CAND2

UniProt ID: O75155
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient

Core Functions

Cullin-RING ligase (CRL/SCF) substrate-receptor exchange factor that binds unneddylated cullin-RBX (CUL1-RBX1) cores and promotes dissociation/exchange of the F-box (substrate-recognition) subunit, regulating the dynamic assembly and cellular repertoire of SCF complexes within the NEDD8/CSN cycle. Human CAND2 acts comparably to CAND1 but with lower exchange efficiency, and the two paralogs can contribute nonredundantly to optimal activity of specific SCF ligases. CAND2 is a regulator/assembly factor, not a ligase.

Molecular Function:
cullin family protein binding
Directly Involved In:
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 that promotes the exchange of the substrate-recognition F-box subunit in SCF 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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:12207886
TBP-interacting protein 120B, which is induced in relation to myogenesis, binds to NOT3.
  • TIP120B is specifically expressed in muscle and induced during myogenesis (unlike ubiquitously expressed TIP120A/CAND1, a transcriptional activator); TIP120B binds the CCR4-NOT complex subunit NOT3/CNOT3.
PMID:12692129
Proteolytic targeting of transcriptional regulator TIP120B by a HECT domain E3 ligase.
  • TIP120B (but not TIP120A/CAND1) is a specific in vitro substrate of the HECT E3 ligase KIAA10/UBE3C, which associates with TIP120B via its N-domain and targets it for proteasomal degradation; localizes to the cytosol.
PMID:23864651
The identification of novel proteins that interact with the GLP-1 receptor and restrain its activity.
  • A membrane yeast two-hybrid screen for GLP-1 receptor interactors identified CAND2 among candidate interactors that can modulate GLP-1R signaling.
PMID:32296183
A reference map of the human binary protein interactome.
file:human/CAND2/CAND2-deep-research-falcon.md
Falcon deep research report for human CAND2
  • CAND2/TIP120B is a large HEAT/ARM-repeat cullin-binding protein of the CAND family that regulates cullin-RING ligases (CRLs) and is not itself an enzyme; it is the muscle-enriched paralog of CAND1.
    "Primary literature explicitly equates TIP120B with CAND2 and places it in the **CAND family** of large HEAT/ARM-repeat cullin-binding proteins involved in **cullin-RING ligase (CRL)** regulation (not an enzyme itself)."
  • CAND-family proteins preferentially bind unneddylated cullins; CAND-bound cullins cannot be neddylated and neddylated cullins do not stably bind CAND, placing CAND2 in the NEDD8/CSN CRL-remodeling cycle.
    "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**"
  • Human CAND2 binds the CUL1ยทRBX1 core and functions as an F-box-protein exchange factor that promotes SCF-mediated degradation, analogous to CAND1 but less efficient (higher KM / faster koff).
    "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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient"
  • In skeletal muscle (C2C12), CAND2/TIP120B is induced during myogenic differentiation, binds CUL1, suppresses SCF-dependent ubiquitination and degradation of myogenin, and accelerates differentiation.
    "is induced during myogenic differentiation,"
  • CAND1 and CAND2 can contribute nonredundantly to optimal SCF activity; in the SCF(FBXL5)-IRP2 pathway loss of either slows IRP2 degradation, and ectopic CAND2 rescues an SCF substrate (p-IkBalpha) in CAND1/CAND2 double-knockout cells.
    "in the **SCFFBXL5โ€“IRP2** pathway, IRP2 half-life increased **2.8-fold in DKO**, **1.7-fold in CAND1-KO**, and **1.8-fold in CAND2-KO**, indicating both proteins contribute to optimal SCF function in that context"

Suggested Questions for Experts

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?

Suggested Experiments

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.

Deep Research

Falcon

(CAND2-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 37 citations 3 artifacts 2026-06-13T07:27:30.784224
Edison artifact artifact-00 (text/markdown)
Edison artifact artifact-01 (text/markdown)
## Context ID: pqac-00000020 The main mechanism and supporting assays for TIP120B (CAND2) action on CUL1 and myogenin are shown in the following figures: - **Fi (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

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Comprehensive research report: Human CAND2 (UniProt O75155; gene CAND2, synonyms TIP120B/KIAA0667)

0) Target verification (critical disambiguation)

The UniProt accession O75155 corresponds to human CAND2, also called TIP120B, described as โ€œcullin-associated and neddylation-dissociated protein 2.โ€ Primary literature explicitly equates TIP120B with CAND2 and places it in the CAND family of large HEAT/ARM-repeat cullin-binding proteins involved in cullin-RING ligase (CRL) regulation (not an enzyme itself). The founding cullin-binding work also identifies CAND2/TIP120B as the muscle-enriched homolog of CAND1, consistent with the UniProt description (liu2002nedd8modificationof pages 1-2, shiraishi2007tbpinteractingprotein120b pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 Cullin-RING ligases (CRLs) and SCF complexes

CRLs are modular E3 ubiquitin ligases built around a cullin scaffold (e.g., CUL1) and a RING protein (e.g., RBX1) that recruits E2~ubiquitin, while variable substrate receptor modules provide target specificity. For the canonical SCF complex, SKP1 links CUL1โ€“RBX1 to one of many F-box proteins, enabling recognition of specific substrates (wang2025molecularmechanismsof pages 1-2).

1.2 Neddylation/deneddylation cycle (NEDD8 and CSN) and where CAND proteins fit

A central regulatory circuit for CRLs is the NEDD8 cycle:
- Neddylation (conjugation of NEDD8 to a cullin) promotes CRL activation.
- Deneddylation is catalyzed by the COP9 signalosome (CSN), reversing NEDD8 attachment and shifting CRLs toward states compatible with remodeling.
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 (wang2024cand1inhibitscullin2ring pages 1-3). Reviews integrate this into a dynamic model in which CSN-dependent deneddylation enables CAND-dependent remodeling/exchange of substrate receptor modules (harper2021cullinringubiquitinligase pages 20-21, zhang2024proteinneddylationand pages 8-10, wang2020assemblyandregulation pages 1-3).

1.3 What CAND2 is (and is not)

CAND2 is best understood as a proteinโ€“protein interaction scaffold/regulator (HEAT/ARM-repeat protein) rather than a catalytic enzyme. Foundational work on CAND proteins reports extensive HEAT-repeat architecture (25 HEAT motifs described for human CAND proteins) consistent with flexible scaffolding roles in multi-protein complex control (liu2002nedd8modificationof pages 1-2).

