MKS-2 is the Caenorhabditis elegans ortholog of human TMEM216 (MKS2), a small multi-pass integral membrane protein of the ciliary transition zone (TZ). It is a core component of the MKS module, one of two protein modules (MKS and NPHP) that together assemble the TZ at the base of sensory cilia, building the Y-link connectors between the axoneme doublet microtubules and the ciliary membrane and establishing the ciliary gate (a membrane diffusion barrier that restricts entry of non-ciliary membrane proteins into the cilium). MKS-2 is expressed in ciliated sensory neurons and concentrates at the TZ immediately distal to the basal body transition fibres. Its TZ localization depends on the upstream assembly factors MKS-5 (RPGRIP1L) and CEP-290, and MKS-2 in turn is required to recruit peripheral MKS-module proteins such as TMEM-218 to the TZ. Consistent with the strong functional redundancy among transition-zone genes, mks-2 single mutants have no overt ciliary phenotype, whereas double mutants combining mks-2 with NPHP-module genes (e.g. nphp-4) disrupt the ciliary gate and cilium integrity. In humans, TMEM216/MKS2 mutations cause Meckel-Gruber and Joubert syndromes.
Definition: The action of a protein that contributes to the structural integrity of the ciliary transition zone, for example by acting as an integral-membrane or scaffold 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:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: MKS-2 is a transition-zone protein; the phylogenetically inferred TZ localization is directly corroborated by experimental imaging in C. elegans (MKS-2::GFP concentrates at the TZ) and matches the conserved role of the TMEM216/MKS module across metazoans. Reason: Core cellular-component annotation. The IBA inference (PANTHER family PTHR13531 / MKS module) is consistent with direct experimental evidence in C. elegans, so it should be retained as a core location. Supporting Evidence: PMID:26982032 MKSR-1::tdTomato and MKS-2::GFP are TZ protein comarkers |
| GO:1905515 non-motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: As a core MKS-module subunit, MKS-2 participates in building the transition zone during assembly of the non-motile (sensory) cilia of C. elegans. Because the module is redundant, the requirement is most evident in combination with NPHP-module loss rather than in the mks-2 single mutant. Reason: The BP inference is appropriate for a core TZ subunit; C. elegans sensory cilia are non-motile and the MKS module is required (redundantly) for their assembly. Retained as a module-level function; note that MKS-2's individual contribution is only unmasked in double mutants. Supporting Evidence: PMID:26982032 combining the tmem-218 mutation with another MKS module mutant, mks-2 |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: MKS-2 is a multi-pass integral membrane protein (UniProt/Phobius predicts four transmembrane helices), so a generic membrane localization is correct. However, this SubCell-derived term is far less informative than the specific ciliary transition-zone localization captured by the IDA/IBA annotations. Reason: The annotation is not wrong — MKS-2 is an integral membrane protein — but the generic 'membrane' term is subsumed by the transition-zone (ciliary membrane) localization that represents the biologically meaningful site of action. Retain as a non-core, low-information electronic annotation. Supporting Evidence: GO_REF:0000044 Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location |
| GO:1905515 non-motile cilium assembly | IMP PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS... | ACCEPT | Summary: Masyukova et al. recovered a novel mks-2 allele (yhw128) in a screen for enhancers of nphp-4 ciliary defects. The mks-2 single mutant has no overt dye-filling defect, consistent with MKS-module redundancy, but the gene is required for normal sensory-cilium assembly when the NPHP module is compromised. Reason: Experimental (IMP) annotation from a WormBase curator. The single-mutant phenotype is subtle (redundancy), but the allele's identity and its ciliary role were confirmed by non-complementation and transgenic rescue. Do not overrule the curator; the annotation reflects MKS-2's role in cilium assembly. Supporting Evidence: PMID:26863025 there was no overt defect in dye uptake in mks-1(yhw146) or mks-2(yhw128) mutants PMID:26863025 failed to complement the Dyf phenotypes of nphp-4(tm925);mks-1(tm2705), nphp-4;mks-2(mx1198), and nphp-4;mks-5(tm3100) |
| GO:1905515 non-motile cilium assembly | IGI PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS... | ACCEPT | Summary: The genetic-interaction (IGI) evidence captures the canonical MKS/NPHP redundancy: mks-2 interacts genetically with nphp-4 (UniProtKB:G5ECP0), and the nphp-4;mks-2 double mutant shows a strong dye-filling (Dyf) defect and MKS-3 mislocalization not seen in either single mutant. Reason: Well-supported IGI annotation. The synthetic phenotype with the NPHP-module gene nphp-4 is the standard genetic signature placing mks-2 in the MKS module and demonstrating its (redundant) requirement for cilium assembly. Supporting Evidence: PMID:26863025 there was no overt defect in dye uptake in mks-1(yhw146) or mks-2(yhw128) mutants PMID:26863025 failed to complement the Dyf phenotypes of nphp-4(tm925);mks-1(tm2705), nphp-4;mks-2(mx1198), and nphp-4;mks-5(tm3100) |
| 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. showed that MKS-2 is required for the transition-zone localization of the peripheral MKS-module protein TMEM-218: in the mks-2 mutant, TMEM-218 is absent from the TZ, whereas MKS-2 itself does not require TMEM-218 for its own localization. This defines MKS-2 as a 'core' subunit needed to recruit/assemble other MKS-module components at the TZ. Reason: Directly supported experimental (IMP) annotation. Loss of mks-2 mislocalizes a downstream TZ protein, demonstrating a role in establishing protein localization to the transition zone. Core function. Supporting Evidence: PMID:26982032 TMEM-218 is no longer present at the TZ in the mks-2 MKS module mutant PMID:26982032 TMEM-218 is not required for the localisation of MKS-5, MKS-2 |
