MKKS (BBS6) is a divergent member of the group II (type II) / TCP-1 (CCT/TRiC) chaperonin family. Rather than acting as a stable structural subunit of the mature BBSome, it functions as a chaperonin-like assembly factor: together with the related chaperonin-like proteins BBS10 and BBS12 and the CCT/TRiC chaperonin, it forms a "BBS-chaperonin complex" that stabilizes BBS7 and nucleates assembly of the BBSome core (BBS7-BBS2-BBS9), thereby promoting biogenesis of the BBSome that traffics membrane cargo to and within primary cilia. The protein localizes predominantly to the centrosome and pericentriolar material and to the ciliary basal body, shuttling rapidly between the cytosol and centrosome and also between the cytoplasm and nucleus. Beyond ciliary roles, MKKS interacts with the SWI/SNF chromatin-remodeling subunit SMARCC1 and can modulate its subcellular localization. Loss-of-function mutations cause McKusick-Kaufman syndrome (hydrometrocolpos, postaxial polydactyly, congenital heart defects) and Bardet-Biedl syndrome 6 (retinal degeneration, obesity, polydactyly, renal and genital anomalies, intellectual disability).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (PAN-GO) propagation of nuclear localization. MKKS does shuttle between cytoplasm and nucleus and has an experimentally documented nuclear pool (PMID:28753627), so the localization is supported, but "is_active_in" is strong for a protein whose principal site of action is the centrosome/PCM. Reason: Nuclear localization is experimentally supported (IDA, PMID:28753627) but is not the core (centrosomal/ciliary) site of MKKS function; retain as non-core. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: General cytoplasmic localization, consistent with the cytosolic pool that shuttles to the centrosome and with the cytosolic BBS-chaperonin complex. Supported but non-specific. Reason: Broad compartment term; correct but uninformative relative to the centrosome/ pericentriolar-material localization that defines MKKS cell biology. |
| GO:0032502 developmental process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Very high-level developmental process term propagated by phylogeny. MKKS loss causes pleiotropic developmental phenotypes, but this term is too general to be informative. Reason: Root-level developmental term carries little functional information; the developmental phenotypes are downstream of the molecular assembly/chaperone role. |
| GO:0051131 chaperone-mediated protein complex assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Captures the central, experimentally established role of MKKS: as part of a chaperonin (BBS6/BBS10/BBS12 + CCT/TRiC) complex it mediates assembly of the BBSome by stabilizing BBS7 and nucleating the BBSome core (PMID:20080638, PMID:22500027). This is the best representation of MKKS core function. The falcon deep research synthesis concurs that MKKS (with BBS12) acts as a substrate-binding unit linking the CCT chaperonins to their client BBS7, stabilizing BBS7 for its association with BBS2 in the early BBSome-assembly step. Reason: Directly supported by experimental literature (PMID:20080638, PMID:22500027); represents the core molecular/biological role of MKKS. Recent reviews (per the falcon synthesis) corroborate the substrate-binding/BBS7-stabilization mechanism. Supporting Evidence: file:human/MKKS/MKKS-deep-research-falcon.md MKKS and BBS12 act as substrate-binding units that mediate the association between the CCT chaperonins and their client protein BBS7 file:human/MKKS/MKKS-deep-research-falcon.md MKKS enables the stabilization of BBS7 and facilitates its productive association with BBS2, which is a critical early step in BBSome assembly |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: MKKS contributes to ciliogenesis indirectly, by enabling BBSome assembly; BBSome-dependent ciliary membrane trafficking is downstream. Supported as an involvement but not the most precise molecular description. Reason: Cilium assembly is a downstream consequence of BBSome biogenesis; keep as a valid but non-core involvement (core is chaperone-mediated complex assembly). |
| GO:1902636 kinociliary basal body | IBA GO_REF:0000033 | MODIFY | Summary: Over-specific localization (a basal body specifically of a kinocilium) propagated from zebrafish/mouse orthologs. Human IDA evidence supports the more general ciliary basal body (GO:0036064), not specifically a kinociliary one. Reason: The kinocilium-specific term is more specific than warranted for the human protein; generalize to ciliary basal body, which is directly supported (HPA IDA). Proposed replacements: ciliary basal body |
