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).
| 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 |
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Download this section (compressed HTML)Q: Does the C2 domain of MKS-6 bind lipids or calcium, and is this required for TZ localization?
Q: What is the direct binding partner of MKS-6 within the MKS module?
Q: Does MKS-6 directly contribute to Y-link formation at the TZ?
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
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