proteolytic targeting of transcriptional regulator TIP120B b... | ACCEPT | Summary: Direct (ARUK-UCL curated) evidence for cytosolic localization from the study of TIP120B targeting by the HECT E3 KIAA10/UBE3C. Reason: IDA-supported localization; a cytosolic pool is consistent with CAND2's role with cytoplasmic CRL components. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt TBP-interacting protein of 120 kDa B |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity assignment of a transcriptional activator role, transferred from the mouse ortholog (P97536/TIP120A-related) and reflecting the TBP-interacting protein origin. Reason: The transcriptional-activator characterization is best established for the paralog TIP120A/CAND1; CAND2/TIP120B's own function is CRL substrate-receptor exchange. The ISS transfer (from P97536) likely over-propagates a transcriptional-activation role; treat as over-annotated relative to the supported CRL-assembly function. Supporting Evidence: PMID:12207886 Classical TIP120, TIP120A, which functions as a transcriptional activator, is expressed ubiquitously whereas TIP120B is specifically expressed in muscle tissues |
| GO:0005515 protein binding | IPI PMID:12207886 TBP-interacting protein 120B, which is induced in relation t... | KEEP AS NON CORE | Summary: Yeast two-hybrid / GST pull-down interaction with CNOT3/NOT3 (UniProtKB:O75175). Bare protein binding is uninformative. Reason: Records a real interaction (CNOT3) from the myogenesis study, but bare protein binding is uninformative; this transcription-related interaction is secondary to the CRL-assembly function. Supporting Evidence: PMID:12207886 hNOT3L is associated with TIP120B but not with TIP120A |
| GO:0005515 protein binding | IPI PMID:12692129 Proteolytic targeting of transcriptional regulator TIP120B b... | KEEP AS NON CORE | Summary: Interaction with the HECT E3 ligase KIAA10/UBE3C (UniProtKB:Q15386), which targets TIP120B for proteasomal degradation. Bare protein binding is uninformative. Reason: Records the functionally relevant UBE3C/KIAA10 interaction (CAND2 is its substrate), but bare protein binding is uninformative. Supporting Evidence: PMID:12692129 TIP120B, but not the closely related protein TIP120A, is a specific substrate of KIAA10 in vitro |
| GO:0097602 cullin family protein binding | ISS GO_REF:0000024 | NEW | Summary: Proposed molecular function annotation. As a CAND-family protein, CAND2 binds unneddylated cullin-RBX cores; this cullin-binding activity is the molecular basis of its SCF substrate-receptor exchange-factor role and is the core molecular function absent from the existing GOA. Reason: CAND2's core molecular function is binding cullin-RBX cores to regulate SCF assembly. This is proposed by similarity to its paralog CAND1 (ISS; GO_REF:0000024 = manual curator-judgment transfer to an ortholog/paralog), which is the basis recorded in the evidence metadata rather than a GOA import. The orthology inference is corroborated by reported human structural/biochemical data (a CAND2-cullin cryo-EM structure, PDB 8VVY, and a reported F-box-protein exchange-factor activity on the CUL1-RBX1 core, less efficient than CAND1, preferentially engaging unneddylated cullins); that primary work is recorded here as a lead (see supported_by) and has not yet been read in full, so the annotation conservatively rests on the CAND-family orthology basis. The term is not in the existing GOA and is added here. Supporting Evidence: file:human/CAND2/CAND2-uniprot.txt Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes file:human/CAND2/CAND2-deep-research-falcon.md a 2025 Nature Communications study (received Feb 2024) showing that human CAND2 can **promote SCF-mediated protein degradation** by functioning as an **F-box protein exchange factor** interacting with the CUL1·RBX1 core, analogous to CAND1 but less efficient |
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Download this section (compressed HTML)Q: Does human CAND2 recapitulate the CAND1 biochemical mechanism (binding unneddylated CUL1-RBX1 and accelerating SCF substrate-receptor exchange), and does it act preferentially on muscle-enriched CRL clients given its tissue-restricted expression?
Q: How are CAND2's apparently distinct activities (CRL assembly regulation versus its historical TBP/CNOT3 transcription-related interactions) related, and is the transcriptional role a genuine function or an artifact of the TBP-affinity discovery method?
Q: In skeletal/cardiac muscle, does CAND2 act predominantly to inhibit specific SCF complexes (e.g. stabilizing myogenin or GRK5 by disrupting their SCF targeting) or as a general F-box exchange factor, and which muscle-enriched CRL clients explain its tissue-restricted expression and atrial-fibrillation association?
Experiment: Reconstitute SCF dynamics in vitro with purified CAND2, neddylated and unneddylated CUL1-RBX1, SKP1 and F-box proteins, and measure CAND2-stimulated F-box exchange rates by FRET or pulldown, directly comparing to CAND1.
Experiment: Solve or analyze the cryo-EM structure of CAND2 bound to a cullin-RBX core (PDB 8VVY corresponds to CAND2) to confirm the CAND1-like binding mode, and perform structure-guided mutagenesis to test which contacts are required for exchange-factor activity versus the reported TBP/CNOT3 interactions.
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