| GO:0003006 developmental process involved in reproduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning electronic prediction. Reproductive/genital anomalies occur in BBS/MKKS syndromes, but this broad term is an indirect, downstream phenotype, not a molecular function, and rests only on automated inference. Reason: Indirect downstream phenotype assigned by ARBA electronic prediction; not a direct functional attribute of MKKS. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Inferred from the conserved chaperonin (Cpn60/GroEL/TCP-1, IPR002423) fold and a predicted ATP-binding motif (UniProt BINDING 192-199, ECO:0000255). Plausible given the family, but MKKS is a divergent chaperonin and no direct ATPase/ATP-binding assay for MKKS is available in the cited literature. The falcon deep research synthesis of recent reviews reinforces this caution: MKKS's ATP-hydrolysis motif is reported to be significantly divergent from canonical chaperonins and the actual ATP-dependent folding is attributed to the associated CCT/TRiC chaperonins, not to MKKS itself. Reason: Sequence/domain-based inference consistent with the chaperonin fold; retain as a plausible non-core molecular attribute pending experimental confirmation. The divergent ATP-hydrolysis motif noted in the literature argues against relying on this as a core, functionally active attribute. Supporting Evidence: file:human/MKKS/MKKS-deep-research-falcon.md The ATP-binding and hydrolysis motif in the equatorial domain, which is highly conserved in group I and II chaperonins and essential for ATP-dependent protein folding, is significantly divergent in MKKS file:human/MKKS/MKKS-deep-research-falcon.md The actual ATP-dependent protein folding activity is performed by the canonical CCT chaperonins, not by MKKS itself |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to nucleus, concordant with experimental IDA nuclear localization (PMID:28753627). Reason: Correct localization but not the core site of action; redundant with the IDA nucleus annotation. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosomal localization, a well-established and defining feature of MKKS (pericentriolar material), also supported by HPA IDA. Reason: Centrosome/pericentriolar localization is a core, experimentally corroborated attribute of MKKS. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytosolic pool consistent with the soluble fraction that shuttles to the centrosome and with the cytosolic BBS-chaperonin complex. Reason: Supported but non-specific compartment localization. |
| GO:0006457 protein folding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-to-GO inference from the chaperonin fold. MKKS is annotated as a molecular chaperone and acts within a chaperonin complex, so generic protein folding involvement is plausible, though its demonstrated role is specifically assembly of the BBSome (chaperone-assisted complex assembly) rather than broad folding of arbitrary substrates. The falcon deep research synthesis emphasizes that MKKS acts as a substrate-binding/co-assembly factor rather than a canonical ATP-dependent folding enzyme, supporting the view that generic "protein folding" over-states MKKS's own activity. Reason: Domain-based inference; plausible but the experimentally supported activity is chaperone-mediated complex assembly rather than general protein folding. Recent reviews (per the falcon synthesis) explicitly distinguish MKKS's substrate-binding role from canonical folding. Supporting Evidence: file:human/MKKS/MKKS-deep-research-falcon.md Critically, MKKS does not function as a canonical ATP-dependent protein folding enzyme; rather, it acts as a substrate-binding and co-assembly factor |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Broad ARBA electronic prediction. Organ development is affected in MKKS/BBS, but the term is high-level and downstream of the molecular function. Reason: High-level developmental term from automated prediction; indirect phenotype, not a direct functional attribute. |
| GO:0048731 system development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very broad ARBA electronic prediction; uninformative root-level developmental term. Reason: Root-level system development term from automated prediction; not informative. |
| GO:0060271 cilium assembly | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA supporting the same cilium-assembly involvement captured by the IBA and IMP annotations. Reason: Redundant with experimentally/phylogenetically supported cilium assembly; downstream of BBSome biogenesis. |
