Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0035869 ciliary transition zone	IBA GO_REF:0000033	ACCEPT	Summary: MKS-6 localization to the ciliary transition zone is well-established through phylogenetic inference from the PANTHER family. The human ortholog CC2D2A and mouse ortholog Cc2d2a are both validated TZ components. This annotation is consistent with direct experimental evidence in C. elegans from PMID:21422230 and PMID:26595381. Reason: The IBA annotation is fully consistent with multiple lines of experimental evidence demonstrating that MKS-6 localizes to the transition zone. The annotation represents a core localization of this protein that is central to its function. Supporting Evidence: PMID:21422230 MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ), an underappreciated region at the base of all cilia characterized by Y-shaped assemblages that link axoneme microtubules to surrounding membrane. file:worm/mks-6/mks-6-deep-research-falcon.md model: Edison Scientific Literature
GO:1904491 protein localization to ciliary transition zone	IBA GO_REF:0000033	ACCEPT	Summary: MKS-6 is part of a module of proteins that collectively recruit each other to the transition zone. The IBA annotation is supported by experimental evidence showing that MKS-5 is required for docking/anchoring MKS-6 and other MKS module proteins at the TZ. Reason: This annotation reflects MKS-6's role in the hierarchical assembly of the MKS module at the transition zone. The protein participates in mutual localization dependencies with other TZ proteins. Supporting Evidence: PMID:21422230 MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules
GO:1905515 non-motile cilium assembly	IBA GO_REF:0000033	ACCEPT	Summary: MKS-6 is required for non-motile cilium assembly in C. elegans, particularly evident in genetic interaction studies. Single mks-6 mutants have mild phenotypes, but combined with nphp-4 mutations show severe ciliogenesis defects. Reason: The IBA annotation accurately reflects MKS-6's role in ciliogenesis. C. elegans possesses only non-motile (primary) cilia in sensory neurons, and MKS-6 is essential for their assembly through its function at the transition zone. Supporting Evidence: PMID:21422230 Functional interactions between NPHP proteins and MKS-5 or MKS-6 are required for ciliogenesis
GO:0035869 ciliary transition zone	IDA PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci...	ACCEPT	Summary: Direct experimental demonstration of MKS-6 localization to the ciliary transition zone in C. elegans. The study by Lambacher et al. examined TZ protein localization in the context of TMEM107 recruitment of ciliopathy proteins. Reason: This IDA annotation provides direct experimental evidence for MKS-6 TZ localization. The study demonstrates that TMEM-107 organizes recruitment of multiple MKS module proteins including the MKS-6 ortholog to the TZ. Supporting Evidence: PMID:26595381 nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
GO:1904491 protein localization to ciliary transition zone	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: Genetic interaction evidence with mksr-2 (WBGene00010898) demonstrates MKS-6's role in protein localization to the TZ. The MKS module proteins function collectively to establish TZ membrane associations. Reason: The IGI annotation appropriately captures the genetic evidence showing that MKS-6 functions together with MKSR-2 and other MKS module proteins in establishing protein localization at the TZ. The hierarchical dependencies between these proteins are well-documented. Supporting Evidence: PMID:21422230 Together, our findings uncover a unified role for eight TZ-localized proteins in basal body anchoring and establishing a ciliary gate during ciliogenesis
GO:0003674 molecular_function	ND GO_REF:0000015	ACCEPT	Summary: The ND annotation indicates no specific molecular function has been experimentally determined for MKS-6. The C2 domain suggests potential lipid or calcium binding, but this has not been directly demonstrated for MKS-6. Reason: This annotation correctly reflects that no specific enzymatic or molecular function has been experimentally characterized for MKS-6. The protein functions as a structural component of the MKS module at the transition zone, but the precise molecular mechanism remains undefined.
GO:0044292 dendrite terminus	IDA PMID:25335890 Ciliopathy proteins establish a bipartite signaling compartm...	ACCEPT	Summary: Nguyen et al. demonstrated that transition zone proteins, including those in the MKS module, unexpectedly localize to the dendrite terminus in AFD thermosensory neurons, where they establish a membrane diffusion barrier despite the absence of canonical TZ ultrastructure. Reason: This localization represents a specialized function of MKS module proteins in AFD neurons. While not a canonical TZ, the dendrite terminus compartment requires TZ proteins for proper compartmentalization of signaling components. Supporting Evidence: PMID:25335890 we reveal the unexpected presence of ciliary transition zone proteins where no canonical transition zone ultrastructure exists
GO:1905515 non-motile cilium assembly	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: Genetic interaction with mks-5 (WBGene00007490) demonstrates MKS-6's role in non-motile cilium assembly. MKS-5 acts as a central hub for the MKS module, and functional interactions between MKS-5/MKS-6 and NPHP proteins are required for proper ciliogenesis. Reason: The IGI annotation correctly captures the genetic evidence that MKS-6 functions with MKS-5 in ciliogenesis. Combined disruption of MKS module proteins with NPHP-4 causes severe ciliogenesis defects. Supporting Evidence: PMID:21422230 Functional interactions between NPHP proteins and MKS-5 or MKS-6 are required for ciliogenesis
GO:0035869 ciliary transition zone	IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: Williams et al. directly demonstrated MKS-6 localization to the ciliary transition zone using fluorescent reporters. This foundational study established MKS-6 as a core component of the TZ-localized MKS module. Reason: This is a primary experimental reference establishing MKS-6 localization to the TZ. The study systematically characterized the localization of multiple MKS and NPHP proteins and demonstrated their collective function at the TZ. Supporting Evidence: PMID:21422230 MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ)
GO:1905515 non-motile cilium assembly	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: Genetic interaction with mksr-2 (WBGene00010898) demonstrates redundant function in non-motile cilium assembly. The MKS module proteins (including MKS-6 and MKSR-2) act together with NPHP module proteins for ciliogenesis. Reason: This IGI annotation captures genetic evidence for MKS-6 function in ciliogenesis through interaction with MKSR-2. Both proteins are part of the MKS module. Supporting Evidence: PMID:21422230 the conserved C. elegans B9 domain (MKS-1, MKSR-1, and MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone
GO:1905515 non-motile cilium assembly	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: Genetic interaction with nphp-4 (WBGene00011261) demonstrates functional redundancy between MKS and NPHP modules. Double mutants of mks-6 with nphp-4 show severe ciliogenesis defects not observed in single mutants. Reason: This is a key IGI annotation demonstrating the critical genetic interaction between MKS-6 and NPHP-4. Joint disruption of MKS module proteins with NPHP-4 results in basal body/TZ membrane association defects and failure of ciliogenesis. Supporting Evidence: PMID:21422230 Joint disruption of an MKS/MKSR protein and NPHP-4 results in BB/TZ membrane association defects

