MKS-5 (also known as NPHP-8/FTM) is the C. elegans ortholog of human RPGRIP1L, a coiled-coil protein that localizes to the ciliary transition zone (TZ). MKS-5 serves as a central scaffolding component required for docking/anchoring both the MKS (Meckel syndrome) and NPHP (nephronophthisis) protein modules at the TZ. Through this hierarchical assembly role, MKS-5 is essential for establishing basal body/transition zone membrane associations, forming the ciliary gate that restricts inappropriate accumulation of non-ciliary components within the cilium, and enabling proper ciliogenesis and cilia-mediated chemosensation. The protein contains coiled-coil domains and a C2-like domain, and is expressed specifically at the transition zone of ciliated sensory neurons including the amphid neurons.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: MKS-5 localization to the ciliary transition zone is well-supported by multiple IDA annotations from PMID:21422230, PMID:21689635, and PMID:27623382. The IBA annotation correctly infers this localization based on phylogenetic evidence across the RPGRIP1 family. Reason: Transition zone localization is the defining characteristic of MKS-5 function. Multiple independent experimental studies have confirmed this localization using fluorescence microscopy in C. elegans (PMID:21689635, PMID:21422230, PMID:27623382). This represents a core function. Supporting Evidence: PMID:21689635 NPHP-8 co-localized with NPHP-4 at the transition zone at the base of cilia. 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-5/mks-5-deep-research-falcon.md model: Edison Scientific Literature |
| GO:1905515 non-motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: MKS-5 involvement in non-motile cilium assembly is supported by multiple IMP and IGI annotations from PMID:21422230 and PMID:26863025. The IBA correctly propagates this functional role from homologs. Reason: Non-motile cilium assembly is a core function of MKS-5. C. elegans sensory cilia are non-motile, and mks-5 mutants display ciliogenesis defects (PMID:21689635, PMID:21422230). The MKS module proteins work together to establish basal body/TZ membrane attachments required for cilium assembly. Supporting Evidence: PMID:21689635 Mutation of nphp-8 led to abnormal dye filling (Dyf) and shorter cilia lengths in a subset of ciliary neurons. PMID:21422230 MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension |
| GO:0005856 cytoskeleton | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This automated annotation is too general. MKS-5 localizes specifically to the ciliary transition zone, not the cytoskeleton broadly. The transition zone is a specialized ciliary subcompartment. Reason: While cilia are cytoskeleton-related structures, this annotation is overly broad and uninformative. The specific localization to the ciliary transition zone (GO:0035869) is much more appropriate and experimentally validated. This IEA is based on ARBA machine learning and lacks specificity. |
| GO:0005929 cilium | IEA GO_REF:0000120 | ACCEPT | Summary: This annotation is correct but less specific than the experimentally validated transition zone localization. MKS-5 is indeed a ciliary protein but localizes specifically to the transition zone subdomain. Reason: Technically correct - MKS-5 is a ciliary protein. However, the more specific GO:0035869 (ciliary transition zone) is preferred based on IDA evidence. This broader annotation can be retained as it is not incorrect. Supporting Evidence: PMID:21689635 NPHP-8/RPGRIP1L plays an important role in cilia formation and cilia-mediated chemosensation |
| GO:0030030 cell projection organization | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This is a very broad term that encompasses cilia organization. While not wrong, it is too general compared to the specific cilium assembly annotations. Reason: This IEA based on UniProt keyword mapping is too broad. The specific terms GO:0060271 (cilium assembly) and GO:1905515 (non-motile cilium assembly) better capture MKS-5 function with experimental support. |
| GO:0035869 ciliary transition zone | IDA PMID:27623382 A Conserved Role for Girdin in Basal Body Positioning and Ci... | ACCEPT | Summary: Direct evidence for MKS-5 localization at the ciliary transition zone from Nechipurenko et al. 2016, which studied Girdin's role in basal body positioning and confirmed MKS-5 TZ localization. Reason: This IDA annotation provides direct experimental evidence for transition zone localization. The study used fluorescence microscopy to show MKS-5 localizes to the proximal region of centrioles/transition zone in C. elegans sensory neurons. Supporting Evidence: PMID:27623382 Primary cilia are ubiquitous sensory organelles that mediate diverse signaling pathways. Cilia position on the cell surface is determined by the location of the basal body (BB) that templates the cilium. |
| GO:0036064 ciliary basal body | IDA PMID:27623382 A Conserved Role for Girdin in Basal Body Positioning and Ci... | ACCEPT | Summary: MKS-5 is reported to localize to the basal body region in this study. However, the transition zone is the more specific and characteristic localization for MKS-5, as noted in PMID:21422230. Reason: The IDA evidence from PMID:27623382 supports basal body localization. The TZ and basal body are adjacent structures, and MKS-5/RPGRIP1L localizes to both. Williams et al. 2011 noted that TZ proteins were often misattributed to the basal body due to co-isolation. Both localizations are valid. Supporting Evidence: PMID:21422230 The TZ is an underappreciated ciliary subcompartment, often incorrectly presumed to be one and the same with the adjacent BB. |
