id: Q9NPJ1
gene_symbol: MKKS
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is experimentally supported (IDA, PMID:28753627) but is
      not the core (centrosomal/ciliary) site of MKKS function; retain as non-core.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad compartment term; correct but uninformative relative to the centrosome/
      pericentriolar-material localization that defines MKKS cell biology.
- term:
    id: GO:0032502
    label: developmental process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Root-level developmental term carries little functional information; the
      developmental phenotypes are downstream of the molecular assembly/chaperone role.
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        MKKS and BBS12 act as substrate-binding units that mediate the association
        between the CCT chaperonins and their client protein BBS7
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        MKKS enables the stabilization of BBS7 and facilitates its productive
        association with BBS2, which is a critical early step in BBSome assembly
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cilium assembly is a downstream consequence of BBSome biogenesis; keep as a
      valid but non-core involvement (core is chaperone-mediated complex assembly).
- term:
    id: GO:1902636
    label: kinociliary basal body
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0036064
      label: ciliary basal body
- term:
    id: GO:0003006
    label: developmental process involved in reproduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect downstream phenotype assigned by ARBA electronic prediction; not a
      direct functional attribute of MKKS.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        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
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        The actual ATP-dependent protein folding activity is performed by the canonical
        CCT chaperonins, not by MKKS itself
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location mapping to nucleus, concordant with experimental
      IDA nuclear localization (PMID:28753627).
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct localization but not the core site of action; redundant with the IDA
      nucleus annotation.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Centrosomal localization, a well-established and defining feature of MKKS
      (pericentriolar material), also supported by HPA IDA.
    action: ACCEPT
    reason: >-
      Centrosome/pericentriolar localization is a core, experimentally corroborated
      attribute of MKKS.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytosolic pool consistent with the soluble fraction that shuttles to the
      centrosome and with the cytosolic BBS-chaperonin complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported but non-specific compartment localization.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        Critically, MKKS does not function as a canonical ATP-dependent protein folding
        enzyme; rather, it acts as a substrate-binding and co-assembly factor
- term:
    id: GO:0048513
    label: animal organ development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Broad ARBA electronic prediction. Organ development is affected in MKKS/BBS,
      but the term is high-level and downstream of the molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-level developmental term from automated prediction; indirect phenotype,
      not a direct functional attribute.
- term:
    id: GO:0048731
    label: system development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Very broad ARBA electronic prediction; uninformative root-level developmental term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Root-level system development term from automated prediction; not informative.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Combined IEA supporting the same cilium-assembly involvement captured by the
      IBA and IMP annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant with experimentally/phylogenetically supported cilium assembly;
      downstream of BBSome biogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20080638
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding term provides no functional information; the underlying
      BBS12/BBS2 interaction is better represented by chaperone-mediated complex assembly.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22500027
  qualifier: enables
  review:
    summary: >-
      IPI to BBS12/BBS2 from the sequential BBSome-assembly study. Meaningful
      interaction but captured uninformatively by the generic term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding; functional content covered by complex-assembly annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26900326
  qualifier: enables
  review:
    summary: >-
      IPI to BBS12 (Q6ZW61); the H395R mutation reduces BBS12 interaction. Relevant
      but uninformative as a bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding term; the BBS12 interaction is better expressed via the
      complex-assembly role.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS (BioPlex 2.0) interaction with BBS12. Supports complex
      membership but provides no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a proteome-scale screen; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary interactome (HuRI) hits with CDR2 (Q01850) and ZBED1 (O96006). These
      are low-specificity high-throughput interactions of unclear biological relevance.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a large-scale binary screen; no functional content,
      partners of uncertain biological relevance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS (BioPlex 3.0) interaction with BBS12. Corroborates complex
      membership but uninformative as a function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a proteome-scale screen; uninformative.
- term:
    id: GO:0031514
    label: motile cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        MKKS and other chaperonin-like BBS proteins are generally not detected along
        the length of the cilium itself
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Ciliary basal body localization, directly supported by human HPA IDA evidence
      and consistent with the centrosomal/pericentriolar localization of MKKS.
    action: ACCEPT
    reason: >-
      Basal body localization is experimentally supported (HPA IDA) and biologically
      central.
- term:
    id: GO:0038108
    label: negative regulation of appetite by leptin-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer from mouse ortholog reflecting the obesity phenotype. This
      is a downstream organismal physiology effect, not a direct molecular role of MKKS.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream physiological phenotype transferred from mouse; not a direct MKKS function.