Core Functions

MKS-6 functions as a structural component of the MKS module at the ciliary transition zone, where it contributes to basal body/TZ membrane associations and establishes the ciliary gate during ciliogenesis. The protein likely functions as a scaffold through its C2 domain.

Molecular Function:

molecular_function

Directly Involved In:

non-motile cilium assembly protein localization to ciliary transition zone

Cellular Locations:

ciliary transition zone

Supporting Evidence:

PMID:21422230
MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ)

References

GO_REF:0000015

Use of the ND evidence code for Gene Ontology (GO) terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

PMID:21422230

MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.

MKS-6/CC2D2A is one of eight TZ proteins that function collectively in ciliogenesis

"MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ)"
MKS-6 localizes specifically to the ciliary transition zone

"MKS/MKSR and NPHP proteins localize specifically to the ciliary TZ"
Functional interactions between NPHP proteins and MKS-5 or MKS-6 are required for ciliogenesis

"Functional interactions between NPHP proteins and MKS-5 or MKS-6 are required for ciliogenesis"
Joint disruption of MKS module proteins with NPHP-4 causes severe BB/TZ membrane association defects

"Joint disruption of an MKS/MKSR protein and NPHP-4 results in BB/TZ membrane association defects"
MKS-5 acts as a central hub required for docking MKS and NPHP protein modules

"MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules"
TZ proteins establish a ciliary gate that restricts nonciliary components from the cilium

"establishing a ciliary gate during ciliogenesis, and suggest that disrupting ciliary gate function contributes to phenotypic features of the MKS/NPHP disease spectrum"

PMID:25335890

Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron.

TZ proteins localize to the dendrite terminus in AFD neurons

"we reveal the unexpected presence of ciliary transition zone proteins where no canonical transition zone ultrastructure exists"
Ciliary proteins help establish distinct signaling compartments in thermosensory neurons

"ciliary proteins help establish two contiguous, yet distinct cyclic GMP (cGMP) signaling compartments in Caenorhabditis elegans thermosensory AFD neurons"
TZ proteins function in membrane diffusion barrier formation at sites without canonical TZ ultrastructure

"Consistent with a requirement for a membrane diffusion barrier at the subcompartment base, we reveal the unexpected presence of ciliary transition zone proteins where no canonical transition zone ultrastructure exists"

PMID:26595381

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome.

TMEM-107 organizes recruitment of MKS module proteins to TZ subdomains

"nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)"
MKS module proteins are immobile at the TZ and show periodic localization patterns

"MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ"
TZ proteins control ciliary composition through diffusion barrier function

"The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base"

file:worm/mks-6/mks-6-deep-research-falcon.md

Deep research report on mks-6

Suggested Experiments

Experiment: Biochemical characterization of MKS-6 C2 domain lipid binding specificity using liposome binding assays

Hypothesis: The C2 domain of MKS-6 mediates membrane association at the TZ through lipid binding

Experiment: Identification of direct protein-protein interactions using co-immunoprecipitation or yeast two-hybrid screening

Hypothesis: MKS-6 directly interacts with MKS-5 or other MKS module components

Experiment: Super-resolution imaging of MKS-6 to determine its precise sub-TZ localization relative to Y-links

Hypothesis: MKS-6 localizes to specific TZ subdomains associated with Y-link structures

📚 Additional Documentation

Deep Research Falcon

(mks-6-deep-research-falcon.md)

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gene_id: mks-6
gene_symbol: mks-6
uniprot_accession: Q21303
protein_description: 'SubName: Full=C2 domain-containing protein {ECO:0000313|EMBL:CAA95830.1};'
gene_info: Name=mks-6 {ECO:0000313|EMBL:CAA95830.1, ECO:0000313|WormBase:K07G5.3};
ORFNames=CELE_K07G5.3 {ECO:0000313|EMBL:CAA95830.1}, K07G5.3 {ECO:0000313|WormBase:K07G5.3};
organism_full: Caenorhabditis elegans.
protein_family: Not specified in UniProt
protein_domains: C2_dom. (IPR000008); C2_domain_sf. (IPR035892); CC2D2AN-C2. (IPR028928);
CEPT76/DRC7_peptidase-like_dom. (IPR056290); Tectonic-like_complex_comp. (IPR052434)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q21303
Protein Description: SubName: Full=C2 domain-containing protein {ECO:0000313|EMBL:CAA95830.1};
Gene Information: Name=mks-6 {ECO:0000313|EMBL:CAA95830.1, ECO:0000313|WormBase:K07G5.3}; ORFNames=CELE_K07G5.3 {ECO:0000313|EMBL:CAA95830.1}, K07G5.3 {ECO:0000313|WormBase:K07G5.3};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: C2_dom. (IPR000008); C2_domain_sf. (IPR035892); CC2D2AN-C2. (IPR028928); CEPT76/DRC7_peptidase-like_dom. (IPR056290); Tectonic-like_complex_comp. (IPR052434)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "mks-6" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'mks-6' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene mks-6 (gene ID: mks-6, UniProt: Q21303) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q21303
Protein Description: SubName: Full=C2 domain-containing protein {ECO:0000313|EMBL:CAA95830.1};
Gene Information: Name=mks-6 {ECO:0000313|EMBL:CAA95830.1, ECO:0000313|WormBase:K07G5.3}; ORFNames=CELE_K07G5.3 {ECO:0000313|EMBL:CAA95830.1}, K07G5.3 {ECO:0000313|WormBase:K07G5.3};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: C2_dom. (IPR000008); C2_domain_sf. (IPR035892); CC2D2AN-C2. (IPR028928); CEPT76/DRC7_peptidase-like_dom. (IPR056290); Tectonic-like_complex_comp. (IPR052434)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "mks-6" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'mks-6' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene mks-6 (gene ID: mks-6, UniProt: Q21303) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: mks-6 (CC2D2A ortholog) in Caenorhabditis elegans (UniProt Q21303)