2) Core molecular function of CAND2 (human): mechanistic evidence

2.1 CAND2 binds CUL1 and associates with SCF complexes

In muscle-cell models (C2C12), TIP120B/CAND2 co-immunoprecipitates with CUL1 under overexpression and at endogenous levels in differentiated cells; microscopy shows broad cellular distribution with slight nuclear enrichment and co-localization with CUL1 (shiraishi2007tbpinteractingprotein120b pages 6-7). These data establish a direct physical basis for CAND2โ€™s effect on SCF activity.

2.2 Substrate-level functional output: inhibition of SCF-mediated ubiquitination of myogenin

A key physiologic context where CAND2 was experimentally assigned a role is myogenesis. Shiraishi et al. (2007) report that TIP120B/CAND2:
- is induced during myogenic differentiation,
- suppresses SCF-dependent ubiquitination and degradation of myogenin, and
- accelerates myogenic differentiation, consistent with stabilization of a differentiation-driving transcription factor (shiraishi2007tbpinteractingprotein120b pages 1-2).
Mechanistically, the authors propose that CAND2 binding to CUL1 leads to breakdown/dissociation of the SCFโ€“myogenin complex, thereby reducing myogenin ubiquitination and proteasomal turnover (shiraishi2007tbpinteractingprotein120b pages 1-2, shiraishi2007tbpinteractingprotein120b media bfb814a0).

2.3 Updated mechanistic model: CAND2 as an F-box protein exchange factor (most direct modern evidence)

The most direct, up-to-date mechanistic dissection in the provided evidence base is 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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient (wang2025molecularmechanismsof pages 1-2).
Key quantitative findings from this study include:
- CAND2-catalyzed SCF disassembly shows higher KM (lower apparent exchange efficiency) than CAND1, while binding CUL1 with comparable structure/affinity (wang2025molecularmechanismsof pages 1-2, wang2025molecularmechanismsof pages 10-10).
- Kinetic parameters (mean ยฑ SEM; n=5) reported: CAND2 koff = 4.4 sโˆ’1; KM = 648 nM vs CAND1 koff = 2.5 sโˆ’1; KM = 355 nM (wang2025molecularmechanismsof pages 10-10).
- Functional overlap with CAND1 is pathway-dependent: in CAND1/CAND2 double knockout (DKO) cells, CAND2HA supplementation restored p-IฮบBฮฑ degradation, demonstrating capacity to support an SCF pathway in cells (wang2025molecularmechanismsof pages 1-2).
- Nonredundant contribution is shown for another SCF: in the SCFFBXL5โ€“IRP2 pathway, IRP2 half-life increased 2.8-fold in DKO, 1.7-fold in CAND1-KO, and 1.8-fold in CAND2-KO, indicating both proteins contribute to optimal SCF function in that context (wang2025molecularmechanismsof pages 1-2).

Interpretation: across historical and modern data, CAND2 appears capable of both inhibitory behavior in specific contexts (e.g., stabilizing myogenin by disrupting SCF targeting) and pro-exchange/pro-turnover behavior consistent with the broader CAND-family role in SCF dynamics. This apparent โ€œparadoxโ€ is a known theme in CRL regulation and is framed in authoritative reviews as emerging from the requirement for dynamic receptor exchange and cycling (harper2021cullinringubiquitinligase pages 20-21, wang2020assemblyandregulation pages 1-3).

3) Localization and tissue context

3.1 Tissue enrichment

Foundational cullin-binding work identifies CAND2/TIP120B as specifically expressed in muscle tissues, distinguishing it from more ubiquitous CAND1 (liu2002nedd8modificationof pages 1-2). The myogenesis-focused study operationalizes this in a skeletal muscle differentiation model (C2C12), showing induction with differentiation (shiraishi2007tbpinteractingprotein120b pages 1-2).

3.2 Subcellular localization

CAND2 localization has been observed as broadly cellular with slight nuclear enrichment in C2C12 cells when visualized as GFP-TIP120B; CUL1 is present in both nucleus and cytoplasm and co-localizes with TIP120B (shiraishi2007tbpinteractingprotein120b pages 6-7). A recent mechanistic paper also reports database-supported localization for CAND2 in cytosol and nuclear bodies (wang2025molecularmechanismsof pages 10-10).

4) Pathways and interaction partners (functional annotation level)

4.1 Primary pathway: SCF/CRL1 regulation within the NEDD8โ€“CSN cycle

CAND2โ€™s best-supported pathway placement is as a regulator of CUL1-based SCF ligases, whose dynamic assembly/remodeling is coupled to the NEDD8 modification state and CSN deneddylation. While many mechanistic details are best established for CAND1, the same regulatory logic is used to interpret CAND2 function as a paralog capable of SCF remodeling (harper2021cullinringubiquitinligase pages 20-21, wang2024cand1inhibitscullin2ring pages 1-3, wang2020assemblyandregulation pages 1-3).

4.2 Validated binding/functional partners and substrates from the provided evidence

  • CUL1: binding and co-localization in muscle cells; required for CAND2-associated SCF regulation (shiraishi2007tbpinteractingprotein120b pages 6-7).
  • SCF complex components (e.g., SKP1): CAND2-mediated SCF complex breakdown/dissociation in the myogenin context (visual evidence includes dissociation assays and model figure) (shiraishi2007tbpinteractingprotein120b media bfb814a0).
  • Myogenin: substrate stabilized by CAND2 through reduced SCF-dependent ubiquitination/degradation (shiraishi2007tbpinteractingprotein120b pages 1-2).
  • FBXL5/IRP2 axis: genetic evidence from KO cells supports that CAND2 contributes to optimal SCFFBXL5-mediated IRP2 degradation (wang2025molecularmechanismsof pages 1-2).

5) Disease associations and real-world applications/implementations

5.1 Atrial fibrillation (AF) genetics at the CAND2 locus (rs4642101)

CAND2 is implicated in AF susceptibility primarily through intronic variant rs4642101 at the CAND2 locus:
- A large AF GWAS-integrative study reported rs4642101 as a novel AF risk locus in Europeans with RR = 1.10 (95% CI 1.06โ€“1.14; P = 9.8ร—10โˆ’9), with discovery including 6,707 AF cases and 52,426 controls and further replication/meta-analytic support (sinner2014integratinggenetictranscriptional pages 9-12).
- Supplemental eQTL results reported significant eQTLs for CAND2 in skeletal muscle (and also thyroid) for proxy SNPs linked to the rs4642101 signal, supporting a regulatory mechanism affecting CAND2 expression (sinner2014integratinggenetictranscriptional pages 63-64).