- term:
    id: GO:0045444
    label: fat cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred phenotype linked to obesity in BBS. Indirect and downstream
      of cilia/BBSome function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect downstream phenotype from ortholog transfer; not a direct function.
- term:
    id: GO:0060296
    label: regulation of cilium beat frequency involved in ciliary motility
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Motile-cilia regulatory term transferred from ortholog; not directly supported
      for human MKKS.
- term:
    id: GO:1902636
    label: kinociliary basal body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Over-specific localization electronically transferred from mouse ortholog. The
      generic ciliary basal body (GO:0036064) is the human-supported localization.
    action: MODIFY
    reason: >-
      More specific than warranted; generalize to ciliary basal body (HPA IDA-supported).
    proposed_replacement_terms:
    - id: GO:0036064
      label: ciliary basal body
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Strong direct evidence for a core localization of MKKS, corroborated by the
      basal-body/centrosome-centered localization described in recent reviews (falcon
      synthesis).
    supported_by:
    - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
      supporting_text: >-
        MKKS localizes predominantly to centrosomes and ciliary basal bodies, where it
        is enriched in the pericentriolar material surrounding centrioles
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence (HPA) localization to the ciliary basal body,
      consistent with MKKS centrosomal/basal-body biology.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for a core localization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33144677
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding term; provides no functional information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28753627
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding; the SMARCC1 interaction and its consequence on SMARCC1
      localization warrant a more specific term rather than bare protein binding.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:28753627
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported nuclear localization, but secondary to the centrosomal/
      ciliary core function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:28753627
  qualifier: located_in
  review:
    summary: >-
      Direct evidence of cytoplasmic localization, consistent with the shuttling
      cytosolic pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported but broad localization term.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:28753627
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported (IMP) but represents a downstream outcome of BBSome
      assembly; keep as a valid non-core involvement.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18762586
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding term; no functional content.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22446187
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding; the CEP290 interaction is meaningful but not captured
      informatively by this term.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:22302990
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16327777
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding term; no functional content.
- term:
    id: GO:0038108
    label: negative regulation of appetite by leptin-mediated signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer from mouse ortholog (obesity phenotype). Downstream
      organismal physiology, not a direct MKKS molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream physiological phenotype transferred by ISS; not a direct function.
- term:
    id: GO:0001947
    label: heart looping
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from zebrafish ortholog reflecting laterality/cardiac phenotypes.
      Indirect developmental consequence of ciliary dysfunction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible cilia-dependent developmental role transferred by similarity; keep as
      non-core, indirect.
- term:
    id: GO:0007286
    label: spermatid development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; consistent with the DLEC1/Mkks spermatogenesis
      interaction (PMID:33144677). Indirect, downstream developmental role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cilia/flagellum-related developmental phenotype from ortholog; non-core.
- term:
    id: GO:0007368
    label: determination of left/right symmetry
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from zebrafish ortholog; laterality determination is a classic
      cilia-dependent process, consistent with MKKS ciliary involvement, but indirect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cilia-dependent developmental process transferred by similarity; non-core, indirect.
- term:
    id: GO:0007608
    label: sensory perception of smell
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog (olfactory ciliary phenotype). Indirect organ-
      level sensory phenotype, downstream of ciliary function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distant downstream sensory phenotype from ortholog transfer; not a direct function.
- term:
    id: GO:0021756
    label: striatum development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; specific brain-region development term that is
      a distant downstream phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-specific brain-region developmental phenotype from ortholog transfer.
- term:
    id: GO:0021766
    label: hippocampus development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; distant downstream brain-region phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-specific brain-region developmental phenotype from ortholog transfer.
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; distant downstream brain-region phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-specific brain-region developmental phenotype from ortholog transfer.
- term:
    id: GO:0031514
    label: motile cilium
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer from mouse ortholog. Not directly supported for human MKKS, whose
      localization is centrosome/basal body.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog-transferred localization not directly supported for human MKKS.
- term:
    id: GO:0032402
    label: melanosome transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from zebrafish ortholog (pigment-granule transport). Distant,
      lineage-specific phenotype with no direct support for human MKKS function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distant ortholog-specific phenotype; not a direct human MKKS function.
- term:
    id: GO:0035176
    label: social behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog (behavioral phenotype). Very distant downstream
      organismal phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distant behavioral phenotype from ortholog transfer; not a direct function.
- term:
    id: GO:0045444
    label: fat cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; indirect, downstream of cilia/obesity biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect downstream phenotype from ortholog transfer.
- term:
    id: GO:0045494
    label: photoreceptor cell maintenance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; retinal degeneration is a hallmark of BBS6.