Verification of gene/protein identity and domain architecture
- Identity and orthology: mks-6 encodes the C. elegans ortholog of human CC2D2A, a Meckel syndrome/Joubert syndrome-associated transition zone (TZ) protein. Multiple studies explicitly list “MKS-6 (Cc2d2a)” as an MKS-module component in C. elegans TZ research (Jensen et al., 2015, The EMBO Journal, published Oct 2015: https://doi.org/10.15252/embj.201488044; Li et al., 2016, PLOS Biology, published Mar 2016: https://doi.org/10.1371/journal.pbio.1002416) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3).
- Domain features: mks-6/CC2D2A is described as a coiled-coil protein containing a C2 domain, consistent with membrane- and scaffold-associated functions at the TZ (Park, 2019, review; see cilia section; publication year 2019) (park2019ciliumlengthregulationa pages 21-24, park2019ciliumlengthregulation pages 21-24). This matches the UniProt domain annotation (C2) provided by the user and aligns with CC2D2A-N/C2 domain family classifications.
- Organism correctness: All cited works explicitly perform or interpret experiments in C. elegans (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8).

1) Key concepts and definitions with current understanding
- Transition zone (TZ) and gating: The TZ is the proximal ciliary domain containing Y-links and the ciliary necklace that establishes a selective diffusion barrier controlling protein and lipid composition of the cilium (“ciliary gate”). These features and functions are conserved across eukaryotes and were defined by ultrastructure and genetic/proteomic mapping (Gonçalves & Pelletier, 2017, Molecules and Cells, published Apr 2017: https://doi.org/10.14348/molcells.2017.0054; Park & Leroux, 2022, EMBO Reports, published Nov 2022: https://doi.org/10.15252/embr.202255420) (goncalves2017theciliarytransition pages 1-3, park2022compositionorganizationand pages 6-8).
- MKS and NPHP modules: TZ proteins partition into at least two major, partially redundant modules—MKS and NPHP—identified by genetic interactions and localization dependencies; CEP-290 acts as a central assembly factor, and MKS-5/RPGRIP1L is an upstream scaffold that coordinates both modules (Li et al., 2016, PLOS Biology; Jensen et al., 2015, The EMBO Journal) (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2).
- Position of MKS-6: MKS-6/CC2D2A is a canonical MKS-module component at the TZ. Its organization and function are considered alongside other MKS-module proteins such as MKS-1, MKS-2 (TMEM216), MKS-3 (TMEM67), the B9 complex (MKSR-1/B9D1, MKSR-2/B9D2), and TMEM family members (TMEM231, TMEM107, TMEM218) (Jensen et al., 2015; Li et al., 2016; Park & Leroux, 2022) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8).

2) Recent developments and latest research (priority to 2023–2024)
- While direct 2023–2024 mks-6-specific primary reports are limited in the retrieved evidence, an updated synthesis in 2022 (Park & Leroux, EMBO Reports) consolidates TZ architecture and gating mechanisms across organisms, emphasizing the hierarchical assembly anchored by MKS-5 and CEP-290 and the integration of MKS components (including MKS-6/CC2D2A) into the gate’s structural and functional model (published Nov 2022: https://doi.org/10.15252/embr.202255420) (park2022compositionorganizationand pages 6-8).
- Broad conceptual advances emphasized by the 2022 review include multiple, potentially cooperative gating mechanisms: protein “picket fences,” specialized lipids, membrane curvature/thickness effects, and size-selective sieving integrated with intraflagellar transport (IFT) systems—frameworks that contextualize the role of MKS-6 in maintaining ciliary compartmentalization (park2022compositionorganizationand pages 6-8).

3) Current applications and real-world implementations
- Disease modeling and variant interpretation: Because mks-6 is orthologous to human CC2D2A, a gene mutated in ciliopathies (Meckel, Joubert syndromes), C. elegans provides a tractable system to model TZ assembly defects, assess gating phenotypes and ultrastructure, and test genetic interactions that mirror human disease complexity (Jensen et al., 2015; Li et al., 2016; Park & Leroux, 2022) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8).
- Assays and readouts: Established readouts include TZ protein localization dependencies, membrane protein leakage into cilia (e.g., mislocalization/accumulation of periciliary membrane proteins), and transmission electron microscopy (TEM) to visualize TZ Y-links and basal body–membrane attachments. These assays are routinely applied to MKS-module mutants (including mks-6) and to combinations with NPHP-module mutants to reveal synthetic defects (Jensen et al., 2015; Li et al., 2016) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3).