A clinically closer implementation setting is postoperative AF:
- A prospective two-stage nested case-control study among Chinese patients undergoing CABG (total 1,400 patients) found rs4642101 associated with postoperative AF risk with pooled OR = 1.21 (95% CI 1.08โ€“1.36; P = 9.8ร—10โˆ’4) per minor allele; genotype risks versus TT included TG OR โ‰ˆ 1.24 and GG OR โ‰ˆ 1.38 in pooled analyses (stage-specific genotype ORs were also reported) (wei2016neurlrs6584555and pages 1-2, wei2016neurlrs6584555and pages 2-5).
- The same study reports that the AF risk allele correlated with increased CAND2 expression in right atrial appendage samples (P < 0.001) (wei2016neurlrs6584555and pages 1-2, wei2016neurlrs6584555and pages 2-5).

Caveat on generalizability: replication in Chinese Han AF case-control cohorts has shown heterogeneity; one study reported no significant allelic association for rs4642101 with AF (OR around ~1.09 with CI spanning 1.0), suggesting population- and design-dependent detectability of this modest effect (wang2018genomicvariantsin pages 2-3).

5.2 Cardiovascular remodeling linkage (mechanistic/functional)

In a cardiac remodeling model, Cand2 was reported to be translationally regulated by mTORC1 and to promote adverse remodeling via a mechanism involving CUL1 and stabilization of GRK5. Quantitative findings include that neddylation inhibition (MLN4924) increased GRK5 protein ~2.5-fold, CUL1 knockdown increased GRK5 ~2-fold, and Cand2 overexpression increased GRK5 half-life from ~18 to ~27 hours (gorska2020musclespecifictranslational pages 7-8). Although this study is in mouse/cardiomyocyte contexts, it is widely cited as mechanistically linking Cand2 to cardiac pathology (diaz2022rolesofcullinring pages 20-21).

5.3 โ€œApplicationsโ€ in practice

CAND2 is not currently a routine therapeutic target; the most concrete real-world uses supported by the provided evidence are:
- Genetic risk stratification research for AF/POAF via variants at the CAND2 locus (rs4642101) (wei2016neurlrs6584555and pages 1-2, sinner2014integratinggenetictranscriptional pages 9-12).
- Pathway-informed interpretation in drug discovery/chemical biology targeting the neddylation/CRL axis: although CAND1 is emphasized in 2023โ€“2024 mechanistic advances, these works shape how CAND2 is interpreted as part of the same CRL-cycling circuitry (zhang2024proteinneddylationand pages 8-10, wang2024cand1inhibitscullin2ring pages 1-3).

6) Recent developments (prioritizing 2023โ€“2024 sources, with explicit evidence limits)

The provided 2023โ€“2024 literature capture contained limited direct primary human CAND2 experimentation; most 2023โ€“2024 content was indirect (CAND1/CRL-cycle and neddylation pathway updates). The most relevant 2023โ€“2024 sources for context include:
- A 2024 review synthesizing neddylation biology and reiterating the CANDโ€“CSNโ€“NEDD8 regulatory logic for CRLs (zhang2024proteinneddylationand pages 8-10).
- A 2024 Nature Structural & Molecular Biology study refining the concept that CAND-family regulation can be cullin-specific (e.g., inhibitory behavior for CRL2), emphasizing that CAND effects are not uniformly activatingโ€”important when inferring potential CAND2 behavior beyond SCF/CRL1 (wang2024cand1inhibitscullin2ring pages 1-3, wang2024cand1inhibitscullin2ring pages 8-9).
- A 2023 Cell commentary framing CAND1 (and homolog CAND2) as exchange-factor-like regulators in updated models of SCF repertoire control (wang2025molecularmechanismsof pages 10-10).

Because of this evidence gap, the newest direct mechanistic clarification for human CAND2 in the provided materials comes from 2025 publication (received 2024), which is included above for completeness (wang2025molecularmechanismsof pages 1-2).

7) Expert opinions / authoritative synthesis

Authoritative reviews in the CRL field emphasize that apparent inhibitory effects of CAND proteins in isolated assays coexist with in vivo requirements for dynamic remodeling of CRLs. This โ€œregulatory circuitโ€ framingโ€”integrating neddylation, CSN deneddylation, and CAND-mediated substrate receptor exchangeโ€”is the prevailing conceptual model used to interpret CAND-family function, and provides the most robust basis for annotating CAND2 as a regulator of SCF/CRL dynamics rather than a simple inhibitor (harper2021cullinringubiquitinligase pages 20-21, wang2020assemblyandregulation pages 1-3).

8) Summary tables (evidence-based)

Two structured summaries are provided below:

