Proposed New Ontology Terms

structural constituent of ciliary transition zone

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

Existing Annotations Review

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

Core Functions

MKSR-1/B9D1 acts as a structural/scaffolding subunit of the MKS module of the ciliary transition zone. As a soluble B9/C2-domain protein it localizes to the TZ (dependent on MKS-5) and contributes to assembly and integrity of the TZ (Y-link connectors and basal body/TZ membrane anchoring) and to the ciliary gate - the membrane diffusion barrier that restricts non-ciliary membrane proteins (e.g. TRAM-1a, RPI-2) from entering the cilium. It is required to recruit/retain other MKS-module proteins (MKS-6, MKS-3) at the TZ and forms a heterodimer with MKSR-2/B9D2. There is no GO molecular-function term that precisely describes a transition-zone diffusion-barrier scaffold subunit; 'structural molecule activity' is used here as the closest available placeholder.

Molecular Function:

structural molecule activity

Directly Involved In:

non-motile cilium assembly protein localization to ciliary transition zone negative regulation of protein localization to cilium

Cellular Locations:

ciliary transition zone

In Complex:

MKS complex

Supporting Evidence:

PMID:21422230
MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane
PMID:21422230
accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and nphp-4 mutants

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:14704431

A map of the interactome network of the metazoan C. elegans.

PMID:18337471

Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis.

The C. elegans B9 proteins (MKS-1/MKSR-1/MKSR-2) form a complex at the base of cilia and function redundantly with the nephrocystins (nph-1/nph-4); B9-gene mutations do not overtly affect cilia unless combined with a nph mutation.

"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"

PMID:19123269

Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.

PMID:19208769

Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.

The B9 domain defines a family of three proteins (MKS-1, MKSR-1, MKSR-2) in ciliated organisms; all three localize co-dependently to transition zones/basal bodies of C. elegans sensory cilia. Double mks/mksr mutants show an increased-lifespan phenotype due to abnormal insulin-IGF-I signaling.

"increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling"

PMID:21422230

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

MKSR-1/B9D1 localizes to the ciliary transition zone and is a member of the MKS/MKSR module (with MKS-1, MKSR-2, MKS-3, MKS-6); the mksr-1;nphp-4 double mutant disrupts TZ membrane anchoring and Y-links.

"Phenotypes nearly identical to mks-6;nphp-4 mutants were observed in the mksr-1;nphp-4 strain"
MKSR-1 is required for the transition-zone localization of other MKS-module proteins (MKS-6 and MKS-3), restricting MKS-3 to the TZ membrane.

"MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane"
MKSR-1 contributes to ciliary-gate function; in mksr-1 mutants the normally-excluded membrane proteins TRAM-1a and RPI-2 accumulate inside cilia.

"accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and nphp-4 mutants"

PMID:26595381

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

TMEM-107 organizes recruitment of MKS-module ciliopathy proteins to subdomains of the ciliary transition zone; MKS-module membrane proteins are immobile and periodically arranged within the TZ.

"TZ-localized MKS module by organizing recruitment of the ciliopathy proteins"

Suggested Experiments

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.

Knowledge Gaps

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):

"MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane" — PMID:21422230

Proposed term (ontology gap):

structural constituent of ciliary transition zone

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):

"This motif is predicted to bind Ca2+/lipids and participate—similar to synaptotagmin—in membrane/vesicle trafficking and fusion" — PMID:21422230

Deep Research

Falcon

(mksr-1-deep-research-falcon.md)

Comprehensive Research Report: *mksr-1* (B9 Domain-Containing Protein 1) in *Caenorhabditis elegans* Falcon Edison Scientific Literature 32 citations 2 artifacts 2026-07-04T20:28:12.708027

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

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.

Comprehensive Research Report: mksr-1 (B9 Domain-Containing Protein 1) in Caenorhabditis elegans

1. Gene and Protein Identity

The gene mksr-1 (MKS1-Related, also designated K03E6.4) encodes a B9 domain-containing protein 1 (UniProt: Q21191) in Caenorhabditis elegans. The name "MKSR" stands for Meckel Syndrome 1-Related, reflecting its evolutionary and functional relationship to the ciliopathy-associated protein MKS1. MKSR-1 is the C. elegans ortholog of mammalian B9D1 (also known as MKS9), a soluble protein containing a single B9 domain that spans nearly the entire length of the protein (bialas2009functionalinteractionsbetween pages 5-6, okazaki2020formationofthe pages 5-7). MKSR-1 belongs to a small family of three B9 domain-containing proteins—MKS-1, MKSR-1, and MKSR-2 (ortholog of B9D2)—that are evolutionarily conserved across ciliated organisms and always co-occur in the proteome, suggesting they function as an obligate complex (zhang2010identificationofnovel pages 8-9, bialas2009functionalinteractionsbetween pages 5-6).

The following table summarizes the key molecular and functional properties of MKSR-1/B9D1:

