MKSR-1 (MKS-1-related protein 1) is the Caenorhabditis elegans ortholog of human B9D1, one of the three B9-domain proteins (with MKS-1/MKS1 and MKSR-2/B9D2). It is a small, soluble B9/C2-domain protein and a core component of the MKS module, one of the two protein modules (MKS and NPHP) that together assemble the ciliary transition zone (TZ) at the base of sensory cilia. The TZ builds the Y-link connectors that tether the axoneme doublet microtubules to the ciliary membrane and forms the ciliary gate, a membrane diffusion barrier that restricts entry of non-ciliary membrane proteins into the cilium. MKSR-1 localizes to the TZ of ciliated sensory neurons; its localization is co-dependent with the other B9 proteins and requires the upstream scaffold MKS-5/RPGRIP1L. MKSR-1 in turn is required for the TZ localization of other MKS-module proteins (e.g. MKS-6/CC2D2A and MKS-3/meckelin) and forms a heterodimer with MKSR-2/B9D2. Consistent with the strong redundancy among transition-zone genes, mksr-1 single mutants have no overt defect in cilium structure or intraflagellar transport, whereas mksr-1;nphp-4 double mutants disrupt TZ membrane anchoring and Y-links; even in the single mutant, however, the ciliary gate leaks, allowing membrane proteins such as TRAM-1a and RPI-2 to enter the cilium. In humans, B9D1 is a Meckel-Gruber syndrome/nephronophthisis-spectrum ciliopathy gene.
Definition: The action of a protein that contributes to the structural integrity of the ciliary transition zone, for example by acting as a scaffold or B9/C2-domain subunit of the MKS or NPHP module that helps build the Y-link connectors and the membrane diffusion barrier at the ciliary base, without itself catalyzing a biochemical reaction.
Parent term: structural molecule activity
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036038 MKS complex | IBA GO_REF:0000033 | ACCEPT | Summary: MKSR-1/B9D1 is a core B9-domain subunit of the MKS module (MKS complex) at the ciliary transition zone. The phylogenetic (IBA) inference is directly corroborated by experimental work in C. elegans placing MKSR-1 in the MKS/MKSR module together with MKS-1, MKSR-2, MKS-3 and MKS-6. Reason: Core cellular-component/complex annotation. The IBA inference from the B9D1 PANTHER family is consistent with direct C. elegans genetics and imaging, so it is retained as a core annotation. Supporting Evidence: PMID:21422230 MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6 |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | MODIFY | Summary: As a core MKS-module subunit, MKSR-1 participates (redundantly with the NPHP module) in building the transition zone during assembly of the non-motile sensory cilia of C. elegans. The generic 'cilium assembly' term is correct but less precise than 'non-motile cilium assembly', which is already experimentally annotated for this gene and matches the fact that all worm cilia are non-motile sensory cilia. Reason: The essence (a role in cilium assembly) is right, but a more specific term is available and better supported. C. elegans sensory cilia are non-motile, and the gene already carries experimental IGI annotations to non-motile cilium assembly; generalize the IBA to the same specific process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000311628 · PANTHER PTHR12968 B9 domain-containing family node SUPPORTS TRANSFER The B9D1 family node correctly propagates a cilium-assembly role, but in C. elegans all cilia are non-motile sensory cilia, so the more specific child term (non-motile cilium assembly) applies and is already supported by experimental IGI annotations for mksr-1. This is a granularity refinement, not an erroneous propagation. Proposed replacements: non-motile cilium assembly Supporting Evidence: PMID:18337471 regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons |
| GO:0005929 cilium | IEA GO_REF:0000117 | MODIFY | Summary: The ARBA electronic annotation places MKSR-1 in the cilium. This is correct at a coarse level but far less informative than the experimentally established ciliary transition-zone localization; MKSR-1 concentrates specifically at the TZ at the ciliary base, not along the ciliary axoneme. Reason: The generic 'cilium' location is subsumed by the specific, experimentally supported 'ciliary transition zone' localization (IDA, PMID:21422230). Replace with the more informative and accurate compartment term. Proposed replacements: ciliary transition zone Supporting Evidence: PMID:21422230 This is evident for MKS-1, MKS-1 related-1 (MKSR-1)/B9D1 |