Claim/Function Molecular mechanism Key partners/substrates Evidence type (biochemical/cell/animal/genetics/review) Key quantitative data Primary sources (include DOI URLs and year)
Human CAND2/TIP120B is the validated mammalian homolog/paralog of CAND1 and belongs to the cullin-associated, NEDD8-dissociated protein family Foundational work identified CAND2/TIP120B as a highly related mammalian homolog of CAND1; CAND proteins are large HEAT-repeat cullin-binding factors associated with deneddylated cullins CUL1 and other cullins; CAND family Biochemical, review CAND1/CAND2 share 63% sequence identity; human CAND proteins contain 25 HEAT motifs Liu et al., 2002, https://doi.org/10.1016/S1097-2765(02)00783-9; Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (liu2002nedd8modificationof pages 1-2, wang2025molecularmechanismsof pages 1-2)
CAND2 binds cullins, especially CUL1, and associates with SCF complexes in muscle cells TIP120B/CAND2 physically associates with CUL1 under overexpression and endogenous conditions; both N- and C-terminal regions are required for efficient CUL1 association; this cullin binding underlies its regulatory effect on SCF CUL1, SCF complex, SKP1 Biochemical, cell C-terminal truncation largely abolishes CUL1 binding; qualitative co-localization shows ubiquitous distribution with slight nuclear concentration Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200 (shiraishi2007tbpinteractingprotein120b pages 1-2, shiraishi2007tbpinteractingprotein120b pages 6-7)
CAND2 inhibits SCF-dependent ubiquitination of myogenin and stabilizes myogenin during myogenic differentiation By binding CUL1, CAND2 disrupts or breaks down the SCF-myogenin complex, reducing SCF-dependent ubiquitination and proteasomal degradation of myogenin, thereby accelerating differentiation Myogenin, CUL1, SCF Biochemical, cell, review MyoD half-life cited as ~60 min for context; direct quantitative half-life for myogenin not provided in extracted text Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (shiraishi2007tbpinteractingprotein120b pages 1-2, shiraishi2007tbpinteractingprotein120b pages 6-7, diaz2022rolesofcullinring pages 20-21)
CAND2 is muscle-enriched/muscle-specific in expression Primary and review sources describe CAND2/TIP120B as a muscle-specific isoform/paralog, distinguishing it from ubiquitously expressed CAND1 Striated muscle tissues; skeletal/cardiac muscle Biochemical, review No absolute expression value in extracted text; described as muscle-specific and detected in striated muscle/testis in review summary Liu et al., 2002, https://doi.org/10.1016/S1097-2765(02)00783-9; Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (liu2002nedd8modificationof pages 1-2, shiraishi2007tbpinteractingprotein120b pages 1-2, diaz2022rolesofcullinring pages 20-21)
Subcellular localization of CAND2 includes cytosol and nucleus/nuclear bodies In C2C12 cells, GFP-TIP120B is observed throughout the cell with slight nuclear enrichment and co-localizes with CUL1; recent summary cites Human Protein Atlas localization to cytosol and nuclear bodies CUL1; nuclear bodies; cytosol Cell, database-backed summary Qualitative localization only in C2C12 assays; no percentages reported Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (shiraishi2007tbpinteractingprotein120b pages 6-7, wang2025molecularmechanismsof pages 10-10)
Current mechanistic understanding: CAND2 can promote SCF dynamics as an F-box protein exchange factor in human cells, but is less efficient than CAND1 CAND2 binds the CUL1ยทRBX1 core similarly to CAND1 and promotes SCF-mediated protein degradation by catalyzing exchange/disassembly of SKP1ยทF-box modules; higher KM indicates lower exchange efficiency, potentially allowing longer retention of F-box proteins on CUL1 CUL1, RBX1, SKP1ยทFBP modules, SCF Biochemical, cell CAND2 koff = 4.4 s^-1 and KM = 648 nM vs CAND1 koff = 2.5 s^-1 and KM = 355 nM (n = 5); weaker activity attributed to higher KM Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (wang2025molecularmechanismsof pages 10-10, wang2025molecularmechanismsof pages 1-2)
CAND2 can support SCF activity in cells and partially overlaps functionally with CAND1 In CAND1/CAND2 double-knockout cells, ectopic CAND2 restores degradation of an SCF substrate, indicating that CAND2 is competent to promote SCF function in vivo, although CAND1 dominates some pathways SCFฮฒ-TrCP, phospho-IฮบBฮฑ Cell p-IฮบBฮฑ degradation rescued by CAND2HA in DKO cells; no defect in CAND2 single-KO for this pathway Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (wang2025molecularmechanismsof pages 1-2)
Both CAND1 and CAND2 are required for optimal activity of at least some SCF ligases In the SCFFBXL5 pathway, loss of either CAND1 or CAND2 slows degradation of IRP2, indicating nonredundant contribution to optimal SCF function FBXL5, IRP2, CUL1-based SCF Cell IRP2 half-life increased 2.8-fold in CAND1/CAND2 DKO, 1.7-fold in CAND1-KO, and 1.8-fold in CAND2-KO Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (wang2025molecularmechanismsof pages 1-2)
In cardiac muscle, Cand2 is translationally upregulated by mTORC1 and promotes adverse remodeling via Grk5 stabilization Cand2 binds/sequesters unneddylated CUL1, altering the neddylated CUL1 pool and reducing Cul1-mediated degradation of Grk5; this links mTORC1-driven translational control to pathological cardiac growth mTORC1, CUL1, GRK5 Cell, animal, review MLN4924 raises GRK5 protein ~2.5-fold; CUL1 knockdown raises GRK5 ~2-fold; Cand2 overexpression prolongs GRK5 half-life from ~18 h to ~27 h Gรณrska et al., 2021, https://doi.org/10.15252/embr.202052170; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (gorska2020musclespecifictranslational pages 7-8, diaz2022rolesofcullinring pages 20-21)
CAND2 has human cardiovascular genetics support, especially for atrial fibrillation/postoperative AF risk AF-associated intronic variant rs4642101 near/in CAND2 is associated with higher CAND2 expression and increased AF/POAF susceptibility in human cohorts; functional zebrafish validation implicated the locus in atrial electrophysiology rs4642101; atrial fibrillation; postoperative AF Genetics AF GWAS: RR 1.10, 95% CI 1.06โ€“1.14, P = 9.8ร—10^-9; cis-eQTL P = 2.6ร—10^-19; zebrafish Cand2 knockdown prolonged atrial APD by 45%; POAF after CABG OR 1.21 per minor allele, 95% CI 1.08โ€“1.36, P = 9.8ร—10^-4 Sinner et al., 2014, https://doi.org/10.1161/CIRCULATIONAHA.114.009892; Wei et al., 2016, https://doi.org/10.18632/oncotarget.9422 (diaz2022rolesofcullinring pages 20-21)
CAND proteins are integrated into the CRL neddylation/deneddylation cycle that controls SCF remodeling In the general CRL cycle, CAND proteins bind unneddylated cullins; neddylation prevents stable CAND binding, whereas CSN-mediated deneddylation restores a state permissive for CAND-dependent receptor exchange and remodeling NEDD8, CSN, CUL1/RBX1, SKP1ยทF-box modules Review, biochemical For CAND1-CUL2, neddylation increased dissociation rate ~5-fold (t1/2 20 min to 4 min), illustrating the principle that neddylation destabilizes CAND-cullin binding Harper & Schulman, 2021, https://doi.org/10.1146/annurev-biochem-090120-013613; Zhang et al., 2024, https://doi.org/10.1038/s41392-024-01800-9; Wang et al., 2024, https://doi.org/10.1038/s41594-023-01167-5; Wang et al., 2020, https://doi.org/10.1007/978-981-15-1025-0_3 (harper2021cullinringubiquitinligase pages 20-21, zhang2024proteinneddylationand pages 8-10, wang2024cand1inhibitscullin2ring pages 1-3, wang2024cand1inhibitscullin2ring pages 8-9, wang2020assemblyandregulation pages 1-3)

Table: This table summarizes validated functional annotation for human CAND2/TIP120B (UniProt O75155), including core molecular roles, key partners, localization, and disease-linked findings. It emphasizes primary-source evidence and quantitative data available from the provided context IDs.