Property	Summary
Gene / protein name	C. elegans: mksr-1 (MKSR-1), UniProt Q21191, annotated as B9 domain-containing protein 1; human ortholog: B9D1 (also called MKS9 in some literature) (bialas2009functionalinteractionsbetween pages 5-6, li2016mks5andcep290 pages 9-11, okazaki2020formationofthe pages 1-5)
Protein family / domain	Member of the B9 domain protein family; contains a B9-C2 / C2_B9-type domain, a specialized C2-domain family associated with ciliary proteins and inferred membrane/lipid interaction functions (zhang2010identificationofnovel pages 8-9, zhang2010identificationofnovel pages 5-6, okazaki2020formationofthe pages 1-5)
Subcellular localization	Localizes specifically to the ciliary transition zone (TZ) at the base of sensory cilia in C. elegans amphid and phasmid neurons; mammalian B9D1 is also a TZ protein (bialas2009functionalinteractionsbetween pages 5-6, li2016mks5andcep290 pages 9-11, bialas2009functionalinteractionsbetween pages 3-5)
Molecular complex	Core component of the MKS/B9 transition-zone complex; in vertebrates the B9 subcomplex is organized as MKS1–B9D2–B9D1, with B9D2 bridging MKS1 and B9D1 (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 5-7, okazaki2020formationofthe pages 21-27)
Functional role	Functions in ciliary gate / diffusion barrier activity at the TZ, helping maintain selective ciliary membrane protein composition and compartmentalization rather than acting as a classical enzyme or transporter; broadly supports TZ organization and ciliary signaling homeostasis (okazaki2020formationofthe pages 1-5, jensen2015formationofthe pages 14-15, jensen2015formationofthe pages 12-14)
Genetic / pathway module	Belongs to the MKS module of TZ proteins; specifically behaves as a core MKS module protein in the hierarchical assembly pathway downstream of MKS-5/RPGRIP1L and CEP-290, and is genetically separable from the NPHP module while functionally redundant with it during ciliogenesis/barrier formation (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 3-5)
Key interacting partners	Strongly linked with MKSR-2/B9D2 and MKS-1 through interdependent localization in worms; mammalian interaction mapping supports a linear MKS1–B9D2–B9D1 arrangement. As a core MKS protein, its proper TZ localization also depends on CEP-290 and upstream MKS-5-dependent assembly. Core/peripheral MKS relationships place it functionally alongside MKS-2/TMEM216, TMEM-231, TMEM-17, TMEM-67, TMEM-218, and TMEM-237 (bialas2009functionalinteractionsbetween pages 5-6, okazaki2020formationofthe pages 5-7, li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 16-18)
Single-mutant phenotype in C. elegans	mksr-1 single mutants are generally non-Dyf (no obvious dye-filling defect) and do not show major defects in gross ciliogenesis, intraflagellar transport, or chemosensation, indicating MKSR-1 is not absolutely required for basal cilium assembly on its own (bialas2009functionalinteractionsbetween pages 1-2, bialas2009functionalinteractionsbetween pages 6-7, bialas2009functionalinteractionsbetween pages 7-9, warburtonpitt2012ciliogenesisincaenorhabditis pages 3-4)
Double-mutant / synthetic phenotype	Stronger phenotypes emerge in combination with other TZ genes. MKS/NPHP double mutants reveal redundant function in ciliogenesis and membrane anchoring, with synthetic defects including dye-filling defects, loss of TZ ultrastructure/Y-links, axoneme malformations, cilium shortening, and TZ displacement. Genetic interactions are especially evident with nphp-1, nphp-4, and sensillum-specific interactions with nphp-2 (jensen2015formationofthe pages 1-2, li2016mks5andcep290 pages 18-20, jensen2015formationofthe pages 14-15, bialas2009functionalinteractionsbetween pages 7-9, warburtonpitt2012ciliogenesisincaenorhabditis pages 4-6, warburtonpitt2015theciliopathygene pages 95-99)
Assembly-dependence / localization dependencies	MKSR-1 localization is interdependent with other core MKS proteins and is disrupted when MKSR-2, MKS-1, or CEP-290 are absent; MKS-5 acts further upstream as a foundational TZ assembly factor (bialas2009functionalinteractionsbetween pages 5-6, li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 3-5)
Human disease associations of ortholog	B9D1 is associated with Meckel syndrome / Meckel syndrome type 9 and Joubert syndrome / Joubert syndrome 27 in human disease databases and primary literature (OpenTargets Search: -B9D1)

Table: This table summarizes the main molecular, cellular, genetic, and disease-related properties of C. elegans MKSR-1 and its human ortholog B9D1. It is useful as a compact reference linking transition-zone localization, MKS-module function, mutant phenotypes, and ciliopathy associations.

2. Structural and Domain Features

MKSR-1 contains a single B9 domain (IPR010796; PF07162), which is classified as a specialized member of the C2 domain superfamily based on profile-profile comparisons and fold recognition analyses (zhang2010identificationofnovel pages 8-9, zhang2010identificationofnovel pages 5-6). C2 domains are typically β-sandwich structures that mediate calcium-dependent or calcium-independent membrane binding through interactions with phospholipids. The B9-type C2 domain, however, represents a distinct evolutionary branch: it occurs as a standalone domain (i.e., not fused with other functional domains) and contains conserved hydrophobic residues on its β-sheet that create a concave ligand-binding surface, consistent with lipid interaction capability (zhang2010identificationofnovel pages 8-9). Structural analyses of related ciliary C2 domains indicate that B9 domains are not expected to bind Ca²⁺ and instead may function primarily as protein-protein interaction modules within the transition zone (zhang2010identificationofnovel pages 8-9).

Studies on the related B9 domain protein B9D2 have demonstrated strong binding affinity to specific phosphoinositides, including PI4P and PI(3,4,5)P3, with lesser binding to PI(4,5)P2 (caenenbraz2024newfunctionsof pages 8-10). Given the high structural similarity within the B9 family, MKSR-1's B9 domain is inferred to possess analogous lipid-interaction properties, which may facilitate its anchoring to specific membrane microdomains at the ciliary transition zone.

3. Primary Function: Structural Component of the Ciliary Transition Zone Gate

MKSR-1 is not an enzyme, transporter, or classical signaling molecule. Rather, it functions as a structural/adapter protein within the ciliary transition zone (TZ), where it serves as a core component of the MKS (Meckel syndrome) module—a multiprotein complex that constitutes part of the ciliary diffusion barrier or "gate" (jensen2015formationofthe pages 1-2, okazaki2020formationofthe pages 1-5).

