KCTD11

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045666 positive regulation of neuron differentiation	IBA GO_REF:0000033	ACCEPT	Summary: KCTD11/REN is induced by neurogenic signals and acts as a marker and regulator of neuronal differentiation. By suppressing Hedgehog signaling through HDAC1 degradation and GLI1 inactivation, KCTD11 promotes differentiation of cerebellar granule cell precursors. The IBA annotation is phylogenetically consistent (file:human/KCTD11/KCTD11-deep-research-falcon.md). Reason: The deep research confirms KCTD11 functions as a differentiation regulator. PMID:15249678 states it is "previously reported to be expressed in differentiating and low proliferating neuroblasts." PMID:21472142 describes KCASH proteins as having expression in cerebellum and affecting Hedgehog-dependent development. Supporting Evidence: PMID:15249678 previously reported to be expressed in differentiating and low proliferating neuroblasts file:human/KCTD11/KCTD11-deep-research-falcon.md KCTD11 acts as a marker and a regulator of neuronal differentiation
GO:0016740 transferase activity	IEA GO_REF:0000043	REMOVE	Summary: This annotation derives from UniProtKB keyword mapping. KCTD11 does not itself possess transferase catalytic activity - it is an adaptor/substrate-recognition subunit of the CRL3 E3 ubiquitin ligase complex. The E3 ligase activity is conferred by the RBX1 RING subunit, not by KCTD11. Reason: PMID:21237243 describes KCTD11 as "cullin E3 ligase adaptor" not as an enzyme. It acts as an adaptor bringing together Cul3 and the substrate HDAC1 for ubiquitination, but does not catalyze any reaction itself. Supporting Evidence: PMID:21237243 KCTD11/REN, the best-characterized member of the family to date, plays a crucial role in the ubiquitination of HDAC1 by acting, in complex with Cullin3, as an E3 ubiquitin ligase
GO:0042802 identical protein binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: KCTD11 forms homo-oligomers via its BTB domain. While this is technically correct, "identical protein binding" is a low-information term. The more meaningful annotation is protein homooligomerization (GO:0051260) which captures the functional consequence. Reason: The identical protein binding is captured by the more informative term GO:0051260 (protein homooligomerization) which is also present. Keeping as non-core since the oligomerization term is more informative of the functional consequence. Supporting Evidence: PMID:27152988 present electron microscopy data highlight the occurrence of well-defined pentameric states for all domains
GO:0051260 protein homooligomerization	IEA GO_REF:0000002	ACCEPT	Summary: KCTD11 forms homopentameric assemblies via its BTB domain, as demonstrated by electron microscopy and biochemical studies. This oligomerization is essential for proper CRL3 complex assembly and function. Reason: PMID:27152988 demonstrated by electron microscopy that KCTD BTB domains form pentamers. PMID:21237243 shows the protein forms oligomers. This is a well-established structural property essential for CRL3 function. Supporting Evidence: PMID:27152988 present electron microscopy data highlight the occurrence of well-defined pentameric states for all domains PMID:21237243 the protein likely forms stable tetramers
GO:0042802 identical protein binding	IPI PMID:27152988 The BTB domains of the potassium channel tetramerization dom...	KEEP AS NON CORE	Summary: This IPI annotation from PMID:27152988 documents the physical self-interaction of KCTD11 BTB domains demonstrated by electron microscopy. While the experimental evidence is strong, the term is low-information. Reason: The experimental evidence from PMID:27152988 is valid - the BTB domain oligomerization was directly demonstrated. However, this is captured more informatively by GO:0051260 (protein homooligomerization). Keeping this as non-core since it has direct experimental evidence but is redundant with the more specific term. Supporting Evidence: PMID:27152988 present electron microscopy data highlight the occurrence of well-defined pentameric states for all domains
GO:0005737 cytoplasm	IEA GO_REF:0000107	ACCEPT	Summary: KCTD11 localizes to the cytoplasm where it functions in the CRL3 E3 ubiquitin ligase complex. This is consistent with its role in proteasomal targeting of HDAC1. Reason: The cytoplasmic localization is consistent with KCTD11's function as part of a cytoplasmic E3 ubiquitin ligase complex. The deep research notes functional suppression of GLI1 occurs downstream of ciliary/centrosomal signal integration in cytoplasmic compartments. Supporting Evidence: file:human/KCTD11/KCTD11-deep-research-falcon.md functional suppression of GLI1 activity occurs downstream of ciliary/centrosomal signal integration