Year Study (first author) Publication type Whatโ€™s new (1โ€“2 sentences) Relevance to CAND2 (direct/indirect) Key data/metrics URL/DOI
2024 Zhang Review Synthesizes the current neddylation field and reiterates the core regulatory logic that CAND proteins bind unneddylated cullins, while CSN-mediated deneddylation restores a CAND-accessible state. This is useful pathway context for interpreting how human CAND2 should function within CRL cycling, even though the review focuses mainly on CAND1. (zhang2024proteinneddylationand pages 8-10) Indirect Describes structural precedents for CAND1-cullin complexes and the CAND/CSN/NEDD8 cycle; no CAND2-specific quantitative dataset reported in the extracted context. (zhang2024proteinneddylationand pages 8-10) https://doi.org/10.1038/s41392-024-01800-9
2024 Wang Primary research (Nature Structural & Molecular Biology) Shows that CAND1 can inhibit CRL2 assembly/activity rather than simply acting as a universal exchange activator, refining the broader CRL regulatory model. This is important for CAND2 annotation because it argues that CAND-family effects are cullin-context dependent, not uniformly activating or inhibitory. (wang2024cand1inhibitscullin2ring pages 3-4, wang2024cand1inhibitscullin2ring pages 1-3, wang2024cand1inhibitscullin2ring pages 8-9) Indirect For CUL2ยทCAND1, neddylation increased dissociation ~5-fold, shortening t1/2 from ~20 min to ~4 min; MLN4924 stabilized a CRL2 substrate, and CSN inhibition mildly enhanced degradation in the reported system. (wang2024cand1inhibitscullin2ring pages 3-4, wang2024cand1inhibitscullin2ring pages 8-9) https://doi.org/10.1038/s41594-023-01167-5
2023 Xie Commentary/News & Views-style article Highlights 2023 advances establishing CAND1 as a dynamic CRL assembly/disassembly factor and explicitly notes that CAND1 and its homolog CAND2 can be viewed as exchange-factor-like regulators. It does not add new CAND2 experiments, but it frames how the field interprets CAND-family function. (wang2025molecularmechanismsof pages 10-10) Indirect No new primary CAND2 metrics in the extracted context; conceptual emphasis on exchange-factor behavior of CAND-family proteins. (wang2025molecularmechanismsof pages 10-10) https://doi.org/10.1016/j.cell.2023.04.001
2023โ€“2024 No direct human CAND2 primary study identified in the provided 2023โ€“2024 context IDs Evidence gap statement Within the provided 2023โ€“2024 context, no direct primary study on human CAND2 itself was captured; most recent evidence is pathway-level or CAND1-centered and therefore must be used cautiously for inference. The strongest direct mechanistic human CAND2 study in the available context is from 2025, outside the user-prioritized 2023โ€“2024 window. (wang2025molecularmechanismsof pages 10-10, zhang2024proteinneddylationand pages 8-10, wang2024cand1inhibitscullin2ring pages 3-4, wang2024cand1inhibitscullin2ring pages 1-3, wang2024cand1inhibitscullin2ring pages 8-9) Direct evidence lacking in 2023โ€“2024; indirect inference only Key implication: current 2023โ€“2024 annotation of human CAND2 relies mainly on CAND-family/CRL-cycle context rather than new CAND2-specific experiments in the provided evidence base. (wang2025molecularmechanismsof pages 10-10, zhang2024proteinneddylationand pages 8-10, wang2024cand1inhibitscullin2ring pages 3-4, wang2024cand1inhibitscullin2ring pages 1-3, wang2024cand1inhibitscullin2ring pages 8-9) n/a

Table: This table summarizes the most relevant 2023โ€“2024 studies in the provided evidence base for interpreting human CAND2 function and pathway context. It also makes explicit that direct human CAND2 primary evidence was not captured in the provided 2023โ€“2024 contexts, so recent annotation depends largely on indirect CAND-family and CRL-cycle studies.

9) Key figure evidence (visual support)

The mechanistic model and core biochemical evidence for CAND2/TIP120B disrupting SCF-dependent ubiquitination of myogenin are captured in figures retrieved from Shiraishi et al. 2007, including the proposed mechanism schematic and binding/ubiquitination/dissociation assays (shiraishi2007tbpinteractingprotein120b media bfb814a0, shiraishi2007tbpinteractingprotein120b media 11601d20, shiraishi2007tbpinteractingprotein120b media 792fadc0, shiraishi2007tbpinteractingprotein120b media c323ecb5).

10) Concise functional annotation statement (for databases / reports)

CAND2 (TIP120B; UniProt O75155) is a HEAT/ARM-repeat cullin-binding regulator enriched in striated muscle that modulates CUL1-based SCF ubiquitin ligases within the NEDD8/CSN CRL-cycling system. Experimentally, CAND2 binds CUL1 and can suppress SCF-dependent ubiquitination of specific substrates (e.g., myogenin) in myogenic differentiation, while newer mechanistic work indicates it can also act as an F-box protein exchange factor that promotes SCF-mediated protein turnover in a pathway-dependent manner. Genetic evidence links regulatory variation at the CAND2 locus (rs4642101) to atrial fibrillation and postoperative atrial fibrillation risk, with eQTL support for altered CAND2 expression in relevant tissues (wang2025molecularmechanismsof pages 1-2, shiraishi2007tbpinteractingprotein120b pages 1-2, wei2016neurlrs6584555and pages 1-2, sinner2014integratinggenetictranscriptional pages 9-12).

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  16. (gorska2020musclespecifictranslational pages 7-8): Agnieszka A. Gorska, Clara Sandmann, Eva Riechert, Christoph Hofmann, Ellen Malovrh, Eshita Varma, Vivien Kmietczyk, Lonny Jรผrgensen, Verena Kamuf-Schenk, Claudia Stroh, Jennifer Furkel, Matthias H. Konstandin, Carsten Sticht, Etienne Boileau, Christoph Dieterich, Hugo A. Katus, Shirin Doroudgar, and Mirko Vรถlkers. Muscle specific translational control of cand2 by mtorc1 regulates adverse cardiac remodeling. BioRxiv, Dec 2020. URL: https://doi.org/10.1101/2020.11.29.403196, doi:10.1101/2020.11.29.403196. This article has 0 citations.