3.1 The Transition Zone as a Ciliary Gate

The transition zone is a specialized ~0.8 μm region at the base of the cilium, located between the basal body and the axoneme proper. It contains characteristic Y-shaped linkers that connect the axonemal microtubule doublets to the ciliary membrane and functions as a selective barrier controlling which proteins and lipids can enter or exit the ciliary compartment (jensen2015formationofthe pages 14-15, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 2-4). This barrier is essential for maintaining the unique protein and lipid composition of cilia, which is required for their sensory and signaling functions.

3.2 The B9 Protein Complex as a Diffusion Barrier

In mammalian cells, the three B9 domain proteins form a linear tripartite complex with the interaction mode MKS1–B9D2–B9D1, where B9D2 serves as a bridge between MKS1 and B9D1, as demonstrated by visible immunoprecipitation and three-hybrid assays (okazaki2020formationofthe pages 5-7, okazaki2020formationofthe pages 21-27). MKS1 and B9D1 do not directly interact with each other (okazaki2020formationofthe pages 5-7). The formation of this complex is essential for creating a functional diffusion barrier for ciliary membrane proteins: loss of MKS1 or B9D2 results in failure of transmembrane proteins (such as GPCRs GPR161 and Smoothened) and lipidated membrane proteins (ARL13B, INPP5E) to properly localize to the ciliary membrane (okazaki2020formationofthe pages 5-7, okazaki2020formationofthe pages 21-27). Importantly, the B9 proteins are involved in, but not absolutely essential for, normal cilia biogenesis; rather, their complex formation is specifically crucial for the barrier/gating function (okazaki2020formationofthe pages 1-5).

3.3 Recent Advances: B9 Complex Interactions with TMEM67 and Microtubule Modifications

Recent work has revealed additional functions of the B9 complex beyond its role as a passive diffusion barrier. The B9D1-B9D2-MKS1 complex interacts with and anchors the transmembrane protein TMEM67 to the TZ membrane. Disruption of this B9-TMEM67 complex reduces posttranslational modifications (acetylation and polyglutamylation) of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia (he2026ciliopathyrelatedb9protein pages 1-2, he2026ciliopathyrelatedb9protein pages 4-5). Furthermore, B9 proteins have been found to localize to centrioles prior to ciliogenesis, where they facilitate initiation of ciliary assembly by promoting membrane vesicle docking to distal appendages and CP110 removal from the mother centriole (he2026ciliopathyrelatedb9protein pages 2-4, he2026ciliopathyrelatedb9protein pages 1-2).

4. Subcellular Localization

In C. elegans, MKSR-1 localizes specifically to the transition zone at the base of sensory cilia in ciliated neurons. Fluorescent reporter studies have demonstrated MKSR-1 localization at transition zones of amphid cilia near the head and phasmid cilia near the tail (bialas2009functionalinteractionsbetween pages 3-5, bialas2009functionalinteractionsbetween pages 5-6). This localization pattern is shared with MKS-1 and MKSR-2, and the three B9 proteins show co-dependent localization: when any one is mutated, the other two show reduced or mislocalized signals at transition zones, with abnormal accumulations in dendrites (bialas2009functionalinteractionsbetween pages 5-6, bialas2009functionalinteractionsbetween pages 6-7). MKSR-1 localization also depends on CEP-290 and MKS-5, the upstream assembly factors of the TZ (li2016mks5andcep290 pages 9-11).

5. Transition Zone Assembly Hierarchy and Module Architecture

The ciliary TZ in C. elegans assembles through a well-characterized hierarchical pathway. MKSR-1 occupies a defined position within this hierarchy as a core MKS module protein:

Level in hierarchy	Protein(s)	Module assignment	Dependence (what it requires for TZ localization)	Role in TZ
1 (most upstream)	MKS-5 / RPGRIP1L	Master TZ assembly factor / scaffold linking MKS and NPHP branches	Localizes independently of CEP-290; required for localization of essentially all tested TZ proteins, including CEP-290, MKS-module, and NPHP-module proteins (li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 3-5, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 8-9)	Foundational organizer of TZ formation; establishes TZ ultrastructure, supports Y-link formation, and helps create the ciliary zone of exclusion/barrier (li2016mks5andcep290 pages 3-5, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 7-8, jensen2015formationofthe pages 4-5)
2A	NPHP-1, NPHP-4	NPHP module	Assemble in the MKS-5-dependent branch; localization does not require CEP-290 (li2016mks5andcep290 pages 11-12, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 3-5)	Parallel TZ branch that works redundantly with the MKS branch to seal the ciliary compartment, maintain membrane attachments, and support ciliogenesis/barrier function (li2016mks5andcep290 pages 16-18, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 7-8, jensen2015formationofthe pages 2-4)
2B	CEP-290	CEP-290-dependent MKS assembly branch	Requires MKS-5 for TZ localization; acts downstream of MKS-5 and upstream of MKS-module proteins (li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 11-12, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 3-5)	Core assembly factor for the MKS pathway; required for Y-links/apical ring integrity and ciliary gate function, and specifically recruits/organizes MKS-module proteins at the TZ (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 11-12)
3 (core MKS layer)	MKS-1, MKSR-1/B9D1, MKSR-2/B9D2, MKS-2/TMEM216, TMEM-231	Core MKS module	Require CEP-290 and MKS-5 for TZ localization; core members are interdependent with one another for proper localization (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 7-9)	Principal MKS gate components; organize the membrane-proximal barrier, support TZ ultrastructure, and are necessary for proper ciliary compartmentalization/gate function (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 16-18, jensen2015formationofthe pages 14-15, jensen2015formationofthe pages 2-4)
4 (peripheral MKS layer)	TMEM-17, TMEM-67, TMEM-218, TMEM-237	Peripheral MKS module	Require CEP-290, MKS-5, and intact core MKS proteins for TZ localization; do not control localization of core MKS proteins (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 16-18, li2016mks5andcep290 pages 7-9)	Downstream effectors/accessory MKS components that elaborate TZ composition and contribute to mature gate/barrier function rather than initiating core assembly (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 16-18, jensen2015formationofthe pages 2-4)

Table: This table summarizes the hierarchical assembly of the C. elegans ciliary transition zone, placing MKSR-1/B9D1 within the CEP-290-dependent core MKS module. It is useful for understanding which proteins act upstream versus downstream in building the transition-zone barrier.