| GO:0035869 ciliary transition zone | IDA PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | ACCEPT | Summary: WormBase IDA annotation for direct localization of MKS-2 to the ciliary transition zone. The cached record for this paper is abstract-only; the abstract establishes that the MKS-module membrane proteins (which include MKS-2/TMEM216) are TZ-localized, immobile, and periodically arranged within the TZ, and the curator assigned the IDA from the full text. Reason: Experimental (IDA) localization to the transition zone, concordant with the IBA annotation and with MKS-2::GFP imaging in PMID:26982032. The full text (not in cache) contains the direct evidence; 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:1903565 negative regulation of protein localization to cilium | IMP PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr... | NEW | Summary: MKS-2 is explicitly named among the 'core' MKS-module TZ proteins (with MKSR-1, MKSR-2, TMEM-231) that are required for ciliary gate function — restricting the inappropriate entry of the membrane-associated protein TRAM-1a into cilia. This gate/diffusion-barrier activity is the central function of the transition zone and is not otherwise captured in GOA for mks-2. Reason: New annotation proposed to capture MKS-2's ciliary-gate role, which is well documented for the core MKS module and directly stated for MKS-2 in Li et al. This mirrors the curated gate-function annotation for the sibling gene mks-3 and represents a core function currently missing from mks-2's GOA record. Supporting Evidence: PMID:26982032 TZ proteins are all necessary for TZ gate function PMID:26982032 restricting the inappropriate entry of membrane-associated TRAM-1a into cilia |
| GO:0036038 MKS complex | IDA PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr... | NEW | Summary: MKS-2 (TMEM216) is repeatedly identified as a 'core' MKS-module / MKSome component together with MKSR-1, MKSR-2, and TMEM-231, co-localizing with these subunits at the transition zone. Reason: New annotation capturing MKS-2 membership in the MKS complex (MKS module), consistent with the sibling gene mks-3 and with its role as a core MKS-module subunit at the transition zone. Supporting Evidence: PMID:26982032 which include MKS-2, MKSR-1, MKSR-2, and TMEM-231 |
| GO:0005198 structural molecule activity | IDA PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr... | NEW | Summary: As a multi-pass integral membrane subunit of the MKS module, MKS-2 contributes to the structural integrity of the transition zone; its loss mislocalizes the downstream TZ protein TMEM-218 and compromises the ciliary gate. This is the closest available molecular-function term for a transition-zone scaffold subunit (see knowledge_gaps). Reason: New molecular-function annotation. MKS-2 has no MF term in GOA; 'structural molecule activity' is used as the nearest placeholder for a diffusion-barrier scaffold subunit, more informative than generic protein binding. The precise MF term is an ontology-level gap (see knowledge_gaps / proposed_new_terms). Supporting Evidence: PMID:26982032 which include MKS-2, MKSR-1, MKSR-2, and TMEM-231 PMID:26982032 TMEM-218 is no longer present at the TZ in the mks-2 MKS module mutant |
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Download this section (compressed HTML)Q: Does MKS-2/TMEM216 make direct physical contacts with specific MKS-module partners (e.g. MKSR-1/MKSR-2, TMEM-231, MKS-5) that define a discrete sub-architecture of the transition zone?
Q: Does MKS-2 have any non-redundant function unmasked only in specific cell types or under stress, or is it fully interchangeable with the other core MKS-module subunits?
Experiment: Proximity labelling (TurboID/BioID) or affinity purification of tagged MKS-2 in C. elegans ciliated neurons to map its direct transition-zone interaction partners.
Hypothesis: MKS-2 occupies a specific position in the MKS-module interaction network with a defined set of direct membrane-protein partners.
Experiment: Structure-guided separation-of-function mutagenesis of MKS-2 transmembrane/loop residues, assayed for TZ localization, TRAM-1a exclusion (gate), TMEM-218 recruitment, and Y-link ultrastructure by TEM.
Hypothesis: Distinct MKS-2 residues are required for membrane anchoring versus barrier function versus recruitment of peripheral MKS-module proteins.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: MKS-2 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 MKS-2 = TMEM216/MKS2 is a small multi-pass membrane protein of the TZ, a core MKS-module component required (redundantly with the NPHP module) for cilium assembly, for the ciliary gate, and for recruiting other MKS-module proteins. What is missing is a molecular-function representation: the worm GOA record carries only cellular-component and biological-process terms and no molecular_function annotation.
Significance: This is the canonical "structural subunit" ontology gap shared across the transition-zone/ciliopathy gene set (cf. the DYF-2/IFT-A gap): 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 MKS-2 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 MKS-2/TMEM216 within the MKS module is undetermined: its direct binding partners in the worm transition zone are not mapped, and it is unknown whether MKS-2 provides a discrete sub-function (e.g. a particular membrane-anchoring or barrier contact) or is largely interchangeable with the other core MKS-module proteins.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Genetics and imaging establish that MKS-2 is a core MKS-module protein whose TZ localization depends on MKS-5 and CEP-290, that it is required to recruit TMEM-218, and that it contributes to the gate; single mks-2 mutants are phenotypically near-normal and defects emerge only in mks-2;nphp-4 double mutants. What is not resolved is MKS-2's molecular interface(s) and whether it has any function that the rest of the module cannot supply.
Significance: Distinguishing a genuine non-redundant role from full module redundancy is the load-bearing question for interpreting TMEM216/MKS2 ciliopathy alleles and for understanding how individual MKS-module subunits partition the barrier-building task.
What would resolve it: Structural/proteomic mapping of MKS-2's direct TZ partners (e.g. affinity purification, proximity labelling, cryo-EM of the MKS module) combined with separation-of-function alleles assayed for gate, Y-link, and recruitment phenotypes.
Provenance (the field's own admissions):
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