  17. (diaz2022rolesofcullinring pages 20-21): Stephanie Diaz, Kankan Wang, Benita Sjรถgren, and Xing Liu. Roles of cullin-ring ubiquitin ligases in cardiovascular diseases. Biomolecules, 12:416, Mar 2022. URL: https://doi.org/10.3390/biom12030416, doi:10.3390/biom12030416. This article has 25 citations.

  18. (wang2024cand1inhibitscullin2ring pages 8-9): Kankan Wang, Stephanie Diaz, Lihong Li, Jeremy R. Lohman, and Xing Liu. Cand1 inhibits cullin-2-ring ubiquitin ligases for enhanced substrate specificity. Nature Structural & Molecular Biology, pages 1-13, Jan 2024. URL: https://doi.org/10.1038/s41594-023-01167-5, doi:10.1038/s41594-023-01167-5. This article has 6 citations and is from a highest quality peer-reviewed journal.

  19. (wang2024cand1inhibitscullin2ring pages 3-4): Kankan Wang, Stephanie Diaz, Lihong Li, Jeremy R. Lohman, and Xing Liu. Cand1 inhibits cullin-2-ring ubiquitin ligases for enhanced substrate specificity. Nature Structural & Molecular Biology, pages 1-13, Jan 2024. URL: https://doi.org/10.1038/s41594-023-01167-5, doi:10.1038/s41594-023-01167-5. This article has 6 citations and is from a highest quality peer-reviewed journal.

  20. (shiraishi2007tbpinteractingprotein120b media 11601d20): Seiji Shiraishi, Chang Zhou, Tsutomu Aoki, Naruki Sato, Tomoki Chiba, Keiji Tanaka, Shosei Yoshida, Yoko Nabeshima, Yo-ichi Nabeshima, and Taka-aki Tamura. Tbp-interacting protein 120b (tip120b)/cullin-associated and neddylation-dissociated 2 (cand2) inhibits scf-dependent ubiquitination of myogenin and accelerates myogenic differentiation*. Journal of Biological Chemistry, 282:9017-9028, Mar 2007. URL: https://doi.org/10.1074/jbc.m611513200, doi:10.1074/jbc.m611513200. This article has 57 citations and is from a domain leading peer-reviewed journal.

  21. (shiraishi2007tbpinteractingprotein120b media 792fadc0): Seiji Shiraishi, Chang Zhou, Tsutomu Aoki, Naruki Sato, Tomoki Chiba, Keiji Tanaka, Shosei Yoshida, Yoko Nabeshima, Yo-ichi Nabeshima, and Taka-aki Tamura. Tbp-interacting protein 120b (tip120b)/cullin-associated and neddylation-dissociated 2 (cand2) inhibits scf-dependent ubiquitination of myogenin and accelerates myogenic differentiation*. Journal of Biological Chemistry, 282:9017-9028, Mar 2007. URL: https://doi.org/10.1074/jbc.m611513200, doi:10.1074/jbc.m611513200. This article has 57 citations and is from a domain leading peer-reviewed journal.

  22. (shiraishi2007tbpinteractingprotein120b media c323ecb5): Seiji Shiraishi, Chang Zhou, Tsutomu Aoki, Naruki Sato, Tomoki Chiba, Keiji Tanaka, Shosei Yoshida, Yoko Nabeshima, Yo-ichi Nabeshima, and Taka-aki Tamura. Tbp-interacting protein 120b (tip120b)/cullin-associated and neddylation-dissociated 2 (cand2) inhibits scf-dependent ubiquitination of myogenin and accelerates myogenic differentiation*. Journal of Biological Chemistry, 282:9017-9028, Mar 2007. URL: https://doi.org/10.1074/jbc.m611513200, doi:10.1074/jbc.m611513200. This article has 57 citations and is from a domain leading peer-reviewed journal.

Artifacts

Citations

  1. wang2025molecularmechanismsof pages 1-2
  2. wang2025molecularmechanismsof pages 10-10
  3. sinner2014integratinggenetictranscriptional pages 9-12
  4. sinner2014integratinggenetictranscriptional pages 63-64
  5. wang2018genomicvariantsin pages 2-3
  6. gorska2020musclespecifictranslational pages 7-8
  7. diaz2022rolesofcullinring pages 20-21
  8. zhang2024proteinneddylationand pages 8-10
  9. harper2021cullinringubiquitinligase pages 20-21
  10. wang2020assemblyandregulation pages 1-3
  11. https://doi.org/10.1016/S1097-2765(02
  12. https://doi.org/10.1038/s41467-025-57065-5
  13. https://doi.org/10.1074/jbc.M611513200
  14. https://doi.org/10.1074/jbc.M611513200;
  15. https://doi.org/10.3390/biom12030416
  16. https://doi.org/10.15252/embr.202052170;
  17. https://doi.org/10.1161/CIRCULATIONAHA.114.009892;
  18. https://doi.org/10.18632/oncotarget.9422
  19. https://doi.org/10.1146/annurev-biochem-090120-013613;
  20. https://doi.org/10.1038/s41392-024-01800-9;
  21. https://doi.org/10.1038/s41594-023-01167-5;
  22. https://doi.org/10.1007/978-981-15-1025-0_3
  23. https://doi.org/10.1038/s41392-024-01800-9
  24. https://doi.org/10.1038/s41594-023-01167-5
  25. https://doi.org/10.1016/j.cell.2023.04.001
  26. https://doi.org/10.1016/s1097-2765(02
  27. https://doi.org/10.1074/jbc.m611513200,
  28. https://doi.org/10.1038/s41467-025-57065-5,
  29. https://doi.org/10.1038/s41594-023-01167-5,
  30. https://doi.org/10.1146/annurev-biochem-090120-013613,
  31. https://doi.org/10.1038/s41392-024-01800-9,
  32. https://doi.org/10.1007/978-981-15-1025-0_3,
  33. https://doi.org/10.1161/circulationaha.114.009892,
  34. https://doi.org/10.18632/oncotarget.9422,
  35. https://doi.org/10.1038/s41598-018-21611-7,
  36. https://doi.org/10.1101/2020.11.29.403196,
  37. https://doi.org/10.3390/biom12030416,

๐Ÿ“š Additional Documentation

Pn Notes

(CAND2-pn-notes.md)

CAND2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O75155
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 2; NEW: 1