MKS-5/RPGRIP1L serves as the foundational scaffold, localizing independently of all other TZ proteins and being required for localization of essentially all known TZ components (li2016mks5andcep290 pages 3-5, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 7-8). Downstream of MKS-5, the pathway bifurcates into two genetically separable branches: the NPHP module (NPHP-1, NPHP-4) and the CEP-290-dependent MKS module (li2016mks5andcep290 pages 11-12, li2016mks5andcep290 pages 16-18). CEP-290 requires MKS-5 for its own TZ localization and is in turn required for proper localization of all MKS module components, including MKSR-1 (li2016mks5andcep290 pages 9-11, li2016mks5andcep290 pages 3-5).

Within the MKS module, MKSR-1 is classified as a core component, along with MKS-1, MKSR-2, MKS-2/TMEM216, and TMEM-231. These core proteins show interdependent localization—removal of any one disrupts TZ localization of the others (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 16-18). Peripheral MKS module proteins (TMEM-17, TMEM-67, TMEM-218, TMEM-237) depend on the core proteins for their TZ localization but do not influence core protein assembly (li2016mks5andcep290 pages 18-20, li2016mks5andcep290 pages 16-18).

6. Genetic Interactions and Functional Redundancy

A hallmark of MKSR-1 function is its genetic redundancy with NPHP module proteins. Single mksr-1 mutants (ok2092) are non-Dyf (no dye-filling defect) and display no overt defects in cilium formation, intraflagellar transport (IFT), or chemosensory behaviors (bialas2009functionalinteractionsbetween pages 1-2, bialas2009functionalinteractionsbetween pages 6-7, warburtonpitt2012ciliogenesisincaenorhabditis pages 3-4). However, when mksr-1 mutations are combined with mutations in NPHP module genes (nphp-1 or nphp-4), severe synthetic phenotypes emerge, including dye-filling defects, loss of basal body-TZ membrane anchoring, disruption of TZ ultrastructure and Y-links, and axoneme malformations (jensen2015formationofthe pages 1-2, bialas2009functionalinteractionsbetween pages 7-9, warburtonpitt2012ciliogenesisincaenorhabditis pages 4-6). These synthetic interactions define the genetic separability of the MKS and NPHP modules while demonstrating their functional redundancy in establishing the ciliary gate.

Additionally, nphp-2;mksr-1 double mutants exhibit sensillum-specific dye-filling defects and abnormal TZ spread in amphid neurons, as well as shortened phasmid dendritic length indicative of TZ displacement (warburtonpitt2012ciliogenesisincaenorhabditis pages 4-6, warburtonpitt2015theciliopathygene pages 95-99).

7. Role in Ciliary Signaling and the Ciliary Zone of Exclusion (CIZE)

The TZ, to which MKSR-1 localizes, establishes a ciliary zone of exclusion (CIZE) that compartmentalizes signaling proteins and controls phosphoinositide abundance within the cilium (jensen2015formationofthe pages 14-15, jensen2015formationofthe pages 1-2, jensen2015formationofthe pages 12-14). The CIZE model, developed primarily from C. elegans studies, demonstrates that PIP2 is highly concentrated at the periciliary membrane but is excluded from the distal ciliary compartment in an MKS-5-dependent manner (jensen2015formationofthe pages 14-15, jensen2015formationofthe pages 12-14). The TZ barrier also prevents inappropriate entry of non-ciliary membrane proteins and retains ciliary residents like ARL-13 within the cilium (jensen2015formationofthe pages 12-14).

While MKSR-1 single mutants do not show gross signaling defects, double mutant analysis with other B9 family members (mksr-1;mksr-2) revealed increased lifespan, suggesting MKSR-1 functions upstream of the DAF-2/DAF-16 insulin-IGF-I signaling pathway to regulate longevity specification, likely through its role in cilia-dependent sensory signaling (bialas2009functionalinteractionsbetween pages 9-10, bialas2009functionalinteractionsbetween pages 10-11).

8. Evolutionary Conservation and Disease Relevance

The B9 protein family is highly conserved across ciliated eukaryotes. Phylogenetic analysis shows that all three B9 domain proteins (MKS1, B9D1/MKSR-1, B9D2/MKSR-2) strictly co-occur in organisms that possess cilia and are independently lost in non-ciliated lineages such as land plants, amoebozoans, and dikaryan fungi (zhang2010identificationofnovel pages 8-9, bialas2009functionalinteractionsbetween pages 5-6).

The human ortholog B9D1 is a causative gene for Meckel syndrome type 9 (MKS9), a severe autosomal recessive lethal ciliopathy characterized by occipital encephalocele, cystic kidneys, and polydactyly (OpenTargets Search: -B9D1). B9D1 mutations have also been identified in patients with Joubert syndrome 27 (JBTS27), a milder ciliopathy characterized by the "molar tooth sign" cerebellar malformation (OpenTargets Search: -B9D1). This spectrum of disease severity from the same gene—ranging from lethal MKS to mild JBTS—reflects the functional complexity of the B9 complex in maintaining ciliary gate function across different tissues and developmental contexts.