4) Expert opinions and analysis from authoritative sources
- Park & Leroux (2022) integrates genetic, structural, and biochemical perspectives to argue that TZ integrity results from an interdigitated network of MKS/NPHP components and accessory factors, with MKS-5 and CEP-290 orchestrating assembly and MKS-6/CC2D2A contributing as a conserved MKS-module component at the membrane–axoneme interface (EMBO Reports; published Nov 2022: https://doi.org/10.15252/embr.202255420) (park2022compositionorganizationand pages 6-8).
- Jensen et al. (2015) introduced the “ciliary zone of exclusion” (CIZE) concept at the TZ, linking MKS-5-dependent assembly to control of signaling protein compartmentalization and PIP2 levels, thus providing a mechanistic framework for how MKS-module components, including MKS-6, maintain ciliary composition (The EMBO Journal; published Oct 2015: https://doi.org/10.15252/embj.201488044) (jensen2015formationofthe pages 1-2).
- Li et al. (2016) demonstrated a hierarchical assembly pathway in which MKS-5 scaffolds the TZ and CEP-290 promotes assembly/localization of many MKS components—principles that encompass MKS-6 and rationalize genetic interaction patterns in C. elegans and human ciliopathies (PLOS Biology; published Mar 2016: https://doi.org/10.1371/journal.pbio.1002416) (li2016mks5andcep290 pages 2-3, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 3-5).

5) Relevant statistics and data from recent studies (mks-6 within module context)
- Gating phenotypes: Loss of core TZ assembly factors disrupts barrier function with membrane-associated proteins mislocalized into cilia; in C. elegans, this includes aberrant presence or leakage of markers such as ARL-13 and periciliary proteins, quantified in cep-290 and related TZ mutants, and conceptually applies to MKS-module defects encompassing mks-6 (Li et al., 2016; Jensen et al., 2015) (li2016mks5andcep290 pages 9-11, jensen2015formationofthe pages 1-2).
- Ultrastructure: Severe TZ defects in C. elegans double mutants that combine MKS- and NPHP-module losses include loss of Y-links, failure of basal body–TZ membrane anchoring, and disorganized or shortened axonemal microtubules; these data emerge from systematic TEM analyses across genotypes and define the synthetic nature of MKS–NPHP interactions (Li et al., 2016; Jensen et al., 2015) (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2).

Functional summary for mks-6 (primary role, processes, localization, and pathway placement)
- Primary role and molecular function: MKS-6 is a conserved MKS-module component with coiled-coil and C2 domains acting within the TZ as part of the ciliary gate. Its molecular role is structural/scaffold-associated rather than enzymatic, helping establish and maintain compartmentalization of ciliary proteins and lipids in cooperation with other MKS/TZ components (Park, 2019; Jensen et al., 2015; Li et al., 2016; Park & Leroux, 2022) (park2019ciliumlengthregulationa pages 21-24, jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8).
- Subcellular localization: MKS-6 localizes to the ciliary TZ; within this compartment it contributes to the “zone of exclusion” that demarcates proximal cilia from periciliary membrane and regulates molecule flux (Jensen et al., 2015; Li et al., 2016) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3).
- Complex/module membership and hierarchy: MKS-6 is embedded in the MKS module with B9 complex proteins (MKSR-1/B9D1, MKSR-2/B9D2), TMEM family members (e.g., TMEM231, TMEM107, TMEM218), and associated factors. MKS-5/RPGRIP1L acts upstream to scaffold both MKS and NPHP modules; CEP-290 is required for assembly/localization of many MKS components, positioning MKS-6 within a CEP-290–dependent TZ assembly branch (Li et al., 2016; Jensen et al., 2015; Park & Leroux, 2022) (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2, park2022compositionorganizationand pages 6-8).
- Genetic and pathway context: Genetic interactions between MKS and NPHP modules are partially redundant for ciliogenesis; double mutants can exhibit severe TZ ultrastructure and gating defects, whereas individual MKS mutants show compromised gating with variable effects on cilium length/structure depending on genetic background and the specific factor perturbed (Jensen et al., 2015; Li et al., 2016; Park & Leroux, 2022; Gonçalves & Pelletier, 2017) (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8, goncalves2017theciliarytransition pages 1-3).

Recent reviews and synthesis relevant to 2023–2024
- The 2022 EMBO Reports review (Park & Leroux) remains a current, authoritative synthesis of TZ composition, organization, and barrier mechanisms, and directly contextualizes MKS-6 within conserved MKS module biology and TZ assembly logic (published Nov 2022: https://doi.org/10.15252/embr.202255420) (park2022compositionorganizationand pages 6-8).