| GO:0005515 protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | KEEP AS NON CORE | Summary: IntAct-curated binary interaction between MKSR-1 (Q21191) and MKSR-2/B9D2 (Q9N423) from the C. elegans interactome map. The interaction is real and biologically meaningful (the B9D1-B9D2 heterodimer is a substructure of the MKS module), but the generic 'protein binding' term conveys no specific molecular function. Reason: Experimental (IPI) interaction data should not be removed. However, 'protein binding' is uninformative and is not the core function; the meaningful fact (MKSR-1-MKSR-2/B9D1-B9D2 heterodimer within the MKS module) is captured by the MKS-complex membership and the structural role in core_functions. Retained as a non-core supporting annotation. Supporting Evidence: PMID:21422230 MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6 |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | KEEP AS NON CORE | Summary: A second IntAct-curated MKSR-1-MKSR-2 binary interaction, from the empirically-controlled C. elegans interactome. As above, the interaction is genuine but 'protein binding' is uninformative. Reason: Do not remove experimental interaction evidence. 'Protein binding' is a low-information term; the MKSR-1-MKSR-2 heterodimer is represented by the MKS-complex membership and structural role. Retained as non-core. Supporting Evidence: PMID:21422230 MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6 |
| GO:1905515 non-motile cilium assembly | IGI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | ACCEPT | Summary: Williams et al. showed the C. elegans B9 proteins (including MKSR-1) function redundantly with the nephrocystins: B9-gene mutations do not overtly affect cilia unless combined with a mutation in nph-1 or nph-4, revealing a (redundant) requirement of MKSR-1 for assembly of the non-motile sensory cilia. Reflected by the genetic interaction with the NPHP module. Reason: Well-supported IGI annotation capturing the canonical MKS/NPHP redundancy. The synthetic ciliary phenotype with nphp genes is the standard genetic signature placing MKSR-1 in the MKS module and demonstrating its redundant role in cilium assembly. Core module-level function. Supporting Evidence: PMID:18337471 Mutations in the B9 genes do not overtly affect cilia formation unless they are in combination with a mutation in nph-1 or nph-4 |
| GO:1904491 protein localization to ciliary transition zone | IMP PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | ACCEPT | Summary: WormBase IMP annotation from the TMEM107 study, which dissected MKS-module recruitment/organization at the TZ. The cached record is abstract-only; the abstract establishes that TMEM-107 organizes recruitment of MKS-module ciliopathy proteins to TZ subdomains, and the curator assigned the IMP for MKSR-1's role in TZ protein localization from the full text. Reason: Experimental (IMP) annotation by a WormBase curator; the full text (not in cache) contains the direct evidence. Concordant with PMID:21422230, which directly shows MKSR-1 is required for TZ localization of MKS-6 and MKS-3. Per curation guidance the experimental annotation is retained rather than second-guessed from an abstract-only cache. Supporting Evidence: PMID:26595381 TZ-localized MKS module by organizing recruitment of the ciliopathy 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. directly show that disrupting MKSR-1 causes TZ delocalization of other MKS-module proteins: MKS-6 and MKS-3 fail to localize to the TZ in mksr-1 mutants (MKS-3 additionally accumulates along the axoneme). This defines MKSR-1 as required for correct protein localization to the transition zone. Reason: Directly supported experimental (IMP) annotation. Loss of mksr-1 mislocalizes downstream TZ proteins, demonstrating a role in establishing protein localization to the transition zone. Core function. Supporting Evidence: PMID:21422230 disrupting MKSR-1, MKSR-2, or MKS-5 results in TZ delocalization of MKS-6 PMID:21422230 MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane |
| GO:1905515 non-motile cilium assembly | IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: The genetic-interaction (IGI) evidence captures the MKS/NPHP redundancy in cilium assembly: the mksr-1;nphp-4 double mutant produces severe TZ ultrastructure defects (TZ not anchored to membrane, missing Y-links) nearly identical to mks-6;nphp-4, whereas the mksr-1 single mutant is structurally near-normal. WITH values reference the NPHP-module genes nphp-4/nphp-1. Reason: Well-supported IGI annotation. The synthetic ultrastructural phenotype with the NPHP module is the standard genetic signature placing mksr-1 in the MKS module and demonstrating its (redundant) requirement for TZ/cilium assembly. Supporting Evidence: PMID:21422230 Phenotypes nearly identical to mks-6;nphp-4 mutants were observed in the mksr-1;nphp-4 strain |
| GO:0035869 ciliary transition zone | IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: Direct imaging of GFP/tdTomato-tagged MKSR-1 (B9D1) shows it concentrates at the ciliary transition zone in C. elegans sensory neurons, adjacent to and distinct from the basal body/transition-fibre region where IFT proteins peak. This is the core experimentally-established localization. Reason: Experimental (IDA) localization to the transition zone, concordant with the IBA annotation and with the conserved TZ localization of B9D1 across metazoans. Core cellular-component annotation. Supporting Evidence: PMID:21422230 This is evident for MKS-1, MKS-1 related-1 (MKSR-1)/B9D1 |