| GO:0005515 protein binding | IPI PMID:20080638 BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family c... | MARK AS OVER ANNOTATED | Summary: IPI to BBS12 (Q6ZW61) / BBS2 (Q9BXC9) within the BBS-chaperonin complex. The interaction is biologically meaningful, but "protein binding" is uninformative; the functional content is captured by the complex-assembly annotation. Reason: Generic protein binding term provides no functional information; the underlying BBS12/BBS2 interaction is better represented by chaperone-mediated complex assembly. |
| GO:0005515 protein binding | IPI PMID:22500027 Intrinsic protein-protein interaction-mediated and chaperoni... | MARK AS OVER ANNOTATED | Summary: IPI to BBS12/BBS2 from the sequential BBSome-assembly study. Meaningful interaction but captured uninformatively by the generic term. Reason: Generic protein binding; functional content covered by complex-assembly annotation. |
| GO:0005515 protein binding | IPI PMID:26900326 A novel H395R mutation in MKKS/BBS6 causes retinitis pigment... | MARK AS OVER ANNOTATED | Summary: IPI to BBS12 (Q6ZW61); the H395R mutation reduces BBS12 interaction. Relevant but uninformative as a bare protein-binding term. Reason: Generic protein binding term; the BBS12 interaction is better expressed via the complex-assembly role. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput AP-MS (BioPlex 2.0) interaction with BBS12. Supports complex membership but provides no specific molecular function. Reason: Generic protein binding from a proteome-scale screen; uninformative. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary interactome (HuRI) hits with CDR2 (Q01850) and ZBED1 (O96006). These are low-specificity high-throughput interactions of unclear biological relevance. Reason: Generic protein binding from a large-scale binary screen; no functional content, partners of uncertain biological relevance. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput AP-MS (BioPlex 3.0) interaction with BBS12. Corroborates complex membership but uninformative as a function. Reason: Generic protein binding from a proteome-scale screen; uninformative. |
| GO:0031514 motile cilium | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from mouse ortholog. MKKS function centers on the basal body/centrosome and primary-cilium biogenesis; a motile-cilium localization is not directly supported in human and likely reflects ortholog-specific contexts. The falcon deep research synthesis notes that, unlike the core BBSome components, MKKS and other chaperonin-like BBS proteins are generally not detected along the cilium itself, consistent with a basal-body-restricted localization. Reason: Ortholog-transferred localization not directly supported for human MKKS; the established localization is centrosome/basal body, and recent reviews (falcon synthesis) report chaperonin-like BBS proteins are not found along the cilium. Supporting Evidence: file:human/MKKS/MKKS-deep-research-falcon.md MKKS and other chaperonin-like BBS proteins are generally not detected along the length of the cilium itself |
| GO:0036064 ciliary basal body | IEA GO_REF:0000120 | ACCEPT | Summary: Ciliary basal body localization, directly supported by human HPA IDA evidence and consistent with the centrosomal/pericentriolar localization of MKKS. Reason: Basal body localization is experimentally supported (HPA IDA) and biologically central. |
| GO:0038108 negative regulation of appetite by leptin-mediated signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from mouse ortholog reflecting the obesity phenotype. This is a downstream organismal physiology effect, not a direct molecular role of MKKS. Reason: Downstream physiological phenotype transferred from mouse; not a direct MKKS function. |
| GO:0045444 fat cell differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred phenotype linked to obesity in BBS. Indirect and downstream of cilia/BBSome function. Reason: Indirect downstream phenotype from ortholog transfer; not a direct function. |
| GO:0060296 regulation of cilium beat frequency involved in ciliary motility | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred motile-cilia phenotype. MKKS/BBSome biology concerns primary-cilium membrane trafficking; ciliary beat-frequency regulation is not a directly supported human MKKS role. Reason: Motile-cilia regulatory term transferred from ortholog; not directly supported for human MKKS. |
| GO:1902636 kinociliary basal body | IEA GO_REF:0000107 | MODIFY | Summary: Over-specific localization electronically transferred from mouse ortholog. The generic ciliary basal body (GO:0036064) is the human-supported localization. Reason: More specific than warranted; generalize to ciliary basal body (HPA IDA-supported). Proposed replacements: ciliary basal body |