Embedded summary table of key facts and sources
| Category | Summary | Key sources (year) |
|---|---|---|
| Identity / ortholog | C. elegans mks-6 corresponds to the worm ortholog of human CC2D2A (UniProt Q21303). | Jensen 2015, Li 2016, Park 2019/2022 (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2019ciliumlengthregulationa pages 21-24, park2022compositionorganizationand pages 6-8) |
| Protein / domain features | Predicted coiled-coil protein containing a C2 domain; consistent with membrane/structural roles at the TZ. | Park 2019, Jensen 2015 (park2019ciliumlengthregulationa pages 21-24, jensen2015formationofthe pages 1-2) |
| Subcellular localization | Localizes to the ciliary transition zone (TZ), contributing to proximal TZ subdomains / zone-of-exclusion that compartmentalize ciliary proteins. | Jensen 2015, Li 2016, Park 2022 (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8) |
| Complex / module membership | Member of the genetically defined MKS module at the TZ (with B9 proteins and multiple TMEMs). Functionally linked to MKS-5 (RPGRIP1L) and CEP-290. | Li 2016, Jensen 2015, Park 2022 (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2, park2022compositionorganizationand pages 6-8) |
| Assembly dependencies / hierarchy | MKS-5 acts upstream as a scaffold; CEP-290 is required for assembling/localizing many MKS components (CEP-290–dependent branch); MKS-6 localization reflects this hierarchical assembly. | Li 2016, Jensen 2015, Park 2022 (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2, park2022compositionorganizationand pages 6-8) |
| Genetic & physical interactions | Genetic and proteomic links to TMEM family members (e.g., TMEM-231/107/218), the B9 complex (MKSR-1/B9D1, MKSR-2/B9D2), and cross-talk / synthetic interactions with NPHP module genes. | Li 2016, Park 2022, Jensen 2015 (li2016mks5andcep290 pages 2-3, park2022compositionorganizationand pages 6-8, jensen2015formationofthe pages 1-2) |
| Mutant phenotypes in worms | As part of MKS module, defects cause impaired TZ gating (membrane protein leakage), dye-filling abnormalities; double mks;nphp mutants show severe ciliogenesis/TZ ultrastructure loss (loss of Y-links, basal body–TZ membrane attachments, axonemal defects). | Li 2016, Jensen 2015, Park 2022 (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2, park2022compositionorganizationand pages 6-8) |
| Recent developments (2022–2024) | Updated TZ architecture and gating models synthesize genetic, proteomic and imaging data; new TMEM component studies and functional refinements reported in 2022–2024 reviews and preprints. | Park 2022, Gonçalves 2017, recent TMEM/TMEM67 preprints (park2022compositionorganizationand pages 6-8, goncalves2017theciliarytransition pages 1-3) |
| Applications / real-world | C. elegans mks-6 serves as a model for human CC2D2A ciliopathies, variant interpretation, and assays of TZ gating/compartmentalization (dye-fill, leakage, TEM/EM phenotyping). | Li 2016, Jensen 2015, Park 2022 (li2016mks5andcep290 pages 2-3, jensen2015formationofthe pages 1-2, park2022compositionorganizationand pages 6-8) |

Table: Compact, evidence‑backed table summarizing identity, domain features, localization, module membership, interactions, phenotypes, recent developments (2022–2024), and applications for C. elegans mks-6 (UniProt Q21303). Citations link to extracted context IDs used in the synthesis.

References (URLs and publication dates)
- Jensen VL et al. Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance. The EMBO Journal. Published Oct 2015. https://doi.org/10.15252/embj.201488044 (jensen2015formationofthe pages 1-2).
- Li C et al. MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. PLOS Biology. Published Mar 2016. https://doi.org/10.1371/journal.pbio.1002416 (li2016mks5andcep290 pages 2-3, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 3-5).
- Park K. Cilium length regulation in Caenorhabditis elegans. Review. Published 2019. (Context excerpt confirming CC2D2A/C2/coiled-coil features and MKS module placement.) (park2019ciliumlengthregulationa pages 21-24, park2019ciliumlengthregulation pages 21-24).
- Park K, Leroux MR. Composition, organization and mechanisms of the transition zone, a gate for the cilium. EMBO Reports. Published Nov 2022. https://doi.org/10.15252/embr.202255420 (park2022compositionorganizationand pages 6-8).
- Gonçalves J, Pelletier L. The Ciliary Transition Zone: Finding the Pieces and Assembling the Gate. Molecules and Cells. Published Apr 2017. https://doi.org/10.14348/molcells.2017.0054 (goncalves2017theciliarytransition pages 1-3).

Notes on symbol ambiguity
- The symbol “mks-6” is used consistently in C. elegans to denote the CC2D2A ortholog localized to the TZ; literature reviewed here is explicitly in C. elegans and aligns with the UniProt entry Q21303, including C2/coiled-coil domain architecture and TZ function (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 2-3, park2019ciliumlengthregulationa pages 21-24, park2022compositionorganizationand pages 6-8).

References

(jensen2015formationofthe pages 1-2): Victor L Jensen, Chunmei Li, Rachel V Bowie, Lara Clarke, Swetha Mohan, Oliver E Blacque, and Michel R Leroux. Formation of the transition zone by mks5/rpgrip1l establishes a ciliary zone of exclusion (cize) that compartmentalises ciliary signalling proteins and controls pip2 ciliary abundance. The EMBO Journal, 34:2537-2556, Oct 2015. URL: https://doi.org/10.15252/embj.201488044, doi:10.15252/embj.201488044. This article has 159 citations.
(li2016mks5andcep290 pages 2-3): Chunmei Li, Victor L. Jensen, Kwangjin Park, Julie Kennedy, Francesc R. Garcia-Gonzalo, Marta Romani, Roberta De Mori, Ange-Line Bruel, Dominique Gaillard, Bérénice Doray, Estelle Lopez, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet, Jeremy F. Reiter, Oliver E. Blacque, Enza Maria Valente, and Michel R. Leroux. Mks5 and cep290 dependent assembly pathway of the ciliary transition zone. PLOS Biology, 14:e1002416, Mar 2016. URL: https://doi.org/10.1371/journal.pbio.1002416, doi:10.1371/journal.pbio.1002416. This article has 165 citations and is from a highest quality peer-reviewed journal.
(park2019ciliumlengthregulationa pages 21-24): K Park. Cilium length regulation in caenorhabditis elegans. Unknown journal, 2019.
(park2019ciliumlengthregulation pages 21-24): K Park. Cilium length regulation in caenorhabditis elegans. Unknown journal, 2019.
(park2022compositionorganizationand pages 6-8): Kwangjin Park and Michel R Leroux. Composition, organization and mechanisms of the transition zone, a gate for the cilium. EMBO reports, Nov 2022. URL: https://doi.org/10.15252/embr.202255420, doi:10.15252/embr.202255420. This article has 71 citations and is from a highest quality peer-reviewed journal.
(goncalves2017theciliarytransition pages 1-3): João Gonçalves and Laurence Pelletier. The ciliary transition zone: finding the pieces and assembling the gate. Molecules and Cells, 40:243-253, Apr 2017. URL: https://doi.org/10.14348/molcells.2017.0054, doi:10.14348/molcells.2017.0054. This article has 234 citations and is from a peer-reviewed journal.
(li2016mks5andcep290 pages 9-11): Chunmei Li, Victor L. Jensen, Kwangjin Park, Julie Kennedy, Francesc R. Garcia-Gonzalo, Marta Romani, Roberta De Mori, Ange-Line Bruel, Dominique Gaillard, Bérénice Doray, Estelle Lopez, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet, Jeremy F. Reiter, Oliver E. Blacque, Enza Maria Valente, and Michel R. Leroux. Mks5 and cep290 dependent assembly pathway of the ciliary transition zone. PLOS Biology, 14:e1002416, Mar 2016. URL: https://doi.org/10.1371/journal.pbio.1002416, doi:10.1371/journal.pbio.1002416. This article has 165 citations and is from a highest quality peer-reviewed journal.
(li2016mks5andcep290 pages 3-5): Chunmei Li, Victor L. Jensen, Kwangjin Park, Julie Kennedy, Francesc R. Garcia-Gonzalo, Marta Romani, Roberta De Mori, Ange-Line Bruel, Dominique Gaillard, Bérénice Doray, Estelle Lopez, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet, Jeremy F. Reiter, Oliver E. Blacque, Enza Maria Valente, and Michel R. Leroux. Mks5 and cep290 dependent assembly pathway of the ciliary transition zone. PLOS Biology, 14:e1002416, Mar 2016. URL: https://doi.org/10.1371/journal.pbio.1002416, doi:10.1371/journal.pbio.1002416. This article has 165 citations and is from a highest quality peer-reviewed journal.