PN Consistency Summary

  • Consistency: Deep research (falcon, HIGH), review YAML, and the dossier note all agree on the substance: CAND2/TIP120B is a muscle-enriched, non-catalytic CAND-family CRL/SCF F-box exchange factor (paralog of CAND1, less efficient; Wang 2025 kinetics, Shiraishi 2007 myogenin/CUL1, Liu 2002). All 14 GOA rows are reviewed. One framing mismatch: the PN node projects an activator term, but the review (correctly) stresses CAND2 can be functionally inhibitory in muscle (it suppresses SCF-mediated myogenin ubiquitination).
  • PN story / NEW pressure: The PN core MF (cullin-RBX binding / exchange-factor activity) is genuinely absent from GOA. The review adds GO:0097602 cullin family protein binding as NEW (verified real, ISS basis) โ€” well-justified and the right altitude. No catalytic-ligase term assigned (correct). SCF complex assembly (GO:0010265) already captures the BP.
  • Evidence alignment: Divergent. PN cites only PMID:40011427 (the 2025 CAND2 exchange-factor paper); the review captures this same study via the falcon report (Wang 2025 Nat Commun) but does not list PMID:40011427 in references. Review PMIDs (12207886, 12692129, 23864651, 32296183) are not in the PN row.
  • Verdict: Substantively consistent; PN activator mapping (GO:1990757) over-reaches and conflicts with the review's non-catalytic/context-inhibitory exchange-factor framing. Prefer review's GO:0097602 + GO:0010265. Recommended edits: [MAP] downgrade CAND2 type/subtype GO:1990757 mapping toward exchange-factor/cullin-binding (GO:0097602) or context_only, rather than "activator". [REF] add PMID:40011427 to CAND2 review references (currently only cited via falcon report).

Full Consistency Review

  • UniProt: O75155 ยท batch: proteostasis-batch-2026-06-13 ยท review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|CRL regulator|F-box exchange factor|Armadillo-like ; PN-node mapping: type/subtype mapped, scope=ok_for_propagation_to_go, GO:1990757 ubiquitin ligase activator activity (group/class context_only; branch no_mapping)
  • Consistency: Deep research (falcon, HIGH), review YAML, and the dossier note all agree on the substance: CAND2/TIP120B is a muscle-enriched, non-catalytic CAND-family CRL/SCF F-box exchange factor (paralog of CAND1, less efficient; Wang 2025 kinetics, Shiraishi 2007 myogenin/CUL1, Liu 2002). All 14 GOA rows are reviewed. One framing mismatch: the PN node projects an activator term, but the review (correctly) stresses CAND2 can be functionally inhibitory in muscle (it suppresses SCF-mediated myogenin ubiquitination).
  • PN story / NEW pressure: The PN core MF (cullin-RBX binding / exchange-factor activity) is genuinely absent from GOA. The review adds GO:0097602 cullin family protein binding as NEW (verified real, ISS basis) โ€” well-justified and the right altitude. No catalytic-ligase term assigned (correct). SCF complex assembly (GO:0010265) already captures the BP.
  • Mapping strategy: Concern. GO:1990757 ("Binds to and increases the activity of a ubiquitin ligase" โ€” verified, strictly positive) over-reaches: CAND family activity is directionally context-dependent (exchange/remodeling, inhibitory in the muscle/myogenin context), echoing the dossier's own "different directionality" caveat at the group level. The review deliberately does NOT assign GO:1990757. PN-projected term is broader/mis-directional vs the review's GO:0097602 + GO:0010265.
  • Evidence alignment: Divergent. PN cites only PMID:40011427 (the 2025 CAND2 exchange-factor paper); the review captures this same study via the falcon report (Wang 2025 Nat Commun) but does not list PMID:40011427 in references. Review PMIDs (12207886, 12692129, 23864651, 32296183) are not in the PN row.
  • Verdict: Substantively consistent; PN activator mapping (GO:1990757) over-reaches and conflicts with the review's non-catalytic/context-inhibitory exchange-factor framing. Prefer review's GO:0097602 + GO:0010265. Recommended edits: [MAP] downgrade CAND2 type/subtype GO:1990757 mapping toward exchange-factor/cullin-binding (GO:0097602) or context_only, rather than "activator". [REF] add PMID:40011427 to CAND2 review references (currently only cited via falcon report).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/CAND2/CAND2-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: O75155
  • In branches: UPS
  • Signature domains: (none)
  • Auxiliary domains: IPR011989
  • PN references (titles):
    • 40011427
  • 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.