      Plausible cilia-dependent role (photoreceptor connecting cilium), though indirect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cilia-dependent phenotype consistent with BBS6 retinopathy; non-core, indirect.
- term:
    id: GO:0048854
    label: brain morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog; broad downstream developmental phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Broad downstream developmental phenotype from ortholog transfer.
- term:
    id: GO:0050910
    label: detection of mechanical stimulus involved in sensory perception of sound
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog (auditory ciliary phenotype). Distant downstream
      sensory phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distant downstream sensory phenotype from ortholog transfer; not a direct function.
- term:
    id: GO:0051877
    label: pigment granule aggregation in cell center
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from zebrafish ortholog (melanosome aggregation). Lineage-specific
      distant phenotype not supported for human MKKS.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distant ortholog-specific phenotype; not a direct human MKKS function.
- term:
    id: GO:0060027
    label: convergent extension involved in gastrulation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from zebrafish ortholog; cilia/PCP-related gastrulation phenotype.
      Indirect developmental role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cilia/PCP-related developmental phenotype transferred by similarity; non-core, indirect.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer corroborating the cilium-assembly involvement also supported by IMP
      and IBA evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant cilium-assembly involvement; downstream of BBSome biogenesis.
- term:
    id: GO:0060296
    label: regulation of cilium beat frequency involved in ciliary motility
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer from mouse ortholog (motile-cilia phenotype). Not directly supported
      for human MKKS, whose role centers on primary-cilium membrane trafficking.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Motile-cilia regulatory phenotype transferred from ortholog; not directly supported.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:10802661
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Author-supported (TAS) general chaperone role; the specific demonstrated function
      is chaperone-mediated complex assembly.
- term:
    id: GO:0007507
    label: heart development
  evidence_type: TAS
  original_reference_id: PMID:10802661
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Disease-supported developmental involvement, mechanistically downstream of MKKS's
      molecular activity; non-core.
- term:
    id: GO:0008406
    label: gonad development
  evidence_type: TAS
  original_reference_id: PMID:10802661
  qualifier: involved_in
  review:
    summary: >-
      Author statement reflecting genital/reproductive anomalies in McKusick-Kaufman
      syndrome. Indirect, downstream developmental phenotype.
    action: KEEP_AS_NON_CORE
    reason: >-
      Disease-associated developmental involvement; indirect and non-core.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:20080638
  qualifier: enables
  review:
    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.
    action: NEW
    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.
core_functions:
- description: >-
    Chaperonin-like assembly factor that, as part of a complex with BBS10, BBS12 and
    the CCT/TRiC chaperonin (the BBS-chaperonin complex), mediates assembly of the
    BBSome by stabilizing BBS7 and nucleating the BBS7-BBS2-BBS9 BBSome core.
  supported_by:
  - reference_id: PMID:20080638
    supporting_text: >-
      a novel complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and
      BBS12) and CCT/TRiC family chaperonins mediates BBSome assembly.
  - reference_id: PMID:22500027
    supporting_text: >-
      the BBS-chaperonin complex plays a role in BBS7 stability. BBS7 interacts with BBS2
      and becomes part of a BBS7-BBS2-BBS9 assembly intermediate referred to as the BBSome
      core complex.
  - reference_id: file:human/MKKS/MKKS-deep-research-falcon.md
    supporting_text: >-
      MKKS and BBS12 act as substrate-binding units that mediate the association between
      the CCT chaperonins and their client protein BBS7
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0051131
    label: chaperone-mediated protein complex assembly
  locations:
  - id: GO:0005813
    label: centrosome
  - id: GO:0036064
    label: ciliary basal body
- description: >-
    Centrosomal/pericentriolar protein that localizes to the basal body and shuttles
    between cytosol and centrosome, providing the spatial context for BBSome biogenesis
    and contributing to ciliogenesis.
  supported_by:
  - reference_id: PMID:28753627
    supporting_text: >-
      BBS6 is actively transported between the cytoplasm and nucleus, and that
      BBS6H84Y; A242S, is defective in this transport.
  locations:
  - id: GO:0005813
    label: centrosome
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
suggested_experiments:
- description: >-
    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).
- description: >-
    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.
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10802661
  title: Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman
    syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Gene-discovery paper; establishes MKKS as a putative chaperonin and links it to
      McKusick-Kaufman syndrome. Supports the chaperone/protein-folding and disease-
      developmental annotations (TAS).
- id: PMID:16327777
  title: Dissection of epistasis in oligogenic Bardet-Biedl syndrome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Identifies CCDC28B/MGC1203 as a pericentriolar protein interacting and
      colocalizing with BBS proteins; supports the MKKS-CCDC28B IPI.
- id: PMID:18762586
  title: 'Recruitment of PCM1 to the centrosome by the cooperative action of DISC1
    and BBS4: a candidate for psychiatric illnesses.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Primarily about DISC1/BBS4/PCM1 centrosomal recruitment; MKKS-PCM1 IPI is a
      peripheral, centrosomal-context interaction.
- id: PMID:20080638
  title: BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and
    mediate BBSome assembly.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Key paper establishing the BBS6/BBS10/BBS12 + CCT/TRiC chaperonin complex that
      mediates BBSome assembly; underpins the core chaperone-mediated complex assembly
      annotation.
- id: PMID:22302990
  title: Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Demonstrates a direct nuclear/transcriptional-regulation role for BBS proteins;
      abstract foregrounds BBS7 but indicates a similar role for other BBS proteins.
      Full text not cached; supports MKKS nuclear/TF-binding IPI assigned by MGI.
- id: PMID:22446187
  title: Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects
    and restores ciliogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows MKKS directly interacts with CEP290 and that BBS mutations disrupt this
      interaction; supports the MKKS-CEP290 IPI within ciliary biology.
- id: PMID:22500027
  title: Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential
    assembly of stable bardet-biedl syndrome protein complex, the BBSome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the sequential BBSome-assembly pathway; the BBS-chaperonin complex
      (incl. MKKS) stabilizes BBS7 and nucleates the BBS7-BBS2-BBS9 core. Confirms
      MKKS is an assembly factor, not a stable BBSome subunit.
- id: PMID:26900326
  title: A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly
    without other findings of Bardet-Biedl or McKusick-Kaufman syndrome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Disease-allele study; H395R reduces MKKS-BBS12 interaction, supporting the
      MKKS-BBS12 IPI and the functional importance of the chaperonin interaction.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale AP-MS (BioPlex 2.0); source of a high-throughput MKKS-BBS12
      interaction. Supports complex membership but provides no specific function.
- id: PMID:28753627
  title: Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease
    through perturbation of a chromatin remodeling protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes active nuclear-cytoplasmic transport of BBS6, the SMARCC1 interaction,
      and a transcriptional/chromatin-remodeling arm relevant to congenital heart disease;
      supports nucleus/cytoplasm IDA, SMARCC1 IPI, and cilium-assembly IMP.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Binary interactome map (HuRI); source of low-specificity MKKS-CDR2 and MKKS-ZBED1
      interactions of uncertain biological relevance.
- id: PMID:33144677
  title: Dlec1 is required for spermatogenesis and male fertility in mice.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Mouse spermatogenesis study reporting a Dlec1-Mkks interaction; source of the
      MKKS-DLEC1 IPI. Peripheral to MKKS core function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale AP-MS (BioPlex 3.0); source of a high-throughput MKKS-BBS12
      interaction corroborating complex membership.
- id: file:human/MKKS/MKKS-deep-research-falcon.md
  title: Falcon deep research report for MKKS
  findings: []
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      LLM-synthesized deep-research report (Falcon/Edison) over recent reviews
      (Alvarez-Satta 2017, Tian 2023, Gupta 2022, etc.). Correctness left UNVERIFIED
      because the underlying review papers are not in the local cache and the synthesis
      was machine-generated. MKKS-CHAPERONIN-SPECIFIC claims that are well anchored and
      consistent with the curated literature: (1) MKKS is a chaperonin-LIKE assembly
      factor, NOT a stable/core BBSome subunit; (2) MKKS does not perform canonical
      ATP-dependent protein folding - its ATP-hydrolysis motif is divergent and the
      actual folding is executed by the associated canonical CCT/TRiC chaperonins;
      (3) MKKS/BBS12 act as substrate-binding units mediating association of CCT with
      the client BBS7, stabilizing BBS7 for the BBS2-BBS7-BBS9 core; (4) basal-body/
      centrosome-centered localization, and chaperonin-like BBS proteins are generally
      NOT detected along the cilium itself. These are used to STRENGTHEN existing
      annotations only, not to add new ones. CLAIMS to treat with caution as
      BBSome/CCT GENERALIZATION rather than direct MKKS evidence: BBSome cargo-adaptor
      trafficking, Hedgehog/GPCR/ARL6 trafficking detail, and SMARCC1/nuclear
      moonlighting (the report itself flags these as less established); these were not
      used to alter MKKS molecular-function calls.