Citations

park2022compositionorganizationand pages 6-8
jensen2015formationofthe pages 1-2
goncalves2017theciliarytransition pages 1-3
park2019ciliumlengthregulationa pages 21-24
park2019ciliumlengthregulation pages 21-24
https://doi.org/10.15252/embj.201488044;
https://doi.org/10.1371/journal.pbio.1002416
https://doi.org/10.14348/molcells.2017.0054;
https://doi.org/10.15252/embr.202255420
https://doi.org/10.15252/embj.201488044
https://doi.org/10.14348/molcells.2017.0054
https://doi.org/10.15252/embj.201488044,
https://doi.org/10.1371/journal.pbio.1002416,
https://doi.org/10.15252/embr.202255420,
https://doi.org/10.14348/molcells.2017.0054,

📄 View Raw YAML

id: Q21303
gene_symbol: mks-6
product_type: PROTEIN
status: COMPLETE
aliases:
  - K07G5.3
  - CELE_K07G5.3
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: MKS-6 is the C. elegans ortholog of human CC2D2A (coiled-coil and 
  C2 domain-containing protein 2A), a component of the MKS (Meckel-Gruber 
  syndrome) module at the ciliary transition zone. The protein contains a C2 
  domain (aa 680-800) and localizes specifically to the transition zone (TZ), 
  where it functions together with other MKS/MKSR proteins (MKS-1, MKSR-1, 
  MKSR-2, MKS-3, MKS-5) and NPHP proteins (NPHP-1, NPHP-4) to establish basal 
  body/TZ membrane associations and the ciliary gate during ciliogenesis. MKS-6 
  exhibits functional redundancy with NPHP-4, as double mutants show severe 
  ciliogenesis defects not seen in single mutants. MKS-6 also localizes to the 
  dendrite terminus in AFD thermosensory neurons, where transition zone proteins
  unexpectedly function in establishing a membrane diffusion barrier. Mutations 
  in the human ortholog CC2D2A cause Meckel-Gruber syndrome (MKS) and Joubert 
  syndrome (JBTS).
existing_annotations:
  - term:
      id: GO:0035869
      label: ciliary transition zone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: MKS-6 localization to the ciliary transition zone is 
        well-established through phylogenetic inference from the PANTHER family.
        The human ortholog CC2D2A and mouse ortholog Cc2d2a are both validated 
        TZ components. This annotation is consistent with direct experimental 
        evidence in C. elegans from PMID:21422230 and PMID:26595381.
      action: ACCEPT
      reason: The IBA annotation is fully consistent with multiple lines of 
        experimental evidence demonstrating that MKS-6 localizes to the 
        transition zone. The annotation represents a core localization of this 
        protein that is central to its function.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, 
            and NPHP-4 proteins exhibit essential, collective functions at the 
            transition zone (TZ), an underappreciated region at the base of all 
            cilia characterized by Y-shaped assemblages that link axoneme 
            microtubules to surrounding membrane.
        - reference_id: file:worm/mks-6/mks-6-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:1904491
      label: protein localization to ciliary transition zone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: MKS-6 is part of a module of proteins that collectively recruit 
        each other to the transition zone. The IBA annotation is supported by 
        experimental evidence showing that MKS-5 is required for 
        docking/anchoring MKS-6 and other MKS module proteins at the TZ.
      action: ACCEPT
      reason: This annotation reflects MKS-6's role in the hierarchical assembly
        of the MKS module at the transition zone. The protein participates in 
        mutual localization dependencies with other TZ proteins.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: MKS-5 is a central component required for 
            docking/anchoring MKS and NPHP protein modules
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: MKS-6 is required for non-motile cilium assembly in C. elegans, 
        particularly evident in genetic interaction studies. Single mks-6 
        mutants have mild phenotypes, but combined with nphp-4 mutations show 
        severe ciliogenesis defects.
      action: ACCEPT
      reason: The IBA annotation accurately reflects MKS-6's role in 
        ciliogenesis. C. elegans possesses only non-motile (primary) cilia in 
        sensory neurons, and MKS-6 is essential for their assembly through its 
        function at the transition zone.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: Functional interactions between NPHP proteins and 
            MKS-5 or MKS-6 are required for ciliogenesis
  - term:
      id: GO:0035869
      label: ciliary transition zone
    evidence_type: IDA
    original_reference_id: PMID:26595381
    review:
      summary: Direct experimental demonstration of MKS-6 localization to the 
        ciliary transition zone in C. elegans. The study by Lambacher et al. 
        examined TZ protein localization in the context of TMEM107 recruitment 
        of ciliopathy proteins.
      action: ACCEPT
      reason: This IDA annotation provides direct experimental evidence for 
        MKS-6 TZ localization. The study demonstrates that TMEM-107 organizes 
        recruitment of multiple MKS module proteins including the MKS-6 ortholog
        to the TZ.
      supported_by:
        - reference_id: PMID:26595381
          supporting_text: nematode TMEM-107 occupies an intermediate layer of 
            the TZ-localized MKS module by organizing recruitment of the 
            ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
  - term:
      id: GO:1904491
      label: protein localization to ciliary transition zone
    evidence_type: IGI
    original_reference_id: PMID:21422230
    review:
      summary: Genetic interaction evidence with mksr-2 (WBGene00010898) 
        demonstrates MKS-6's role in protein localization to the TZ. The MKS 
        module proteins function collectively to establish TZ membrane 
        associations.
      action: ACCEPT
      reason: The IGI annotation appropriately captures the genetic evidence 
        showing that MKS-6 functions together with MKSR-2 and other MKS module 
