KCTD7 encodes BTB/POZ domain-containing protein KCTD7, a soluble protein of ~289 amino acids with an N-terminal BTB/POZ domain homologous to the T1 tetramerization domain of Kv channels. It lacks transmembrane segments and is not itself an ion channel. KCTD7 functions as a CUL3 adaptor in CRL3-type E3 ubiquitin ligase complexes. The protein hyperpolarizes neuronal membranes in a K+-dependent manner and regulates the neuronal glutamine transporter SAT2 (SLC38A2), coupling K+ homeostasis to neurotransmitter precursor supply. Biallelic pathogenic variants cause progressive myoclonic epilepsy type 3 (EPM3/CLN14).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference. KCTD7 localizes to the plasma membrane as demonstrated by experimental studies (PMID:22748208). Wild-type KCTD7 localizes to plasma membrane and cytoplasm in expression systems and neurons. Reason: Well-supported by phylogenetic analysis and consistent with experimental evidence from multiple studies showing plasma membrane localization (PMID:22748208). The deep research confirms "Wild-type KCTD7 localizes to the plasma membrane and cytoplasm in expression systems and neurons" (KCTD7-deep-research-falcon.md). Supporting Evidence: PMID:22748208 The identified variant altered the localization pattern of KCTD7 file:human/KCTD7/KCTD7-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0060081 membrane hyperpolarization | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for membrane hyperpolarization. KCTD7 hyperpolarizes neuronal membranes in a K+-dependent manner as demonstrated experimentally (PMID:27742667). Reason: Strong experimental support for this function. Moen et al. (Brain 2016, PMID:27742667) demonstrated that "wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner" using Xenopus laevis oocyte expression. This is a core function of KCTD7. Supporting Evidence: PMID:27742667 wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location mapping. UniProt indicates "Cytoplasm, cytosol" localization. Reason: Consistent with experimental evidence. UniProt annotation is based on literature evidence showing cytosolic localization. The deep research confirms KCTD7 localizes to cytoplasm in addition to plasma membrane. Supporting Evidence: PMID:22748208 The identified variant altered the localization pattern of KCTD7 |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for plasma membrane localization based on combined automated annotation. Reason: Consistent with experimental evidence from PMID:22748208 and phylogenetic IBA annotation. Plasma membrane localization is well-established for KCTD7. Supporting Evidence: PMID:22748208 The identified variant altered the localization pattern of KCTD7 |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation for identical protein binding based on ARBA machine learning. KCTD7 forms homopentamers via its BTB domain. Reason: Well-supported by structural studies. KCTD family BTB domains form pentamers. UniProt shows KCTD7 self-interaction (Q96MP8-2:Q96MP8-2 with NbExp=5). The deep research confirms homopentameric BTB assemblies and cryo-EM demonstrates KCTD7-CUL3 complex formation (KCTD7-deep-research-falcon.md). |
| GO:0051260 protein homooligomerization | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping. BTB domains are known to mediate oligomerization. Reason: Well-supported by domain architecture. The BTB/POZ domain (IPR000210) mediates oligomerization. Structural work shows KCTD family proteins form homopentamers. The deep research states structural work across KCTDs shows homopentameric BTB assemblies (KCTD7-deep-research-falcon.md). |
| GO:0030007 intracellular potassium ion homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation based on ortholog transfer via Ensembl Compara. KCTD7 regulates K+ fluxes in neurons. Reason: Experimentally supported. Moen et al. (PMID:27742667) demonstrated that KCTD7 regulates K+ fluxes and pathogenic variants impair K+ fluxes. Supporting Evidence: PMID:27742667 our data demonstrate that KCTD7 has an impact on K+ fluxes |
| GO:0060081 membrane hyperpolarization | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation for membrane hyperpolarization based on ortholog transfer. Reason: Consistent with experimental evidence and IBA annotation. KCTD7 hyperpolarizes membranes in a K+-dependent manner (PMID:27742667). This is a core function. Supporting Evidence: PMID:27742667 wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner |
| GO:0090461 intracellular glutamate homeostasis | IMP PMID:27742667 Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and ... | ACCEPT | Summary: IMP annotation based on mutant phenotype. KCTD7 regulates SAT2-dependent glutamine transport which affects glutamate/glutamine homeostasis. Patient CSF showed decreased glutamate and increased glutamine. Reason: Directly supported by the cited publication. Moen et al. (PMID:27742667) showed that KCTD7 regulates activity of the neuronal glutamine transporter SAT2 and pathogenic variants obliterate SAT2-dependent glutamine transport. Patient CSF showed decreased glutamate while glutamine was increased, demonstrating impact on glutamate homeostasis. Supporting Evidence: PMID:27742667 The cerebrospinal fluid level of glutamate was decreased while glutamine was increased PMID:27742667 regulates activity of the neuronal glutamine transporter SAT2 |
| GO:0005515 protein binding | IPI PMID:22748208 A homozygous mutation in KCTD7 links neuronal ceroid lipofus... | REMOVE | Summary: IPI annotation for generic protein binding. KCTD7 interacts with CUL3 as demonstrated by co-immunoprecipitation. Reason: Per curation guidelines, "protein binding" (GO:0005515) is uninformative and should be replaced with more specific terms. The actual interaction is with CUL3, which is functionally relevant to KCTD7's role as a CRL3 E3 ubiquitin ligase adaptor. More informative annotations exist (identical protein binding GO:0042802, and the Reactome annotations capture the E3 ligase complex context). Proposed replacements: Cul3-RING ubiquitin ligase complex Supporting Evidence: PMID:22748208 2012 Jun 28. A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system. |
| GO:0005737 cytoplasm | IDA PMID:22748208 A homozygous mutation in KCTD7 links neuronal ceroid lipofus... | ACCEPT | Summary: IDA annotation for cytoplasm localization based on direct assay. Reason: Experimentally determined localization from Staropoli et al. (PMID:22748208). KCTD7 localizes to both plasma membrane and cytoplasm. The pathogenic R184C variant showed markedly diminished localization at the cell membrane and appearance of prominent cytoplasmic aggregates (UniProt variant annotation from PMID:22748208). Supporting Evidence: PMID:22748208 The identified variant altered the localization pattern of KCTD7 |
| GO:0005886 plasma membrane | IDA PMID:22748208 A homozygous mutation in KCTD7 links neuronal ceroid lipofus... | ACCEPT | Summary: IDA annotation for plasma membrane localization based on direct assay. Reason: Experimentally determined from Staropoli et al. (PMID:22748208). The R184C pathogenic variant showed markedly diminished localization at the cell membrane, demonstrating that wild-type KCTD7 normally localizes to the plasma membrane. Supporting Evidence: PMID:22748208 The identified variant altered the localization pattern of KCTD7 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952630 | ACCEPT | Summary: TAS annotation from Reactome pathway "NEDD8:AcM-UBE2M binds CRL3 E3 ubiquitin ligase complex." KCTD7 participates in CRL3 complexes as a BTB adaptor. Reason: KCTD7 functions as a CUL3 adaptor in CRL3 E3 ubiquitin ligase complexes, which are cytosolic. This is consistent with the KCTD7-CUL3 interaction demonstrated in PMID:22748208 and structural studies. Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952631 | ACCEPT | Summary: TAS annotation from Reactome pathway "AcM-UBE2M transfers NEDD8 to CRL3 E3 ubiquitin ligase complex." Reason: KCTD7 is part of CRL3 complexes that undergo neddylation. Consistent with its role as a CUL3 adaptor and cytosolic localization. Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: TAS annotation from Reactome pathway "CAND1 binds cytosolic CRL E3 ubiquitin ligases." Reason: KCTD7 is a component of CRL3 E3 ligase complexes. These complexes are regulated by CAND1 in the cytosol. Consistent with KCTD7's role as a BTB adaptor. Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: TAS annotation from Reactome pathway "COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes." Reason: Part of CRL3 regulation. KCTD7 is a CRL3 adaptor, and these complexes are regulated in the cytosol. Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: TAS annotation from Reactome pathway "COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes." Reason: KCTD7-containing CRL3 complexes undergo deneddylation by COP9 signalosome in the cytosol. Consistent with its role as a CRL3 adaptor. Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IDA PMID:22748208 A homozygous mutation in KCTD7 links neuronal ceroid lipofus... | NEW | Summary: KCTD7 is a component of CRL3 E3 ubiquitin ligase complexes via its BTB domain interaction with CUL3. Reason: KCTD7 functions as a CUL3 adaptor in CRL3-type E3 ubiquitin ligase complexes. This is demonstrated by co-immunoprecipitation showing KCTD7-CUL3 interaction, and the pathogenic R184C variant abrogates this interaction. The deep research confirms cryo-EM structure of KCTD7-CUL3 complex (KCTD7-deep-research-falcon.md). Supporting Evidence: PMID:22748208 abrogated interaction with cullin-3 |
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