9. Summary

MKSR-1 (B9D1) is a non-enzymatic, non-transporter structural/adapter protein that functions as a core component of the ciliary transition zone diffusion barrier in C. elegans. Its primary role is to form part of the B9 protein complex (MKS1–MKSR-2–MKSR-1), which is essential for maintaining selective ciliary membrane composition by preventing non-selective diffusion of proteins and lipids across the transition zone. MKSR-1 localizes specifically to the transition zone of sensory cilia, where it participates in the MKS module—a multiprotein assembly that works redundantly with the NPHP module to establish the ciliary gate. The protein assembles hierarchically downstream of MKS-5 and CEP-290, and its localization is interdependent with other core MKS components. Through its role in ciliary compartmentalization, MKSR-1 indirectly supports multiple signaling pathways that depend on proper ciliary function, including insulin-IGF signaling and sensory perception. Mutations in the human ortholog B9D1 cause the ciliopathies Meckel syndrome and Joubert syndrome, underscoring the critical importance of this protein in ciliary biology.

References

(bialas2009functionalinteractionsbetween pages 5-6): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(okazaki2020formationofthe pages 5-7): Misato Okazaki, Takuya Kobayashi, Shuhei Chiba, Ryota Takei, Luxiaoxue Liang, Kazuhisa Nakayama, and Yohei Katoh. Formation of the b9-domain protein complex mks1–b9d2–b9d1 is essential as a diffusion barrier for ciliary membrane proteins. Molecular Biology of the Cell, 31:2259-2268, Sep 2020. URL: https://doi.org/10.1091/mbc.e20-03-0208, doi:10.1091/mbc.e20-03-0208. This article has 32 citations and is from a domain leading peer-reviewed journal.
(zhang2010identificationofnovel pages 8-9): Dapeng Zhang and L. Aravind. Identification of novel families and classification of the c2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes. Gene, 469 1-2:18-30, Dec 2010. URL: https://doi.org/10.1016/j.gene.2010.08.006, doi:10.1016/j.gene.2010.08.006. This article has 169 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 176 citations and is from a highest quality peer-reviewed journal.
(okazaki2020formationofthe pages 1-5): Misato Okazaki, Takuya Kobayashi, Shuhei Chiba, Ryota Takei, Luxiaoxue Liang, Kazuhisa Nakayama, and Yohei Katoh. Formation of the b9-domain protein complex mks1–b9d2–b9d1 is essential as a diffusion barrier for ciliary membrane proteins. Molecular Biology of the Cell, 31:2259-2268, Sep 2020. URL: https://doi.org/10.1091/mbc.e20-03-0208, doi:10.1091/mbc.e20-03-0208. This article has 32 citations and is from a domain leading peer-reviewed journal.
(zhang2010identificationofnovel pages 5-6): Dapeng Zhang and L. Aravind. Identification of novel families and classification of the c2 domain superfamily elucidate the origin and evolution of membrane targeting activities in eukaryotes. Gene, 469 1-2:18-30, Dec 2010. URL: https://doi.org/10.1016/j.gene.2010.08.006, doi:10.1016/j.gene.2010.08.006. This article has 169 citations and is from a peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 3-5): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(okazaki2020formationofthe pages 21-27): Misato Okazaki, Takuya Kobayashi, Shuhei Chiba, Ryota Takei, Luxiaoxue Liang, Kazuhisa Nakayama, and Yohei Katoh. Formation of the b9-domain protein complex mks1–b9d2–b9d1 is essential as a diffusion barrier for ciliary membrane proteins. Molecular Biology of the Cell, 31:2259-2268, Sep 2020. URL: https://doi.org/10.1091/mbc.e20-03-0208, doi:10.1091/mbc.e20-03-0208. This article has 32 citations and is from a domain leading peer-reviewed journal.
(jensen2015formationofthe pages 14-15): 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 164 citations.
(jensen2015formationofthe pages 12-14): 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 164 citations.
(li2016mks5andcep290 pages 18-20): 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 176 citations and is from a highest quality peer-reviewed journal.
(li2016mks5andcep290 pages 16-18): 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 176 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 176 citations and is from a highest quality peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 1-2): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 6-7): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 7-9): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(warburtonpitt2012ciliogenesisincaenorhabditis pages 3-4): Simon R. F. Warburton-Pitt, Andrew R. Jauregui, Chunmei Li, Juan Wang, M. Leroux, and M. Barr. Ciliogenesis in caenorhabditis elegans requires genetic interactions between ciliary middle segment localized nphp-2 (inversin) and transition zone-associated proteins. Journal of Cell Science, 125:2592-2603, Jun 2012. URL: https://doi.org/10.1242/jcs.095539, doi:10.1242/jcs.095539. This article has 57 citations and is from a domain leading peer-reviewed journal.
(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 164 citations.
(warburtonpitt2012ciliogenesisincaenorhabditis pages 4-6): Simon R. F. Warburton-Pitt, Andrew R. Jauregui, Chunmei Li, Juan Wang, M. Leroux, and M. Barr. Ciliogenesis in caenorhabditis elegans requires genetic interactions between ciliary middle segment localized nphp-2 (inversin) and transition zone-associated proteins. Journal of Cell Science, 125:2592-2603, Jun 2012. URL: https://doi.org/10.1242/jcs.095539, doi:10.1242/jcs.095539. This article has 57 citations and is from a domain leading peer-reviewed journal.
(warburtonpitt2015theciliopathygene pages 95-99): Simon R. F. Warburton-Pitt. The ciliopathy gene nphp 2 functions in multiple gene networks and regulates ciliogenesis in c. elegans. ArXiv, Jan 2015. URL: https://doi.org/10.7282/t3v40wx3, doi:10.7282/t3v40wx3. This article has 0 citations.
(OpenTargets Search: -B9D1): Open Targets Query (-B9D1, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(caenenbraz2024newfunctionsof pages 8-10): Chloe Caenen-Braz, Latifa Bouzhir, and Pascale Dupuis-Williams. New functions of b9d2 in tight junctions and epithelial polarity. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-75577-w, doi:10.1038/s41598-024-75577-w. This article has 4 citations and is from a peer-reviewed journal.
(jensen2015formationofthe pages 2-4): 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 164 citations.
(he2026ciliopathyrelatedb9protein pages 1-2): Ruida He, Yan Li, Minjun Jin, Huike Jiao, Yue Shen, Qize Han, Xilang Pan, Suning Wang, Zaisheng Lin, Jingshi Li, Chao Lu, Dan Meng, Zongfu Cao, Qing Shang, Nan Lv, Kai Wan, Huafang Gao, Xu Ma, Haiyan Yin, Haishuang Chang, Liang Wang, Minna Luo, Junmin Pan, Chengtian Zhao, and Muqing Cao. Ciliopathy-related b9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis. Journal of Clinical Investigation, Oct 2026. URL: https://doi.org/10.1172/jci196365, doi:10.1172/jci196365. This article has 0 citations and is from a highest quality peer-reviewed journal.
(he2026ciliopathyrelatedb9protein pages 4-5): Ruida He, Yan Li, Minjun Jin, Huike Jiao, Yue Shen, Qize Han, Xilang Pan, Suning Wang, Zaisheng Lin, Jingshi Li, Chao Lu, Dan Meng, Zongfu Cao, Qing Shang, Nan Lv, Kai Wan, Huafang Gao, Xu Ma, Haiyan Yin, Haishuang Chang, Liang Wang, Minna Luo, Junmin Pan, Chengtian Zhao, and Muqing Cao. Ciliopathy-related b9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis. Journal of Clinical Investigation, Oct 2026. URL: https://doi.org/10.1172/jci196365, doi:10.1172/jci196365. This article has 0 citations and is from a highest quality peer-reviewed journal.
(he2026ciliopathyrelatedb9protein pages 2-4): Ruida He, Yan Li, Minjun Jin, Huike Jiao, Yue Shen, Qize Han, Xilang Pan, Suning Wang, Zaisheng Lin, Jingshi Li, Chao Lu, Dan Meng, Zongfu Cao, Qing Shang, Nan Lv, Kai Wan, Huafang Gao, Xu Ma, Haiyan Yin, Haishuang Chang, Liang Wang, Minna Luo, Junmin Pan, Chengtian Zhao, and Muqing Cao. Ciliopathy-related b9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis. Journal of Clinical Investigation, Oct 2026. URL: https://doi.org/10.1172/jci196365, doi:10.1172/jci196365. This article has 0 citations and is from a highest quality peer-reviewed journal.
(jensen2015formationofthe pages 8-9): 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 164 citations.
(jensen2015formationofthe pages 7-8): 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 164 citations.
(jensen2015formationofthe pages 4-5): 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 164 citations.
(li2016mks5andcep290 pages 11-12): 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 176 citations and is from a highest quality peer-reviewed journal.
(li2016mks5andcep290 pages 7-9): 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 176 citations and is from a highest quality peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 9-10): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.
(bialas2009functionalinteractionsbetween pages 10-11): Nathan J. Bialas, Peter N. Inglis, Chunmei Li, Jon F. Robinson, Jeremy D. K. Parker, Michael P. Healey, Erica E. Davis, Chrystal D. Inglis, Tiina Toivonen, David C. Cottell, Oliver E. Blacque, Lynne M. Quarmby, Nicholas Katsanis, and Michel R. Leroux. Functional interactions between the ciliopathy-associated meckel syndrome 1 (mks1) protein and two novel mks1-related (mksr) proteins. Journal of Cell Science, 122:611-624, Mar 2009. URL: https://doi.org/10.1242/jcs.028621, doi:10.1242/jcs.028621. This article has 98 citations and is from a domain leading peer-reviewed journal.