        proteins in establishing protein localization at the TZ. The 
        hierarchical dependencies between these proteins are well-documented.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: Together, our findings uncover a unified role for 
            eight TZ-localized proteins in basal body anchoring and establishing
            a ciliary gate during ciliogenesis
  - term:
      id: GO:0003674
      label: molecular_function
    evidence_type: ND
    original_reference_id: GO_REF:0000015
    review:
      summary: The ND annotation indicates no specific molecular function has 
        been experimentally determined for MKS-6. The C2 domain suggests 
        potential lipid or calcium binding, but this has not been directly 
        demonstrated for MKS-6.
      action: ACCEPT
      reason: This annotation correctly reflects that no specific enzymatic or 
        molecular function has been experimentally characterized for MKS-6. The 
        protein functions as a structural component of the MKS module at the 
        transition zone, but the precise molecular mechanism remains undefined.
  - term:
      id: GO:0044292
      label: dendrite terminus
    evidence_type: IDA
    original_reference_id: PMID:25335890
    review:
      summary: Nguyen et al. demonstrated that transition zone proteins, 
        including those in the MKS module, unexpectedly localize to the dendrite
        terminus in AFD thermosensory neurons, where they establish a membrane 
        diffusion barrier despite the absence of canonical TZ ultrastructure.
      action: ACCEPT
      reason: This localization represents a specialized function of MKS module 
        proteins in AFD neurons. While not a canonical TZ, the dendrite terminus
        compartment requires TZ proteins for proper compartmentalization of 
        signaling components.
      supported_by:
        - reference_id: PMID:25335890
          supporting_text: we reveal the unexpected presence of ciliary 
            transition zone proteins where no canonical transition zone 
            ultrastructure exists
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IGI
    original_reference_id: PMID:21422230
    supporting_entities:
      - WB:WBGene00007490
    review:
      summary: Genetic interaction with mks-5 (WBGene00007490) demonstrates 
        MKS-6's role in non-motile cilium assembly. MKS-5 acts as a central hub 
        for the MKS module, and functional interactions between MKS-5/MKS-6 and 
        NPHP proteins are required for proper ciliogenesis.
      action: ACCEPT
      reason: The IGI annotation correctly captures the genetic evidence that 
        MKS-6 functions with MKS-5 in ciliogenesis. Combined disruption of MKS 
        module proteins with NPHP-4 causes severe ciliogenesis defects.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: Functional interactions between NPHP proteins and 
            MKS-5 or MKS-6 are required for ciliogenesis
  - term:
      id: GO:0035869
      label: ciliary transition zone
    evidence_type: IDA
    original_reference_id: PMID:21422230
    review:
      summary: Williams et al. directly demonstrated MKS-6 localization to the 
        ciliary transition zone using fluorescent reporters. This foundational 
        study established MKS-6 as a core component of the TZ-localized MKS 
        module.
      action: ACCEPT
      reason: This is a primary experimental reference establishing MKS-6 
        localization to the TZ. The study systematically characterized the 
        localization of multiple MKS and NPHP proteins and demonstrated their 
        collective function at the TZ.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, 
            and NPHP-4 proteins exhibit essential, collective functions at the 
            transition zone (TZ)
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IGI
    original_reference_id: PMID:21422230
    supporting_entities:
      - WB:WBGene00010898
    review:
      summary: Genetic interaction with mksr-2 (WBGene00010898) demonstrates 
        redundant function in non-motile cilium assembly. The MKS module 
        proteins (including MKS-6 and MKSR-2) act together with NPHP module 
        proteins for ciliogenesis.
      action: ACCEPT
      reason: This IGI annotation captures genetic evidence for MKS-6 function 
        in ciliogenesis through interaction with MKSR-2. Both proteins are part 
        of the MKS module.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: the conserved C. elegans B9 domain (MKS-1, MKSR-1, 
            and MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
            NPHP-4 proteins exhibit essential, collective functions at the 
            transition zone
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IGI
    original_reference_id: PMID:21422230
    supporting_entities:
      - WB:WBGene00011261
    review:
      summary: Genetic interaction with nphp-4 (WBGene00011261) demonstrates 
        functional redundancy between MKS and NPHP modules. Double mutants of 
        mks-6 with nphp-4 show severe ciliogenesis defects not observed in 
        single mutants.
      action: ACCEPT
      reason: This is a key IGI annotation demonstrating the critical genetic 
        interaction between MKS-6 and NPHP-4. Joint disruption of MKS module 
        proteins with NPHP-4 results in basal body/TZ membrane association 
        defects and failure of ciliogenesis.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: Joint disruption of an MKS/MKSR protein and NPHP-4 
            results in BB/TZ membrane association defects
references:
  - id: GO_REF:0000015
    title: Use of the ND evidence code for Gene Ontology (GO) terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: PMID:21422230
    title: MKS and NPHP modules cooperate to establish basal body/transition 
      zone membrane associations and ciliary gate function during ciliogenesis.
    findings:
      - statement: MKS-6/CC2D2A is one of eight TZ proteins that function 
          collectively in ciliogenesis
