KCTD4 encodes a BTB/POZ domain-containing protein belonging to the potassium channel tetramerization domain (KCTD) family. The protein contains an N-terminal BTB/T1 (T1-type BTB) domain that mediates oligomerization, predicted to form pentameric assemblies. Unlike some KCTD family members, KCTD4 is not predicted to form stable complexes with Cullin 3 (Cul3) based on AlphaFold modeling, and is not part of the GABAB receptor-associated KCTD subclade (KCTD8/12/16). KCTD4 can form hetero-oligomeric complexes with other KCTD family members such as KCTD5. The protein is expressed in brain tissue and its precise molecular function remains to be fully characterized experimentally. Limited KCTD4-specific mechanistic literature exists, with function largely inferred from family-level analyses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: KCTD4 contains a BTB/T1 domain that mediates homo-oligomerization, a conserved feature of the KCTD family. Structural predictions indicate KCTD4 forms pentameric assemblies. The BTB domain is well-documented to drive self-association in KCTD proteins (KCTD4-deep-research-falcon.md). Reason: The identical protein binding annotation is well-supported by structural and family-level evidence. KCTD proteins characteristically oligomerize via their N-terminal BTB/T1 domain. AlphaFold-based structural clustering places KCTD4 in a pentameric cluster (Balasco et al. 2024). Family reviews confirm that KCTDs are intracellular proteins whose N-terminal BTB/T1 domain is structurally related to BTB/POZ folds and adapted to drive homo-oligomerization (Teng et al. 2019). Supporting Evidence: file:human/KCTD4/KCTD4-deep-research-falcon.md Structural clustering (AlphaFold/analysis) groups KCTD4 in a pentameric cluster (Cluster 4). file:human/KCTD4/KCTD4-deep-research-falcon.md KCTDs are intracellular proteins whose N-terminal BTB/T1 domain is structurally related to BTB/POZ folds and adapted to drive homo-oligomerization. |
| GO:0051260 protein homooligomerization | IEA GO_REF:0000002 | ACCEPT | Summary: KCTD4 is predicted to form pentameric homooligomers via its BTB/T1 domain, consistent with the structural architecture of other KCTD family members (KCTD4-deep-research-falcon.md). Reason: The protein homooligomerization annotation is supported by structural predictions and family-level evidence. AlphaFold-based analysis specifically assigns KCTD4 to a pentameric assembly cluster (Balasco et al. 2024). The InterPro2GO mapping is appropriate given the T1-type BTB domain (IPR003131) present in KCTD4, which is known to mediate oligomerization. Supporting Evidence: file:human/KCTD4/KCTD4-deep-research-falcon.md Assigned/predicted pentameric assembly for KCTD4. Structural clustering (AlphaFold/analysis) groups KCTD4 in a pentameric cluster (Cluster 4). |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: This annotation derives from a large-scale interactome study examining how disease-associated mutations affect protein-protein interactions. The study was not focused on characterizing KCTD4 function specifically. Reason: Per GO curation guidelines, the term "protein binding" (GO:0005515) is uninformative and should be avoided. This annotation comes from a high-throughput Y2H screen studying disease mutation effects on protein interactions (Sahni et al. 2015). While the interaction data may be valid, the generic "protein binding" annotation provides no insight into KCTD4's actual molecular function. More specific molecular function terms should be used when available. Supporting Evidence: PMID:25910212 Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | REMOVE | Summary: This annotation derives from a yeast-human inter-species interactome mapping study examining evolutionary conservation of protein interactions. KCTD4 was detected in high-throughput screens but not specifically characterized. Reason: Per GO curation guidelines, the term "protein binding" (GO:0005515) is uninformative and should be avoided. This annotation comes from an inter-species interactome mapping study (Zhong et al. 2016) examining yeast-human protein interactions across evolutionary distance. While the detection of KCTD4 in interaction screens may be valid, the generic "protein binding" term provides no functional insight. The interaction could reflect the BTB domain's oligomerization properties rather than a specific functional interaction. Supporting Evidence: PMID:27107014 We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: This annotation derives from the HuRI (Human Reference Interactome) project, a systematic all-by-all binary protein interaction screen. KCTD4 was detected as having protein interactions but without specific functional characterization. Reason: Per GO curation guidelines, the term "protein binding" (GO:0005515) is uninformative and should be avoided. This annotation comes from the HuRI project (Luck et al. 2020), a systematic reference interactome map. While HuRI provides high-quality binary interaction data, the generic "protein binding" annotation does not convey specific molecular function information. UniProt lists specific interactions with DAXX, EFHC1, and NTAQ1 (from IntAct), but the functional significance of these interactions for KCTD4 remains unclear. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. |
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Download this section (compressed HTML)Q: Does KCTD4 interact with Gbetagamma subunits of heterotrimeric G proteins, as demonstrated for other KCTD family members (KCTD2/5/17)?
Q: What is the functional significance of KCTD4 hetero-oligomerization with KCTD5?
Q: Does KCTD4 have any role in ubiquitin-proteasome pathways despite predicted lack of stable Cul3 binding?
Q: What is the subcellular localization of KCTD4 in brain tissue where it is preferentially expressed?
Experiment: Biochemical characterization of KCTD4-Cul3 interaction using co-IP and in vitro reconstitution to confirm or refute AlphaFold predictions
Hypothesis: KCTD4 does not form stable complexes with Cul3, unlike some other KCTD family members
Experiment: Direct binding assays (BRET, co-IP) to test KCTD4-Gbetagamma interaction
Hypothesis: KCTD4 may bind Gbetagamma subunits similar to KCTD2/5/17 family members
Experiment: Subcellular localization studies in neurons to determine where KCTD4 functions
Hypothesis: KCTD4 localizes to specific neuronal compartments consistent with its brain-enriched expression
Experiment: Interactome mapping to identify specific binding partners beyond generic protein binding annotations
Hypothesis: KCTD4 has specific functional interaction partners that inform its molecular function
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