Artifacts

Citations

zhang2010identificationofnovel pages 8-9
caenenbraz2024newfunctionsof pages 8-10
okazaki2020formationofthe pages 5-7
okazaki2020formationofthe pages 1-5
jensen2015formationofthe pages 12-14
bialas2009functionalinteractionsbetween pages 5-6
zhang2010identificationofnovel pages 5-6
bialas2009functionalinteractionsbetween pages 3-5
okazaki2020formationofthe pages 21-27
jensen2015formationofthe pages 14-15
bialas2009functionalinteractionsbetween pages 1-2
bialas2009functionalinteractionsbetween pages 6-7
bialas2009functionalinteractionsbetween pages 7-9
warburtonpitt2012ciliogenesisincaenorhabditis pages 3-4
jensen2015formationofthe pages 1-2
warburtonpitt2012ciliogenesisincaenorhabditis pages 4-6
warburtonpitt2015theciliopathygene pages 95-99
jensen2015formationofthe pages 2-4
jensen2015formationofthe pages 8-9
jensen2015formationofthe pages 7-8
jensen2015formationofthe pages 4-5
bialas2009functionalinteractionsbetween pages 9-10
bialas2009functionalinteractionsbetween pages 10-11
https://doi.org/10.1242/jcs.028621,
https://doi.org/10.1091/mbc.e20-03-0208,
https://doi.org/10.1016/j.gene.2010.08.006,
https://doi.org/10.1371/journal.pbio.1002416,
https://doi.org/10.15252/embj.201488044,
https://doi.org/10.1242/jcs.095539,
https://doi.org/10.7282/t3v40wx3,
https://doi.org/10.1038/s41598-024-75577-w,
https://doi.org/10.1172/jci196365,