        supporting_text: MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
          NPHP-4 proteins exhibit essential, collective functions at the 
          transition zone (TZ)
      - statement: MKS-6 localizes specifically to the ciliary transition zone
        supporting_text: MKS/MKSR and NPHP proteins localize specifically to the
          ciliary TZ
      - statement: Functional interactions between NPHP proteins and MKS-5 or 
          MKS-6 are required for ciliogenesis
        supporting_text: Functional interactions between NPHP proteins and MKS-5
          or MKS-6 are required for ciliogenesis
      - statement: Joint disruption of MKS module proteins with NPHP-4 causes 
          severe BB/TZ membrane association defects
        supporting_text: Joint disruption of an MKS/MKSR protein and NPHP-4 
          results in BB/TZ membrane association defects
      - statement: MKS-5 acts as a central hub required for docking MKS and NPHP
          protein modules
        supporting_text: MKS-5 is a central component required for 
          docking/anchoring MKS and NPHP protein modules
      - statement: TZ proteins establish a ciliary gate that restricts 
          nonciliary components from the cilium
        supporting_text: establishing a ciliary gate during ciliogenesis, and 
          suggest that disrupting ciliary gate function contributes to 
          phenotypic features of the MKS/NPHP disease spectrum
  - id: PMID:25335890
    title: Ciliopathy proteins establish a bipartite signaling compartment in a 
      C. elegans thermosensory neuron.
    findings:
      - statement: TZ proteins localize to the dendrite terminus in AFD neurons
        supporting_text: we reveal the unexpected presence of ciliary transition
          zone proteins where no canonical transition zone ultrastructure exists
      - statement: Ciliary proteins help establish distinct signaling 
          compartments in thermosensory neurons
        supporting_text: ciliary proteins help establish two contiguous, yet 
          distinct cyclic GMP (cGMP) signaling compartments in Caenorhabditis 
          elegans thermosensory AFD neurons
      - statement: TZ proteins function in membrane diffusion barrier formation 
          at sites without canonical TZ ultrastructure
        supporting_text: Consistent with a requirement for a membrane diffusion 
          barrier at the subcompartment base, we reveal the unexpected presence 
          of ciliary transition zone proteins where no canonical transition zone
          ultrastructure exists
  - id: PMID:26595381
    title: TMEM107 recruits ciliopathy proteins to subdomains of the ciliary 
      transition zone and causes Joubert syndrome.
    findings:
      - statement: TMEM-107 organizes recruitment of MKS module proteins to TZ 
          subdomains
        supporting_text: nematode TMEM-107 occupies an intermediate layer of the
          TZ-localized MKS module by organizing recruitment of the ciliopathy 
          proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
      - statement: MKS module proteins are immobile at the TZ and show periodic 
          localization patterns
        supporting_text: MKS module membrane proteins are immobile and 
          super-resolution microscopy in worms and mammalian cells reveals 
          periodic localizations within the TZ
      - statement: TZ proteins control ciliary composition through diffusion 
          barrier function
        supporting_text: The transition zone (TZ) ciliary subcompartment is 
          thought to control cilium composition and signalling by facilitating a
          protein diffusion barrier at the ciliary base
  - id: file:worm/mks-6/mks-6-deep-research-falcon.md
    title: Deep research report on mks-6
    findings: []
core_functions:
  - description: MKS-6 functions as a structural component of the MKS module at 
      the ciliary transition zone, where it contributes to basal body/TZ 
      membrane associations and establishes the ciliary gate during 
      ciliogenesis. The protein likely functions as a scaffold through its C2 
      domain.
    molecular_function:
      id: GO:0003674
      label: molecular_function
    locations:
      - id: GO:0035869
        label: ciliary transition zone
    directly_involved_in:
      - id: GO:1905515
        label: non-motile cilium assembly
      - id: GO:1904491
        label: protein localization to ciliary transition zone
    supported_by:
      - reference_id: PMID:21422230
        supporting_text: MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
          NPHP-4 proteins exhibit essential, collective functions at the 
          transition zone (TZ)
proposed_new_terms: []
suggested_questions:
  - question: Does the C2 domain of MKS-6 bind lipids or calcium, and is this 
      required for TZ localization?
  - question: What is the direct binding partner of MKS-6 within the MKS module?
  - question: Does MKS-6 directly contribute to Y-link formation at the TZ?
suggested_experiments:
  - description: Biochemical characterization of MKS-6 C2 domain lipid binding 
      specificity using liposome binding assays
    hypothesis: The C2 domain of MKS-6 mediates membrane association at the TZ 
      through lipid binding
  - description: Identification of direct protein-protein interactions using 
      co-immunoprecipitation or yeast two-hybrid screening
    hypothesis: MKS-6 directly interacts with MKS-5 or other MKS module 
      components
  - description: Super-resolution imaging of MKS-6 to determine its precise 
      sub-TZ localization relative to Y-links
    hypothesis: MKS-6 localizes to specific TZ subdomains associated with Y-link
      structures
tags:
  - caeel-ciliopathy

mks-6

Gene Description

Existing Annotations Review

Core Functions

MKS-6 functions as a structural component of the MKS module at the ciliary transition zone, where it contributes to basal body/TZ membrane associations and establishes the ciliary gate during ciliogenesis. The protein likely functions as a scaffold through its C2 domain.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

📄 View Raw YAML