| GO:0008340 determination of adult lifespan | IGI PMID:19208769 Functional interactions between the ciliopathy-associated Me... | KEEP AS NON CORE | Summary: Bialas et al. found that all double mks/mksr mutant combinations (including those involving mksr-1) show an increased-lifespan phenotype caused by abnormal insulin-IGF-I signaling. This is an indirect, downstream consequence of compromised ciliary signaling under module redundancy, not a direct molecular function of MKSR-1. Reason: Valid experimental (IGI) genetic-interaction annotation, but lifespan determination is a pleiotropic downstream effect of impaired cilium/sensory signaling rather than a core function of a transition-zone scaffold subunit. Retained as a non-core annotation. Supporting Evidence: PMID:19208769 increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling |
| GO:0005515 protein binding | IPI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | KEEP AS NON CORE | Summary: WormBase IPI annotation for a physical interaction of MKSR-1 with another B9 protein (WITH/FROM WBGene00021416 = mksr-2/B9D2), consistent with the co-dependent B9-protein complex at the ciliary base. As with the IntAct IPIs, the interaction is real but 'protein binding' is uninformative. Reason: Do not remove experimental interaction evidence. The MKSR-1-MKSR-2 heterodimer it captures is represented by MKS-complex membership and the structural role in core_functions; the generic term itself is non-core and low-information. Supporting Evidence: PMID:18337471 the C. elegans B9 proteins form a complex that localizes to the base of cilia |
| GO:0008104 intracellular protein localization | IMP PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | MODIFY | Summary: This generic 'intracellular protein localization' IMP reflects MKSR-1's role in localizing other ciliary/TZ proteins (the B9 proteins localize co-dependently at the ciliary base, and MKSR-1 is required for TZ localization of MKS-module proteins). A far more specific and better-supported term exists: protein localization to the ciliary transition zone. Reason: The essence is right (MKSR-1 governs the localization of specific proteins), but 'intracellular protein localization' is over-general. Replace with the specific process protein localization to ciliary transition zone, which is directly documented and already annotated for this gene. Proposed replacements: protein localization to ciliary transition zone Supporting Evidence: PMID:18337471 the C. elegans B9 proteins form a complex that localizes to the base of cilia |
| GO:0035177 larval foraging behavior | IGI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | KEEP AS NON CORE | Summary: WormBase IGI annotation linking mksr-1 (redundantly with the NPHP module) to larval foraging behavior. Foraging/roaming in C. elegans depends on functional sensory cilia, so a B9-gene x nphp genetic interaction that compromises cilia would be expected to affect foraging. The cached record is abstract-only and does not itself state 'foraging', so this rests on the curator's reading of the full text. Reason: Downstream sensory-behavior phenotype rather than a core molecular/cellular function of a TZ scaffold subunit. The experimental IGI annotation is retained (not overruled from an abstract-only cache) but marked non-core. Supporting Evidence: PMID:18337471 regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons |
| GO:1903565 negative regulation of protein localization to cilium | IMP PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | NEW | Summary: MKSR-1 is required for ciliary-gate (diffusion-barrier) function. In the mksr-1 single mutant, membrane-associated proteins that are normally excluded from cilia accumulate inside them: TRAM-1a and RPI-2 (RP2 ortholog) both accumulate within cilia of mksr-1 mutants, and MKS-3 abnormally accumulates inside cilia. This gate/barrier activity is the central function of the TZ and is not otherwise captured in GOA for mksr-1. Reason: New annotation proposed to capture MKSR-1's ciliary-gate role, directly demonstrated in the mksr-1 single mutant (leak of TRAM-1a, RPI-2 and MKS-3 into cilia). This mirrors the curated gate-function annotation modeled for the sibling gene mks-2 and represents a core function currently missing from mksr-1's GOA record. Supporting Evidence: PMID:21422230 accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and nphp-4 mutants PMID:21422230 TZ proteins normally function to maintain a boundary at the cilium base, establishing the TZ as a bona fide ciliary gate |
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Download this section (compressed HTML)Q: Does the MKSR-1/B9D1 B9/C2 domain bind Ca2+ and/or membrane lipids in vitro, as predicted from its synaptotagmin-like C2 fold, and is any such activity required for its transition-zone function?