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: KCTD11 participates in protein ubiquitination as the substrate adaptor for the CRL3 E3 ligase complex, specifically targeting HDAC1 for ubiquitination and proteasomal degradation. Reason: PMID:20081843 demonstrates KCTD11 is involved in HDAC1 degradation through an E3 ubiquitin ligase complex. PMID:21237243 confirms KCTD11 "plays a crucial role in the ubiquitination of HDAC1." Supporting Evidence: PMID:20081843 HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN PMID:21237243 plays a crucial role in the ubiquitination of HDAC1 by acting, in complex with Cullin3, as an E3 ubiquitin ligase
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:20081843 Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase...	NEW	Summary: KCTD11's primary molecular function is as a substrate adaptor for the CRL3 E3 ubiquitin ligase complex. This is the most precise MF term for its role. Reason: GO:1990756 is defined as "The binding activity of a molecule that brings together a ubiquitin-like ligase and its substrate. Usually mediated by F-box BTB/POZ domain proteins." This perfectly describes KCTD11's function. PMID:21237243 confirms it acts "as an E3 ubiquitin ligase" adaptor. Supporting Evidence: PMID:21237243 plays a crucial role in the ubiquitination of HDAC1 by acting, in complex with Cullin3, as an E3 ubiquitin ligase file:human/KCTD11/KCTD11-deep-research-falcon.md KCTD11/KCASH1 is a BTB/POZ-domain substrate adaptor for a CRL3 (Cullin 3-Rbx1) E3 ubiquitin ligase complex
GO:0031463 Cul3-RING ubiquitin ligase complex	IDA PMID:20081843 Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase...	NEW	Summary: KCTD11 is a component of the Cul3-RING ubiquitin ligase complex (BCR/CRL3 complex), serving as the BTB-domain substrate adaptor subunit. Reason: GO:0031463 is defined as "A ubiquitin ligase complex in which a cullin from the Cul3 subfamily and a RING domain protein form the catalytic core; substrate specificity is conferred by a BTB-domain-containing protein." PMID:20081843 and PMID:25974686 confirm KCTD11 forms complexes with Cul3. Supporting Evidence: PMID:20081843 E3 ubiquitin ligase complex formed by Cullin3 and REN PMID:25974686 Our data indicate that KCTD6(BTB) and KCTD11(BTB) bind Cul3 with high affinity forming stable complexes with 4:4 stoichiometries
GO:0097602 cullin family protein binding	IPI PMID:21237243 Molecular organization of the cullin E3 ligase adaptor KCTD1...	NEW	Summary: KCTD11 directly binds to CUL3 via its BTB domain, as demonstrated by biochemical and structural studies. Reason: PMID:25974686 quantified the KCTD11-Cul3 interaction by ITC and gel filtration, demonstrating direct binding with nanomolar affinity. Supporting Evidence: PMID:25974686 KCTD11BTB form a tight complex with Cul3NTD PMID:21237243 sKCTD11 is still able to bind Cul3
GO:0045879 negative regulation of smoothened signaling pathway	IDA PMID:15249678 REN(KCTD11) is a suppressor of Hedgehog signaling and is del...	NEW	Summary: KCTD11/REN is a well-established antagonist of Hedgehog/Smoothened signaling. It suppresses GLI1 transcriptional activity by targeting HDAC1 for degradation, thereby maintaining GLI1 in an acetylated, inactive state. Reason: The foundational paper (PMID:15249678) directly identified REN/KCTD11 as a Hedgehog antagonist. The title states it is "a suppressor of Hedgehog signaling." Supporting Evidence: PMID:15249678 we identify REN(KCTD11) as a suppressor of Hedgehog signaling PMID:20081843 This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist
GO:0042826 histone deacetylase binding	IPI PMID:20081843 Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase...	NEW	Summary: KCTD11 directly binds HDAC1 as its substrate for ubiquitination. This interaction is central to KCTD11's mechanism of action in suppressing Hedgehog signaling. Reason: PMID:21472142 demonstrates the KCASH proteins including REN/KCTD11 interact with HDAC1 and mediate its ubiquitination and degradation. Supporting Evidence: PMID:21472142 HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling PMID:20081843 HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN