Affinage

Showing MKKS — BBS6 is a alias.

MKKS

Molecular chaperone MKKS · UniProt Q9NPJ1

Length
570 aa
Mass
62.3 kDa
Annotated
2026-06-10
28 papers in source corpus 7 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MKKS/BBS6 is a divergent Group II chaperonin-like protein that operates at the centrosome and primary cilium to coordinate cell division and ciliogenesis (PMID:15731008). Unlike canonical chaperonins it does not oligomerize; instead it localizes to the pericentriolar material via its predicted substrate-binding apical domain, shifting from the lateral PCM in interphase to the whole PCM and the intercellular bridge during mitosis, and its loss causes cytokinesis failure with multinucleate, multicentrosomal cells (PMID:15731008). Wild-type BBS6 shuttles between the centrosome and cytosol, whereas disease-causing mutations misfold the protein so that it fails to reach the centrosome and is recognized by HSP70/HSC70 and HSP90 together with the chaperone-dependent E3 ligase CHIP, which targets the mutants for ubiquitin-proteasome degradation (PMID:18094050). At the ciliary transition zone and basal body BBS6 directly binds CEP290, an interaction disrupted by BBS patient mutations and required for the integrity of multiprotein complexes that govern ciliogenesis and sensory function (PMID:22446187). BBS6 also undergoes active nuclear-cytoplasmic transport and interacts with the SWI/SNF chromatin-remodeling subunit SMARCC1, controlling SMARCC1 localization and acting upstream of its transcriptional output; the McKusick-Kaufman syndrome allele BBS6-H84Y;A242S is selectively defective in this nuclear transport while retaining cilia function (PMID:28753627). Consistent with these cellular roles, Mkks-null mice display a Bardet-Biedl-like phenotype including retinal degeneration, sperm flagellar failure, obesity, and sensory deficits (PMID:15772095). BBS6 additionally engages other BBS chaperonin-family proteins, with patient mutations weakening its interaction with BBS12 (PMID:26900326).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Established the first cellular consequence of disease-associated BBS6 mutations and a genetic role as an epistatic modifier, framing BBS6 as a misfolding-prone protein within an oligogenic disease architecture.

    Evidence Transfection of wild-type vs. patient missense BBS6 with immunofluorescence localization; epistasis analysis in human pedigrees

    PMID:12837689

    Open questions at the time
    • Did not define the normal subcellular compartment of BBS6
    • No biochemical mechanism for mislocalization
    • Triallelic modifier effect from pedigrees only
  2. 2005 High

    Defined where BBS6 acts and what it does in the cell cycle, showing it is a non-oligomerizing chaperonin-like protein that targets the PCM via its apical domain and is required for cytokinesis.

    Evidence Live-cell imaging, fractionation, domain-deletion mapping, patient mutation assays, and RNAi cytokinesis readout

    PMID:15731008

    Open questions at the time
    • No substrate of the apical domain identified
    • Mechanism linking centrosomal loss to cytokinesis failure unresolved
    • Whether chaperonin folding activity is exerted at all
  3. 2005 High

    Connected the molecular role to organismal physiology, showing complete loss of MKKS produces a BBS-like multisystem phenotype distinct from MKS-specific alleles.

    Evidence Mkks(-/-) knockout mouse with histological, physiological, and behavioral phenotyping

    PMID:15772095

    Open questions at the time
    • Cellular mechanism behind each phenotype not dissected
    • Does not explain why MKS-specific alleles differ
    • No tissue-specific causal pathway
  4. 2007 High

    Explained why disease mutants fail functionally, showing they adopt abnormal conformations recognized by HSP70/HSP90-CHIP and are cleared by the proteasome before reaching the centrosome.

    Evidence Protein stability assays, proteasome inhibition, reciprocal Co-IP of CHIP/HSP70/HSP90, live-cell imaging, and CHIP RNAi

    PMID:18094050

    Open questions at the time
    • Native folded structure of wild-type BBS6 not solved
    • Whether CHIP regulates wild-type turnover normally unclear
    • Centrosomal shuttling mechanism undefined
  5. 2012 High

    Placed BBS6 in a direct interaction with CEP290 at the transition zone, revealing that altered BBS6-CEP290 association reshapes the integrity of ciliary basal body complexes.

    Evidence Direct Co-IP, patient mutation validation, zebrafish morpholino epistasis, and mouse double-mutant genetic epistasis with ciliary readouts

    PMID:22446187

    Open questions at the time
    • Mechanism of the paradoxical double-mutant rescue unexplained
    • Stoichiometry and architecture of the transition-zone complex unknown
    • How BBS6 stabilizes the complex not defined
  6. 2016 Medium

    Extended the misfolding model to BBS-complex assembly, showing a patient mutation weakens the BBS6-BBS12 interaction in proportion to phenotypic severity.

    Evidence Co-IP/protein interaction assays in HEK-293T and ARPE-19 cells comparing wild-type and H395R mutant

    PMID:26900326

    Open questions at the time
    • No in vitro reconstitution of the interaction
    • Functional consequence of reduced BBS12 binding untested
    • Single method
  7. 2017 High

    Revealed a non-ciliary, nuclear role: BBS6 shuttles into the nucleus and partners with the SWI/SNF subunit SMARCC1 to control its localization and transcription, separating the transcriptional function (McKusick-Kaufman allele) from ciliary function.

    Evidence Nuclear-cytoplasmic fractionation/transport assays, inducible-bbs6 pulldown/MS, Co-IP, SMARCC1 localization imaging, and transcriptional profiling in zebrafish

    PMID:28753627

    Open questions at the time
    • Direct chromatin targets downstream of BBS6-SMARCC1 not defined
    • Whether BBS6 acts as a chaperone for SMARCC1 unknown
    • Link to congenital heart defects mechanistic detail limited
  8. 2022 Medium

    Proposed a chaperonin co-complex mechanism, with BBS6 acting alongside TRiC/CCT to deliver client GPCR ADGRV1 to the cilium and protect it from proteasomal degradation.

    Evidence siRNA knockdown with ciliogenesis phenotype, ciliary proteome interaction network, ADGRV1 localization imaging, and proteasome inhibition (preprint)

    Open questions at the time
    • Preprint, single lab, not peer-reviewed
    • Direct chaperone activity on ADGRV1 not reconstituted
    • Generality of clients beyond ADGRV1 untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what endogenous substrates BBS6 folds and how its chaperonin-like apical domain, centrosomal, ciliary, and nuclear activities are mechanistically integrated within a single protein.
  • No structure of wild-type BBS6 or defined folding cycle
  • No validated direct folding substrate
  • Coordination of centrosomal, transition-zone, and nuclear pools unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005929 cilium 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-1640170 Cell Cycle 1
Partners
BBS12CEP290HSP90HSPA8SMARCC1STUB1
Complex memberships
BBSome-related BBS chaperonin module (BBS6-BBS12)TRiC/CCT-BBS chaperonin co-complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 MKKS/BBS6 is a Group II chaperonin-like protein that does not oligomerize (unlike canonical chaperonins) and localizes predominantly within the pericentriolar material (PCM). During interphase it is confined to lateral surfaces of the PCM; during mitosis it relocalizes throughout the PCM and to the intercellular bridge. Its predicted substrate-binding apical domain is sufficient for centrosomal association. Patient-derived mutations in this domain cause mislocalization of BBS6. siRNA-mediated silencing of BBS6 causes cytokinesis defects resulting in multinucleate and multicentrosomal cells. Live-cell imaging, immunofluorescence/fractionation for localization; domain-deletion constructs to map centrosomal targeting; patient mutation functional assays; RNAi knockdown with cytokinesis phenotype readout; phylogenomic analysis of chaperonin evolution Journal of cell science High 15731008
2007 Disease-causing mutant forms of MKKS are rapidly degraded via the ubiquitin-proteasome pathway in a manner dependent on the E3 ubiquitin ligase CHIP (a chaperone-dependent ubiquitin ligase). Wild-type MKKS shuttles between the centrosome and cytosol; rapidly degraded mutants fail to localize to the centrosome. Proteasome inhibition causes MKKS mutants to form insoluble structures at the centrosome. CHIP and partner chaperones HSP70/HSC70 and HSP90 preferentially recognize MKKS mutants, indicating abnormal conformation of disease mutants. Pulse-chase/protein stability assays; proteasome inhibitor experiments; co-immunoprecipitation of CHIP/HSP70/HSP90 with MKKS; live-cell imaging of centrosomal shuttling; RNAi knockdown of CHIP; immunofluorescence after proteasome inhibition Molecular biology of the cell High 18094050
2012 The domain deleted in the Cep290rd16 allele directly interacts with MKKS. BBS patient-derived MKKS mutations disrupt this CEP290-MKKS interaction. Combined subminimal knockdown of mkks and cep290 in zebrafish produces synergistic sensory defects. Paradoxically, combining Cep290rd16 and Mkks knockout alleles in mice improves ciliogenesis and sensory function compared with either mutant alone, suggesting that altered CEP290-MKKS association affects integrity of multiprotein complexes at the cilia transition zone and basal body. Co-immunoprecipitation (direct protein-protein interaction); zebrafish morpholino epistasis; mouse double-mutant genetic epistasis with ciliogenesis and sensory functional readouts The Journal of clinical investigation High 22446187
2017 BBS6 undergoes active nuclear-cytoplasmic transport. The McKusick-Kaufman syndrome allele BBS6-H84Y;A242S is defective in nuclear-cytoplasmic transport but maintains cilia function. BBS6 interacts with the SWI/SNF chromatin remodeling protein SMARCC1 (smarcc1a in zebrafish), and through this interaction modulates SMARCC1 subcellular localization. Transcriptional profiling shows similar changes following smarcc1a and bbs6 manipulation, placing BBS6 upstream of SMARCC1-dependent transcriptional regulation. Nuclear-cytoplasmic fractionation and transport assays; transgenic zebrafish with inducible bbs6 for pulldown/mass spectrometry identification of binding partners; co-immunoprecipitation of BBS6-SMARCC1; immunofluorescence of SMARCC1 localization upon BBS6 manipulation; transcriptional profiling PLoS genetics High 28753627
2005 Mkks knockout mice develop retinal degeneration (via apoptosis), failure of spermatozoa flagella formation, elevated blood pressure, obesity (associated with hyperphagia and decreased activity), and olfactory/social dominance deficits, but not polydactyly or vaginal abnormalities, indicating that complete loss of MKKS function causes BBS-like phenotype whereas MKS-specific alleles produce distinct outcomes. Mkks(-/-) mouse knockout with histological, physiological, and behavioral phenotyping Human molecular genetics High 15772095
2003 A BBS6 (putative chaperonin) missense mutation introduced in mammalian cells causes dramatic mislocalization of the BBS6 protein compared with wild-type, and heterozygous BBS6 mutations can act as epistatic modifiers potentiating a phenotype caused by two recessive mutations at an independent BBS locus (triallelic model). Transfection of wild-type vs. patient-derived missense mutant BBS6 in mammalian cells with immunofluorescence localization; genetic epistasis analysis in human pedigrees Human molecular genetics Medium 12837689
2016 The MKKS/BBS6 H395R patient mutation decreases the interaction of MKKS/BBS6 with BBS12 in protein-protein interaction assays in HEK-293T and ARPE-19 cells, though to a lesser extent than other BBS6 mutations associated with syndromic retinitis pigmentosa, consistent with a milder phenotype. Co-immunoprecipitation / protein-protein interaction assays in two cell lines (HEK-293T and ARPE-19) comparing wild-type vs. H395R mutant MKKS/BBS6 interaction with BBS12 Molecular vision Medium 26900326
2022 BBS6, together with TRiC/CCT chaperonins, forms a co-complex required for the localization of the adhesion GPCR ADGRV1 to primary cilia. Knockdown of BBS6 results in reduced ciliated cells and shorter primary cilia. In the absence of the TRiC/CCT-BBS chaperonin co-complex, ADGRV1 is depleted from the ciliary base and degraded via the proteasome. siRNA knockdown of BBS6 with ciliogenesis phenotype (reduced ciliated cells, shorter cilia); co-complex interaction identified by ciliary proteome interaction network; immunofluorescence of ADGRV1 localization upon BBS6 knockdown; proteasome inhibitor experiments bioRxivpreprint Medium
2022 Loss of Bbs6 in RPE-J cells showed no functionality phenotype for phagocytosis (negative finding: Bbs6 loss did not impair photoreceptor outer segment binding or phagocytosis in RPE cells, in contrast to loss of IFT20 or IFT88). Bbs6 depletion in RPE-J cells with phagocytosis assay (outer segment binding and internalization) and apical membrane morphology analysis bioRxivpreprint Low

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nature genetics 241 10973251
2000 Mutations in MKKS cause Bardet-Biedl syndrome. Nature genetics 209 10973238
2005 Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Human molecular genetics 161 15772095
2003 Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Human molecular genetics 153 12837689
2005 MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. Journal of cell science 137 15731008
2012 Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis. The Journal of clinical investigation 67 22446187
2001 Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. American journal of human genetics 60 11179009
2002 Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. Human genetics 49 12107442
2010 LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins. Neuro-degenerative diseases 46 20173330
2010 Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes. European journal of medical genetics 35 21044901
2017 Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PLoS genetics 28 28753627
2019 Matrine Suppresses Reactive Oxygen Species (ROS)-Mediated MKKs/p38-Induced Inflammation in Oxidized Low-Density Lipoprotein (ox-LDL)-Stimulated Macrophages. Medical science monitor : international medical journal of experimental and clinical research 25 31156213
2007 MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination. Molecular biology of the cell 21 18094050
2022 Bardet-Biedl syndrome: The pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins. American journal of medical genetics. Part C, Seminars in medical genetics 18 35373910
2016 A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome. Molecular vision 14 26900326
2005 No evidence for triallelic inheritance of MKKS/BBS loci in Amish Mckusick-Kaufman syndrome. American journal of medical genetics. Part A 12 16104012
2018 Novel ASK1 Inhibitor AGI-1067 Attenuates AGE-Induced Fibrotic Response by Suppressing the MKKs/p38 MAPK Pathway in Human Coronary Arterial Smooth Muscle Cells. International heart journal 10 30305582
2008 Association between BBS6/MKKS gene polymorphisms, obesity and metabolic syndrome in the Greek population. International journal of obesity (2005) 10 18813213
2017 Phylogenomic analysis of MKKs and MAPKs from 16 legumes and detection of interacting pairs in chickpea divulge MAPK signalling modules. Scientific reports 9 28694440
2021 Novel Compound Heterozygous BBS2 and Homozygous MKKS Variants Detected in Chinese Families with Bardet-Biedl Syndrome. Journal of ophthalmology 8 33520300
2019 Two novel MKKs (MKK4 and MKK7) from Ctenopharyngodon idella are involved in the intestinal immune response to bacterial muramyl dipeptide challenge. Developmental and comparative immunology 7 30633955
2018 Novel ASK1 inhibitor AGI-1067 improves AGE-induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF-κB apoptotic signaling. FEBS open bio 7 30186746
2022 Novel Mutations in the MKKS, BBS7, and ALMS1 Genes in Iranian Children with Clinically Suspected Bardet-Biedl Syndrome. Case reports in ophthalmological medicine 6 35912300
2022 Behavioral Phenotyping of Bbs6 and Bbs8 Knockout Mice Reveals Major Alterations in Communication and Anxiety. International journal of molecular sciences 6 36498834
2020 Legg-Calvé-Perthes disease in a patient with Bardet-Biedl syndrome: A case report of a novel MKKS/BBS6 mutation. Clinical case reports 3 33363891
2022 [Genetic analysis of novel MKKS variants in a Chinese patient with Bardet-Biedl syndrome]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 35810436
2020 Novel mutation in MKKS/BBS6 linked with arRP and polydactyly in a family of North Indian origin. Clinical & experimental ophthalmology 1 31989739
2025 Assessment of genetic variation(s) in BBS10, BBS6, and BBS12 in a family from Sindh, Pakistan diagnosed with Bardet-Biedl Syndrome. JPMA. The Journal of the Pakistan Medical Association 0 41418239

Missed literature

Know a paper Affinage missed for MKKS? Flag it for the maintainers and the community.

No submissions yet.