📚 Additional Documentation

Notes

(mksr-1-notes.md)

mksr-1 (K03E6.4 / WBGene00019364 / Q21191) — research notes

Identity

UniProt Q21191 (Q21191_CAEEL), Caenorhabditis elegans, 229 aa.
RecName: B9 domain-containing protein 1 (i.e. B9D1 ortholog) [UniProt Q21191, "RecName: Full=B9 domain-containing protein 1"].
Gene: mksr-1 ("MKS-1-related protein 1"); ORF K03E6.4; WormBase WBGene00019364; on Chromosome X.
Domain content: a single B9 (C2-B9-type) domain (InterPro IPR010796 "C2_B9-type_dom"; Pfam PF07162 "B9-C2"; PROSITE PS51381 C2_B9). PANTHER PTHR12968:SF1 "B9 DOMAIN-CONTAINING PROTEIN 1".
Belongs to the B9D family [UniProt Q21191, "Belongs to the B9D family."].
NOT an integral membrane protein: no signal peptide, no transmembrane keyword. This distinguishes it from mks-2 (TMEM216, multi-pass membrane). mksr-1 is a peripheral B9/C2-domain component of the MKS module. (UniProt keywords: Cell projection, Cilium biogenesis/degradation, Cytoplasm, Cytoskeleton.)
UniProt subcellular location: "Cytoplasm, cytoskeleton, cilium basal body" (ARBA electronic).
UniProt binary interaction: Q21191; Q9N423: mksr-2; NbExp=3; IntAct=EBI-330284, EBI-330279 — i.e. MKSR-1 binds MKSR-2 (B9D2, Q9N423).

Nomenclature caution

Older literature uses conflicting names for the three worm B9 proteins. Williams et al. 2008 (PMID:18337471) named them XBX-7 (MKS1), TZA-1 (B9D2), TZA-2 (B9D1). Bialas et al. 2009 (PMID:19208769) and Williams et al. 2011 (PMID:21422230) use the now-standard MKS-1, MKSR-1/B9D1, MKSR-2/B9D2. UniProt, WormBase and the CAEEL_CILIOPATHY project all use mksr-1 = B9D1, mksr-2 = B9D2. I use the standard naming; where a paper uses other names I note the correspondence.

What is KNOWN

Family, domain, evolution

The B9 domain occurs "exclusively within a family of three proteins distributed widely in ciliated organisms" [PMID:19208769 abstract, "this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms"].
Structure/fold predictions relate the B9 domain to a C2 domain (Ca2+/lipid-binding, synaptotagmin-like) [PMID:21422230, "B9 domains of MKS-1, MKSR-1, and MKSR-2 may be structurally related to C2 domains"; "This motif is predicted to bind Ca2+/lipids and participate—similar to synaptotagmin—in membrane/vesicle trafficking and fusion"]. This is a predicted biochemical property; no direct Ca2+/lipid-binding assay for MKSR-1 exists in these papers.

Localization (experimental)

All three C. elegans B9 proteins (MKS-1, MKSR-1, MKSR-2) "localize to transition zones/basal bodies of sensory cilia" [PMID:19208769 abstract].
Direct imaging: MKSR-1/B9D1 localizes to the ciliary transition zone in C. elegans sensory neurons [PMID:21422230, "This is evident for MKS-1, MKS-1 related-1 (MKSR-1)/B9D1, MKS-1 related-2 (MKSR-2)/B9D2, MKS-3/meckelin, NPHP-1, and NPHP-4"; GFP-MKSR-1 imaged at TZ, Fig 1–2, Fig 8G]. This is the basis of the WormBase IDA GO:0035869 (ciliary transition zone) annotation (PMID:21422230).
Localization is co-dependent among the B9 proteins: "Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins" [PMID:19208769 abstract].
MKSR-1 TZ localization depends on upstream MKS-5: "mks-5 mutants failed to properly localize MKS-1, MKSR-1, and MKSR-2" PMID:21422230.
MKSR-1::tdTomato is used as a TZ comarker [mks-2 review cites PMID:26982032, "MKSR-1::tdTomato and MKS-2::GFP are TZ protein comarkers"].

The MKS module / complex

MKSR-1 is a member of the MKS/MKSR module together with MKS-1, MKSR-2, MKS-3, MKS-6: "MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6" PMID:21422230. Modeled in GO as the MKS complex (GO:0036038).
The MKS module and the NPHP module (NPHP-1/NPHP-4) are recruited/anchored by the central scaffold MKS-5/RPGRIP1L.

Function: transition-zone assembly / Y-links / membrane anchoring

MKSR-1 acts, redundantly with the NPHP module, in building the TZ. The mksr-1;nphp-4 double mutant has severe TZ ultrastructure defects — TZ not anchored to membrane, missing Y-links: "Phenotypes nearly identical to mks-6;nphp-4 mutants were observed in the mksr-1;nphp-4 strain" PMID:21422230. (Table I: mksr-1;nphp-4 shows enlarged TZ membrane diameter and 0% of TZs with Y-links.)
MKSR-1 is required for the TZ localization of other MKS-module proteins (MKS-6, MKS-3): "disrupting MKSR-1, MKSR-2, or MKS-5 results in TZ delocalization of MKS-6 ... and MKS-3" PMID:21422230. This underlies the IMP GO:1904491 (protein localization to ciliary transition zone) and GO:0008104 (intracellular protein localization) annotations.