๐Ÿ“„ View Raw YAML

 
id: O75155
gene_symbol: CAND2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of nuclear localization, consistent with UniProt's reported nuclear localization and the TBP-interaction history.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0010265
    label: SCF complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    additional_reference_ids:
    - file:human/CAND2/CAND2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 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
    - reference_id: file:human/CAND2/CAND2-deep-research-falcon.md
      supporting_text: '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**'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in protein ubiquitination. CAND2 has no ligase activity; it regulates CRL assembly, indirectly affecting ubiquitination flux.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of nuclear localization, transferred from the UniProt subcellular location / mouse ortholog.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0010265
    label: SCF complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment (CAND1/CAND2 family signature IPR039852) of involvement in SCF complex assembly. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with the IBA assignment and consistent with the CAND family's exchange-factor role.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23864651
  qualifier: enables
  review:
    summary: Membrane yeast two-hybrid interaction with the GLP-1 receptor (GLP1R) from a screen for GLP-1R interactors. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 'O75155; P43220: GLP1R; NbExp=2; IntAct=EBI-5656182, EBI-7466542;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interactions (e.g. SYP, FHL2, CIDEB). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 'O75155; P08247: SYP; NbExp=3; IntAct=EBI-5656182, EBI-9071725;'
- term:
    id: GO:0017025
    label: TBP-class protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-based electronic assignment of TBP-class protein binding, reflecting the original identification of TIP120B as a TBP-interacting protein.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: 'SUBUNIT: Binds TBP, CNOT3 and UBE3C.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:12692129
  qualifier: located_in
  review:
    summary: Direct (ARUK-UCL curated) evidence for cytosolic localization from the study of TIP120B targeting by the HECT E3 KIAA10/UBE3C.
    action: ACCEPT
    reason: IDA-supported localization; a cytosolic pool is consistent with CAND2's role with cytoplasmic CRL components.
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: TBP-interacting protein of 120 kDa B
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of a transcriptional activator role, transferred from the mouse ortholog (P97536/TIP120A-related) and reflecting the TBP-interacting protein origin.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:12207886
      supporting_text: Classical TIP120, TIP120A, which functions as a transcriptional activator, is expressed ubiquitously whereas TIP120B is specifically expressed in muscle tissues
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12207886
  qualifier: enables
  review:
    summary: Yeast two-hybrid / GST pull-down interaction with CNOT3/NOT3 (UniProtKB:O75175). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:12207886
      supporting_text: hNOT3L is associated with TIP120B but not with TIP120A
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12692129
  qualifier: enables
  review:
    summary: Interaction with the HECT E3 ligase KIAA10/UBE3C (UniProtKB:Q15386), which targets TIP120B for proteasomal degradation. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally relevant UBE3C/KIAA10 interaction (CAND2 is its substrate), but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:12692129
      supporting_text: TIP120B, but not the closely related protein TIP120A, is a specific substrate of KIAA10 in vitro
- term:
    id: GO:0097602
    label: cullin family protein binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    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.
    action: NEW
    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.
    additional_reference_ids:
    - file:human/CAND2/CAND2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/CAND2/CAND2-uniprot.txt
      supporting_text: Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes
    - reference_id: file:human/CAND2/CAND2-deep-research-falcon.md
      supporting_text: 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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12207886
  title: TBP-interacting protein 120B, which is induced in relation to myogenesis, binds to NOT3.
  findings:
  - statement: TIP120B is specifically expressed in muscle and induced during myogenesis (unlike ubiquitously expressed TIP120A/CAND1, a transcriptional activator); TIP120B binds the CCR4-NOT complex subunit NOT3/CNOT3.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes TIP120B muscle-specific expression and the CNOT3 interaction; contrasts TIP120B with the transcriptional-activator paralog TIP120A. Abstract-only in cache.
- id: PMID:12692129
  title: Proteolytic targeting of transcriptional regulator TIP120B by a HECT domain E3 ligase.
  findings:
  - statement: TIP120B (but not TIP120A/CAND1) is a specific in vitro substrate of the HECT E3 ligase KIAA10/UBE3C, which associates with TIP120B via its N-domain and targets it for proteasomal degradation; localizes to the cytosol.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the cytosol (IDA) localization and the UBE3C/KIAA10 interaction; establishes CAND2 as a degradation substrate of a HECT E3. Abstract-only in cache.
- id: PMID:23864651
  title: The identification of novel proteins that interact with the GLP-1 receptor and restrain its activity.
  findings:
  - statement: A membrane yeast two-hybrid screen for GLP-1 receptor interactors identified CAND2 among candidate interactors that can modulate GLP-1R signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput GLP-1R interaction screen; source of a bare protein binding (GLP1R) annotation peripheral to CAND2's core function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of several bare protein binding annotations (SYP, FHL2, CIDEB).
- id: file:human/CAND2/CAND2-deep-research-falcon.md
  title: Falcon deep research report for human CAND2
  findings:
  - statement: CAND2/TIP120B is a large HEAT/ARM-repeat cullin-binding protein of the CAND family that regulates cullin-RING ligases (CRLs) and is not itself an enzyme; it is the muscle-enriched paralog of CAND1.
    supporting_text: Primary literature explicitly equates TIP120B with CAND2 and places it in the **CAND family** of large HEAT/ARM-repeat cullin-binding proteins involved in **cullin-RING ligase (CRL)** regulation (not an enzyme itself).
  - statement: CAND-family proteins preferentially bind unneddylated cullins; CAND-bound cullins cannot be neddylated and neddylated cullins do not stably bind CAND, placing CAND2 in the NEDD8/CSN CRL-remodeling cycle.
    supporting_text: '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**'
  - statement: Human CAND2 binds the CUL1ยทRBX1 core and functions as an F-box-protein exchange factor that promotes SCF-mediated degradation, analogous to CAND1 but less efficient (higher KM / faster koff).
    supporting_text: 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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient
  - statement: In skeletal muscle (C2C12), CAND2/TIP120B is induced during myogenic differentiation, binds CUL1, suppresses SCF-dependent ubiquitination and degradation of myogenin, and accelerates differentiation.
    supporting_text: 'is induced during myogenic differentiation,'
  - statement: CAND1 and CAND2 can contribute nonredundantly to optimal SCF activity; in the SCF(FBXL5)-IRP2 pathway loss of either slows IRP2 degradation, and ectopic CAND2 rescues an SCF substrate (p-IkBalpha) in CAND1/CAND2 double-knockout cells.
    supporting_text: 'in the **SCFFBXL5โ€“IRP2** pathway, IRP2 half-life increased **2.8-fold in DKO**, **1.7-fold in CAND1-KO**, and **1.8-fold in CAND2-KO**, indicating both proteins contribute to optimal SCF function in that context'
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon deep-research synthesis; anchors CAND2 as a non-catalytic CAND-family CRL/SCF exchange factor that binds unneddylated CUL1-RBX cores (Wang 2025 kinetics; Shiraishi 2007 myogenin/CUL1; Liu 2002 family identity). Treated as leads cross-checked against UniProt; the muscle/myogenin and F-box-exchange roles are experimentally supported, while AF-locus and cardiac-remodeling associations are genetic/indirect.
core_functions:
- description: Cullin-RING ligase (CRL/SCF) substrate-receptor exchange factor that binds unneddylated cullin-RBX (CUL1-RBX1) cores and promotes dissociation/exchange of the F-box (substrate-recognition) subunit, regulating the dynamic assembly and cellular repertoire of SCF complexes within the NEDD8/CSN cycle. Human CAND2 acts comparably to CAND1 but with lower exchange efficiency, and the two paralogs can contribute nonredundantly to optimal activity of specific SCF ligases. CAND2 is a regulator/assembly factor, not a ligase.
  molecular_function:
    id: GO:0097602
    label: cullin family protein binding
  supported_by:
  - reference_id: file:human/CAND2/CAND2-uniprot.txt
    supporting_text: Probable assembly factor of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes that promotes the exchange of the substrate-recognition F-box subunit in SCF complexes
  - reference_id: file:human/CAND2/CAND2-deep-research-falcon.md
    supporting_text: 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 CUL1ยทRBX1 core, analogous to CAND1 but less efficient
  directly_involved_in:
  - id: GO:0010265
    label: SCF complex assembly
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
- question: 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?
suggested_experiments:
- description: 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.
- description: 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.