| GO:1905515 non-motile cilium assembly | IMP PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS... | ACCEPT | Summary: This study identified yhw91 as a novel mks-5 allele through a genetic screen for modifiers of nphp-4 cilia phenotypes. mks-5 mutants showed ciliary defects in combination with nphp-4. Reason: The genetic screen in PMID:26863025 confirmed MKS-5's role in ciliogenesis by identifying it as a modifier of nphp-4 ciliary phenotypes. The double mutant phenotypes demonstrate functional involvement in non-motile cilium assembly. Supporting Evidence: PMID:26863025 Four loci have been identified, three of which are established ciliopathy genes mks-1, mks-2, and mks-5. |
| GO:1905515 non-motile cilium assembly | IGI PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS... | ACCEPT | Summary: Genetic interaction with MKS-1 (G5ECP0) shows functional redundancy in cilium assembly between MKS module components. Reason: The IGI annotation with mks-1 reflects the modular organization of TZ proteins where MKS module members show genetic interactions affecting ciliogenesis. Supporting Evidence: PMID:26863025 Four loci have been identified, three of which are established ciliopathy genes mks-1, mks-2, and mks-5. |
| GO:1905515 non-motile cilium assembly | IGI PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS... | ACCEPT | Summary: Genetic interaction with NPHP-4 (P46873) demonstrating functional cooperation between MKS and NPHP modules. Reason: This IGI with nphp-4 is central to understanding MKS-5 function. The screen was based on nphp-4 mutant background, and mks-5 mutations exacerbate the ciliary phenotype, demonstrating the modular cooperation at the TZ. Supporting Evidence: PMID:21422230 Functional interactions between NPHP proteins and MKS-5 or MKS-6 are required for ciliogenesis |
| GO:0097500 receptor localization to non-motile cilium | IMP PMID:24646679 Diverse cell type-specific mechanisms localize G protein-cou... | ACCEPT | Summary: This study examined GPCR localization to cilia and found that transition zone proteins are required for proper ciliary localization of receptors in specific neuron types. Reason: MKS-5 as a TZ component is involved in the ciliary gate function that regulates what enters the cilium, including receptors. This is consistent with the gate function described in PMID:21422230. Supporting Evidence: PMID:21422230 TZ proteins establish a gate that modulates ciliary composition PMID:24646679 we identify diverse proteins required for ciliary localization of individual GPCRs in AWB and ASK |
| GO:1904491 protein localization to ciliary transition zone | IMP PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr... | ACCEPT | Summary: Li et al. 2016 demonstrated that MKS-5 is required for CEP-290 localization to the TZ, and that MKS-5's coiled-coil region is essential for this function. Reason: This annotation captures the central scaffolding role of MKS-5. The study showed CEP-290 depends on MKS-5 for TZ localization, demonstrating MKS-5's role in assembling other TZ proteins. Supporting Evidence: PMID:26982032 CEP-290 is specifically required for the assembly of the MKS module but not NPHP module components, and depends on MKS-5 for its own TZ localisation. PMID:26982032 TMEM-218 depends on MKS-5 and a core MKS module component (MKS-2) for transition zone localisation but does not itself influence other TZ proteins. |
| GO:1904491 protein localization to ciliary transition zone | IMP PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: Williams et al. 2011 established that MKS-5 is a central component required for docking/anchoring both MKS and NPHP protein modules at the transition zone. Reason: This is a core function of MKS-5 - serving as a hierarchical assembly factor for recruiting other TZ proteins. In mks-5 mutants, other MKS and NPHP module components fail to localize properly to the TZ. 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 | IMP PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: mks-5 mutants in combination with nphp-4 show severe ciliogenesis defects including loss of axoneme extension and basal body/TZ membrane detachment. Reason: Core function annotation. Williams et al. 2011 demonstrated that MKS/NPHP modules cooperate in ciliogenesis, with double mutants showing severe defects in cilium assembly. Supporting Evidence: PMID:21422230 MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension |
| 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 (WBGene00010642) showing synthetic ciliogenesis defects in double mutants. Reason: The modular genetic interactions between MKS-5 and NPHP-4 are essential for understanding ciliopathy pathogenesis. Double mutants show more severe ciliogenesis defects than single mutants. Supporting Evidence: PMID:21422230 Joint disruption of an MKS/MKSR protein and NPHP-4 results in BB/TZ membrane association defects |
| 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-3 (WBGene00011261) demonstrating functional cooperation within the MKS module. Reason: MKS-3 (TMEM67 homolog) is part of the MKS module. Genetic interactions between MKS module members confirm their cooperative role in ciliogenesis. 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 |