| GO:0005813 centrosome | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) localization to the centrosome, the defining and most consistently reported localization of MKKS. The falcon deep research synthesis concurs that MKKS localizes predominantly to centrosomes/ciliary basal bodies, enriched in pericentriolar material. Reason: Strong direct evidence for a core localization of MKKS, corroborated by the basal-body/centrosome-centered localization described in recent reviews (falcon synthesis). Supporting Evidence: file:human/MKKS/MKKS-deep-research-falcon.md MKKS localizes predominantly to centrosomes and ciliary basal bodies, where it is enriched in the pericentriolar material surrounding centrioles |
| GO:0036064 ciliary basal body | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) localization to the ciliary basal body, consistent with MKKS centrosomal/basal-body biology. Reason: Direct experimental evidence for a core localization. |
| GO:0005515 protein binding | IPI PMID:33144677 Dlec1 is required for spermatogenesis and male fertility in ... | MARK AS OVER ANNOTATED | Summary: IPI to DLEC1 (Q9Y238) from a mouse spermatogenesis study reporting a Dlec1-Mkks interaction. Real interaction but uninformative as a bare protein-binding term. Reason: Generic protein binding term; provides no functional information. |
| GO:0005515 protein binding | IPI PMID:28753627 Nuclear/cytoplasmic transport defects in BBS6 underlie conge... | MARK AS OVER ANNOTATED | Summary: IPI to SMARCC1 (Q92922), an experimentally validated and biologically important interaction (modulation of SMARCC1 localization; relevance to congenital heart disease). The interaction itself is meaningful, but "protein binding" is uninformative; the functional consequence is better captured by a regulatory term. Reason: Generic protein binding; the SMARCC1 interaction and its consequence on SMARCC1 localization warrant a more specific term rather than bare protein binding. |
| GO:0005634 nucleus | IDA PMID:28753627 Nuclear/cytoplasmic transport defects in BBS6 underlie conge... | KEEP AS NON CORE | Summary: Direct evidence that BBS6 is actively transported to the nucleus; the McKusick- Kaufman allele is defective in this transport (PMID:28753627). Supports a genuine nuclear pool. Reason: Experimentally supported nuclear localization, but secondary to the centrosomal/ ciliary core function. |
| GO:0005737 cytoplasm | IDA PMID:28753627 Nuclear/cytoplasmic transport defects in BBS6 underlie conge... | KEEP AS NON CORE | Summary: Direct evidence of cytoplasmic localization, consistent with the shuttling cytosolic pool. Reason: Supported but broad localization term. |
| GO:0060271 cilium assembly | IMP PMID:28753627 Nuclear/cytoplasmic transport defects in BBS6 underlie conge... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that MKKS/BBS6 is required for ciliogenesis. This reflects the downstream consequence of impaired BBSome assembly. A valid involvement; core function is the chaperone-mediated assembly step upstream. Reason: Experimentally supported (IMP) but represents a downstream outcome of BBSome assembly; keep as a valid non-core involvement. |
| GO:0005515 protein binding | IPI PMID:18762586 Recruitment of PCM1 to the centrosome by the cooperative act... | MARK AS OVER ANNOTATED | Summary: IPI to PCM1 (Q9NRI5) in a centrosomal-recruitment study primarily about DISC1/BBS4/PCM1. The MKKS-PCM1 interaction is centrosomal-context but the term is uninformative. Reason: Generic protein binding term; no functional content. |
| GO:0005515 protein binding | IPI PMID:22446187 Combining Cep290 and Mkks ciliopathy alleles in mice rescues... | MARK AS OVER ANNOTATED | Summary: IPI to CEP290 (O15078). MKKS directly interacts with CEP290 and BBS mutations disrupt this interaction (PMID:22446187); biologically relevant within ciliary biology, but uninformative as a bare protein-binding term. Reason: Generic protein binding; the CEP290 interaction is meaningful but not captured informatively by this term. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:22302990 Direct role of Bardet-Biedl syndrome proteins in transcripti... | KEEP AS NON CORE | Summary: IPI assigned by MGI to a transcription factor (Q99496) from a study showing a direct role of BBS proteins in transcriptional regulation. The cached abstract foregrounds BBS7 but states a similar role for other BBS proteins; full text not available. This is a curator experimental IPI and the nuclear/transcription role of MKKS is independently supported (SMARCC1, PMID:28753627), so it is retained. Reason: Experimental IPI by a curator with full-text access; consistent with MKKS's documented nuclear/chromatin-associated role; secondary to the core chaperonin function. |