Q: Beyond the MKSR-1-MKSR-2 (B9D1-B9D2) heterodimer, what are MKSR-1's direct contacts within the MKS module, and does it occupy a discrete sub-position in the transition-zone architecture?
Experiment: In vitro biochemistry of the recombinant MKSR-1 B9/C2 domain (Ca2+ and phospholipid binding assays), complemented by structure-guided mutagenesis of candidate Ca2+/lipid-binding residues assayed in vivo for TZ localization and gate function.
Hypothesis: The MKSR-1 B9/C2 domain binds Ca2+/membrane lipids and this contributes to its anchoring or barrier role at the transition zone.
Experiment: Proximity labelling (TurboID/BioID) or affinity purification of tagged MKSR-1 in C. elegans ciliated neurons to map its direct transition-zone interaction partners, and separation-of-function alleles tested for TRAM-1a exclusion (gate), MKS-6/MKS-3 recruitment, and Y-link ultrastructure by TEM.
Hypothesis: MKSR-1 occupies a specific position in the MKS-module interaction network with a defined set of direct partners and separable recruitment vs barrier functions.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: MKSR-1 has no assigned molecular function and there is no GO term to express one. Its role is to be a structural/diffusion-barrier scaffold subunit of the ciliary transition-zone MKS module, but GO has no molecular-function term such as "structural constituent of the ciliary transition zone" (or "diffusion barrier component"), so the gene reads as MF-dark despite a well-understood cellular-component and biological-process role.
OPEN ONTOLOGYCURATION MF_DARK
What is known: It is firmly established that MKSR-1 = B9D1 is a B9/C2-domain protein of the TZ, a core MKS-module component required (redundantly with the NPHP module) for cilium/TZ assembly, for the ciliary gate, and for recruiting other MKS-module proteins (MKS-6, MKS-3). What is missing is a molecular-function representation: the worm GOA record carries only cellular-component and biological-process terms plus an uninformative 'protein binding', and no informative molecular_function annotation.
Significance: This is the canonical "structural subunit" ontology gap shared across the transition-zone/ciliopathy gene set (cf. the mks-2 review): a mechanistically well-placed protein that cannot be given an informative MF term, contributing to apparent molecular-function darkness across MKS/NPHP-module genes.
What would resolve it: Develop/adopt a molecular-function term for a structural constituent of the ciliary transition zone (analogous to "structural constituent of ribosome"), then annotate MKSR-1 and the other core MKS/NPHP-module subunits to it.
Provenance (the field's own admissions):
Proposed term (ontology gap):
Gap: The specific, non-redundant molecular contribution of MKSR-1/B9D1 within the MKS module is undetermined: whether its predicted C2/B9 Ca2+/lipid-binding activity is real, its direct binding partners in the worm TZ beyond MKSR-2/B9D2, and whether MKSR-1 provides a discrete sub-function or is largely interchangeable with the other core MKS-module proteins.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Genetics and imaging establish that MKSR-1 is a core MKS-module protein whose TZ localization depends on MKS-5, that it is required to recruit MKS-6/MKS-3, that it forms a heterodimer with MKSR-2, and that it contributes to the gate. The predicted C2/B9 fold suggests Ca2+/lipid binding, but this has not been assayed for MKSR-1. mksr-1 single mutants are structurally near-normal (defects emerge in mksr-1;nphp-4 doubles), yet the single mutant already leaks TRAM-1a/RPI-2 into cilia, indicating at least a partial non-redundant barrier contribution.
Significance: Distinguishing a genuine non-redundant role (and testing the predicted C2/B9 membrane-binding activity) from full module redundancy is the load-bearing question for interpreting B9D1 ciliopathy alleles and for understanding how individual MKS-module subunits partition the barrier-building task.
What would resolve it: Direct biochemistry of MKSR-1's B9/C2 domain (Ca2+/lipid binding), proximity labelling/affinity purification of tagged MKSR-1 in ciliated neurons to map its direct TZ partners, and separation-of-function alleles assayed for gate, Y-link, and recruitment phenotypes.
Provenance (the field's own admissions):
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