| 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-1 (WBGene00019364) demonstrating functional cooperation within the MKS module. Reason: MKS-1 is a B9 domain protein in the MKS module. Genetic interactions support the modular organization of TZ proteins in ciliogenesis. 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 mksr-2 (WBGene00021416), another MKS module component. Reason: MKSR-2 is a B9 domain protein related to MKS-1. The genetic interaction network supports the modular function of TZ proteins in cilium assembly. 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:0022615 protein to membrane docking | IMP PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: MKS-5 is required for establishing basal body/transition zone membrane attachments. This docking function is essential for early ciliogenesis. Reason: This annotation captures a key mechanistic function of MKS-5 - facilitating the docking of the MKS and NPHP protein modules to the ciliary membrane at the transition zone. Williams et al. 2011 showed TZ proteins establish BB/TZ membrane attachments. Supporting Evidence: PMID:21422230 MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension PMID:21422230 Our analyses revealed that MKS/MKSR and NPHP modules are collectively required for two essential aspects of ciliogenesis, namely membrane anchoring of the BB/TZ and formation of an intact TZ region. |
| GO:0060271 cilium assembly | IMP PMID:21689635 Caenorhabditis elegans ciliary protein NPHP-8, the homologue... | ACCEPT | Summary: Liu et al. 2011 showed that nphp-8/mks-5 mutants have shorter cilia and abnormal dye filling, indicating defects in cilium assembly. Reason: Core function annotation. The study demonstrates that MKS-5 is required for proper cilium formation in C. elegans sensory neurons. Supporting Evidence: PMID:21689635 Mutation of nphp-8 led to abnormal dye filling (Dyf) and shorter cilia lengths in a subset of ciliary neurons. PMID:21689635 NPHP-8/RPGRIP1L plays an important role in cilia formation and cilia-mediated chemosensation in a cell type-specific manner. |
| GO:0006935 chemotaxis | IMP PMID:21689635 Caenorhabditis elegans ciliary protein NPHP-8, the homologue... | KEEP AS NON CORE | Summary: mks-5/nphp-8 mutants show significantly impaired chemotaxis to volatile attractants, reflecting defective sensory cilia function. Reason: Chemotaxis is a downstream phenotype of ciliary dysfunction rather than a direct molecular function of MKS-5. The chemosensory defects arise as a consequence of abnormal cilia structure. This represents a secondary, behavioral consequence of the primary ciliary role. Supporting Evidence: PMID:21689635 chemotaxis to several volatile attractants was significantly impaired in nphp-8 mutants |
| GO:0035869 ciliary transition zone | IDA PMID:21689635 Caenorhabditis elegans ciliary protein NPHP-8, the homologue... | ACCEPT | Summary: Liu et al. 2011 demonstrated that NPHP-8/MKS-5 co-localizes with NPHP-4 at the transition zone at the base of cilia using fluorescence microscopy. Reason: Primary experimental evidence for transition zone localization. This IDA annotation confirms the defining subcellular localization of MKS-5. Supporting Evidence: PMID:21689635 NPHP-8 co-localized with NPHP-4 at the transition zone at the base of cilia. |
| GO:0035869 ciliary transition zone | IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: Williams et al. 2011 demonstrated MKS-5 localization to the transition zone and established its central role in TZ organization. Reason: Foundational experimental evidence for MKS-5 TZ localization and function. This study established the modular organization of TZ proteins with MKS-5 as a central component. 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 PMID:21422230 MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules |
| GO:0060090 molecular adaptor activity | IMP PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | NEW | Summary: MKS-5 functions as a central molecular adaptor/scaffold at the ciliary transition zone, required for docking and anchoring both MKS and NPHP protein modules. Multiple TZ proteins depend on MKS-5 for their localization. Reason: This molecular function annotation is supported by extensive evidence from multiple studies. Williams et al. 2011 established MKS-5 as a central component required for docking/anchoring MKS and NPHP protein modules. Li et al. 2016 showed CEP-290 and TMEM-218 depend on MKS-5 for TZ localization. This adaptor/scaffolding function is the primary molecular activity of MKS-5 and warrants explicit annotation. Supporting Evidence: PMID:21422230 MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules PMID:26982032 CEP-290 is specifically required for the assembly of the MKS module but not NPHP module components, and depends on MKS-5 for its own TZ localisation. PMID:26982032 TMEM-218 depends on MKS-5 and a core MKS module component (MKS-2) for transition zone localisation |
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Download this section (compressed HTML)Q: What is the precise stoichiometry of MKS-5 within the transition zone complex, and how does it coordinate binding of MKS and NPHP module proteins?
Q: Are there cell-type specific differences in MKS-5 function among the different sensory neuron types in C. elegans?
Q: What post-translational modifications regulate MKS-5 localization and function?
Experiment: Structure-function analysis of MKS-5 coiled-coil domains to define binding sites for CEP-290 and other TZ proteins
Experiment: Super-resolution microscopy to map the precise nanoscale organization of MKS-5 relative to Y-link structures at the TZ
Experiment: Phosphoproteomics to identify regulatory modifications of MKS-5 during ciliogenesis
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