| GO:0005515 protein binding | IPI PMID:16327777 Dissection of epistasis in oligogenic Bardet-Biedl syndrome. | MARK AS OVER ANNOTATED | Summary: IPI to CCDC28B/MGC1203 (Q9BUN5), a pericentriolar protein that interacts and colocalizes with BBS proteins and acts as an epistatic BBS modifier (PMID:16327777). Relevant but uninformative as a generic binding term. Reason: Generic protein binding term; no functional content. |
| GO:0038108 negative regulation of appetite by leptin-mediated signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity transfer from mouse ortholog (obesity phenotype). Downstream organismal physiology, not a direct MKKS molecular function. Reason: Downstream physiological phenotype transferred by ISS; not a direct function. |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from zebrafish ortholog reflecting laterality/cardiac phenotypes. Indirect developmental consequence of ciliary dysfunction. Reason: Plausible cilia-dependent developmental role transferred by similarity; keep as non-core, indirect. |
| GO:0007286 spermatid development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from mouse ortholog; consistent with the DLEC1/Mkks spermatogenesis interaction (PMID:33144677). Indirect, downstream developmental role. Reason: Cilia/flagellum-related developmental phenotype from ortholog; non-core. |
| GO:0007368 determination of left/right symmetry | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from zebrafish ortholog; laterality determination is a classic cilia-dependent process, consistent with MKKS ciliary involvement, but indirect. Reason: Cilia-dependent developmental process transferred by similarity; non-core, indirect. |
| GO:0007608 sensory perception of smell | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog (olfactory ciliary phenotype). Indirect organ- level sensory phenotype, downstream of ciliary function. Reason: Distant downstream sensory phenotype from ortholog transfer; not a direct function. |
| GO:0021756 striatum development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog; specific brain-region development term that is a distant downstream phenotype. Reason: Over-specific brain-region developmental phenotype from ortholog transfer. |
| GO:0021766 hippocampus development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog; distant downstream brain-region phenotype. Reason: Over-specific brain-region developmental phenotype from ortholog transfer. |
| GO:0021987 cerebral cortex development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog; distant downstream brain-region phenotype. Reason: Over-specific brain-region developmental phenotype from ortholog transfer. |
| GO:0031514 motile cilium | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog. Not directly supported for human MKKS, whose localization is centrosome/basal body. Reason: Ortholog-transferred localization not directly supported for human MKKS. |
| GO:0032402 melanosome transport | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from zebrafish ortholog (pigment-granule transport). Distant, lineage-specific phenotype with no direct support for human MKKS function. Reason: Distant ortholog-specific phenotype; not a direct human MKKS function. |
| GO:0035176 social behavior | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog (behavioral phenotype). Very distant downstream organismal phenotype. Reason: Distant behavioral phenotype from ortholog transfer; not a direct function. |
| GO:0045444 fat cell differentiation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog; indirect, downstream of cilia/obesity biology. Reason: Indirect downstream phenotype from ortholog transfer. |
| GO:0045494 photoreceptor cell maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from mouse ortholog; retinal degeneration is a hallmark of BBS6. Plausible cilia-dependent role (photoreceptor connecting cilium), though indirect. Reason: Cilia-dependent phenotype consistent with BBS6 retinopathy; non-core, indirect. |
| GO:0048854 brain morphogenesis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog; broad downstream developmental phenotype. Reason: Broad downstream developmental phenotype from ortholog transfer. |
| GO:0050910 detection of mechanical stimulus involved in sensory perception of sound | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog (auditory ciliary phenotype). Distant downstream sensory phenotype. Reason: Distant downstream sensory phenotype from ortholog transfer; not a direct function. |
| GO:0051877 pigment granule aggregation in cell center | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from zebrafish ortholog (melanosome aggregation). Lineage-specific distant phenotype not supported for human MKKS. Reason: Distant ortholog-specific phenotype; not a direct human MKKS function. |
| GO:0060027 convergent extension involved in gastrulation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from zebrafish ortholog; cilia/PCP-related gastrulation phenotype. Indirect developmental role. Reason: Cilia/PCP-related developmental phenotype transferred by similarity; non-core, indirect. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer corroborating the cilium-assembly involvement also supported by IMP and IBA evidence. Reason: Redundant cilium-assembly involvement; downstream of BBSome biogenesis. |
| GO:0060296 regulation of cilium beat frequency involved in ciliary motility | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse ortholog (motile-cilia phenotype). Not directly supported for human MKKS, whose role centers on primary-cilium membrane trafficking. Reason: Motile-cilia regulatory phenotype transferred from ortholog; not directly supported. |
| GO:0006457 protein folding | TAS PMID:10802661 Mutation of a gene encoding a putative chaperonin causes McK... | KEEP AS NON CORE | Summary: Author statement from the original gene-discovery paper describing MKKS as a putative chaperonin (PMID:10802661). Reflects the family-based expectation of a protein-folding role; the experimentally demonstrated activity is chaperone- assisted BBSome assembly. Retained as a plausible general attribute. Reason: Author-supported (TAS) general chaperone role; the specific demonstrated function is chaperone-mediated complex assembly. |
| GO:0007507 heart development | TAS PMID:10802661 Mutation of a gene encoding a putative chaperonin causes McK... | KEEP AS NON CORE | Summary: Author statement linking MKKS to cardiac development (congenital heart defects in McKusick-Kaufman syndrome), mechanistically connected to BBS6-SMARCC1 perturbation (PMID:28753627). Genuine disease association but an indirect, downstream role. Reason: Disease-supported developmental involvement, mechanistically downstream of MKKS's molecular activity; non-core. |
| GO:0008406 gonad development | TAS PMID:10802661 Mutation of a gene encoding a putative chaperonin causes McK... | KEEP AS NON CORE | Summary: Author statement reflecting genital/reproductive anomalies in McKusick-Kaufman syndrome. Indirect, downstream developmental phenotype. Reason: Disease-associated developmental involvement; indirect and non-core. |
| GO:0044183 protein folding chaperone | IDA PMID:20080638 BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family c... | NEW | Summary: Proposed molecular-function annotation capturing MKKS's chaperone activity. MKKS acts as a chaperonin-like factor that, with CCT/TRiC and BBS10/BBS12, binds and stabilizes BBS7 to drive BBSome assembly (PMID:20080638, PMID:22500027). This replaces the now-obsolete GO:0051082 "unfolded protein binding" (UniProt TAS) with the current MF term for chaperone activity. MKKS is a divergent chaperonin and independent foldase/ATPase activity has not been directly demonstrated, so the activity is best described as a (contributing) protein folding chaperone. Reason: The chaperone molecular function of MKKS is supported experimentally (stabilization of BBS7 within the BBS-chaperonin complex), and the prior MF term (unfolded protein binding) is obsolete; GO:0044183 is the appropriate current MF term. |
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Download this section (compressed HTML)Q: Does MKKS possess intrinsic ATPase activity and a genuine substrate-folding cycle, or does it act primarily as a scaffolding/adaptor chaperonin within the CCT/TRiC- containing BBS-chaperonin complex?
Q: Is the nuclear/SMARCC1-related function of MKKS mechanistically separable from its centrosomal BBSome-assembly role, and what cargo/regulatory signals govern its cytoplasm-nucleus shuttling?
Experiment: Reconstitute the BBS6/BBS10/BBS12 + CCT/TRiC complex in vitro and test ATP-dependent binding/release of BBS7 and BBSome-core intermediates to define MKKS's biochemical contribution (holdase vs ATP-driven foldase vs scaffold).
Experiment: Use proximity labeling (BioID/TurboID) on wild-type vs McKusick-Kaufman (H84Y;A242S) and BBS6 disease alleles, in cycling vs ciliating cells, to map compartment-specific interactomes (centrosome vs nucleus) and dissect the SMARCC1-dependent transcriptional arm from the BBSome-assembly arm.
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