Function: ciliary gate / diffusion barrier

MKSR-1 is required to restrict membrane-associated proteins from entering the cilium (ciliary gate). In the mksr-1 single mutant, three normally-excluded proteins accumulate inside cilia:
MKS-3: "accumulates abnormally inside cilia (cil) and at dendritic tips (DT) in mks-5, mksr-1, and mksr-2 mutants" [PMID:21422230, Fig 9L].
RPI-2 (RP2 ortholog): "accumulates within cilia of ... mksr-1, mksr-2, mks-5, mks-6, and nphp-4 single mutants" [PMID:21422230, Fig 9M].
TRAM-1a: "accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and nphp-4 mutants" [PMID:21422230, Fig 9N].
General model: "TZ proteins normally function to maintain a boundary at the cilium base, establishing the TZ as a bona fide ciliary gate" PMID:21422230. This supports a NEW GO:1903565 (negative regulation of protein localization to cilium) annotation, mirroring the mks-2 review.
Notably, the mksr-1 single mutant already shows the gate defect (RPI-2, TRAM-1a, MKS-3 mislocalization) even though gross cilium structure is normal — the gate phenotype is more sensitive than the structural phenotype.

Redundancy / single-mutant subtlety

Single, double and triple mks/mksr mutants "do not display overt defects in ciliary structure, intraflagellar transport or chemosensation" [PMID:19208769 abstract].
B9-gene mutations "do not overtly affect cilia formation unless they are in combination with a mutation in nph-1 or nph-4" [PMID:18337471 abstract]. → basis of the IGI GO:1905515 (non-motile cilium assembly) annotations (mksr-1 × nphp-1/nphp-4, WITH WBGene00011261=nphp-4, WBGene00007490=nphp-1).

Lifespan / insulin-IGF phenotype

Double mks/mksr mutants have an increased lifespan phenotype due to abnormal insulin-IGF-I signaling: "we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling" [PMID:19208769 abstract]. → basis of the IGI GO:0008340 (determination of adult lifespan) annotations. This is an indirect, module-redundancy phenotype (a downstream consequence of impaired ciliary signaling), not a direct molecular function of MKSR-1.

Larval foraging behavior

GO:0035177 (larval foraging behavior) IGI annotation from PMID:18337471 (WITH WBGene00011261 = nphp-4). Foraging/roaming behavior in worms depends on functional sensory cilia; a B9×nphp genetic interaction affecting cilia would plausibly affect foraging. The cached record is abstract-only (does not state "foraging" explicitly), so this is a curator judgment from full text — retained (KEEP_AS_NON_CORE), not overruled.

Protein interactions

MKSR-1 binds MKSR-2 (B9D2). UniProt binary interaction Q21191–Q9N423 (NbExp=3); IntAct EBI-330284/EBI-330279; DIP-27480N. GOA has IPI GO:0005515 (protein binding) annotations with WITH/FROM UniProtKB:Q9N423 from PMID:14704431 (Li et al. 2004 worm interactome) and PMID:19123269 (Simonis et al. 2009 empirically-controlled interactome), plus one WB IPI from PMID:18337471 (WITH WBGene00021416 = mksr-2). The interaction is real, but protein binding is uninformative; the biologically meaningful fact is the B9D1–B9D2 (MKSR-1–MKSR-2) heterodimer within the MKS module.

What is NOT known

No molecular-function GO term captures what MKSR-1 does. It is a structural/scaffold subunit of the TZ MKS module (diffusion-barrier / Y-link scaffold). GO has no "structural constituent of the ciliary transition zone" MF term; structural molecule activity (GO:0005198) is the closest placeholder. (Ontology gap — shared across MKS/NPHP-module genes; cf. the mks-2 review.)
Whether the predicted C2/B9 Ca2+/lipid-binding activity is real for MKSR-1 (no direct biochemical assay).
MKSR-1's direct binding partners beyond MKSR-2 in the worm TZ, and its precise position within the MKS-module architecture (super-resolution / proteomics not resolved for MKSR-1 specifically).
Whether MKSR-1 has any non-redundant sub-function distinct from the other core MKS-module proteins (single mutants near-normal structurally; phenotypes emerge in nphp double mutants), though the single-mutant gate leak (RPI-2/TRAM-1a) indicates at least some non-fully-redundant barrier contribution.

Annotation review plan (summary)

GO term	Evid	Ref	Planned action
GO:0036038 MKS complex (part_of)	IBA	GO_REF:0000033	ACCEPT (core; corroborated by direct imaging/genetics)
GO:0060271 cilium assembly (involved_in)	IBA	GO_REF:0000033	MODIFY → GO:1905515 non-motile cilium assembly (worm sensory cilia are non-motile; more specific)
GO:0005929 cilium (located_in)	IEA	GO_REF:0000117	MODIFY → GO:0035869 ciliary transition zone (specific; IDA-supported) / or KEEP_AS_NON_CORE
GO:0005515 protein binding (enables) ×3	IPI	PMID:14704431 / 19123269 / 18337471	KEEP_AS_NON_CORE (real MKSR-1–MKSR-2 interaction; uninformative term; do not remove experimental IPI)
GO:1905515 non-motile cilium assembly (involved_in) ×2	IGI	PMID:18337471 / 21422230	ACCEPT (core, redundant module function)
GO:1904491 protein localization to ciliary transition zone (involved_in) ×2	IMP	PMID:26595381 / 21422230	ACCEPT (PMID:21422230 shows MKSR-1 required for MKS-6/MKS-3 TZ localization; PMID:26595381 abstract-only, defer to curator)
GO:0035869 ciliary transition zone (located_in)	IDA	PMID:21422230	ACCEPT (core CC; direct imaging)
GO:0008340 determination of adult lifespan (involved_in) ×4	IGI	PMID:19208769	KEEP_AS_NON_CORE (indirect insulin-IGF phenotype in double mutants; not a core function)
GO:0008104 intracellular protein localization (involved_in)	IMP	PMID:18337471	MODIFY → GO:1904491 (the specific process is protein localization to the TZ)
GO:0035177 larval foraging behavior (involved_in)	IGI	PMID:18337471	KEEP_AS_NON_CORE (downstream sensory-cilium behavior; curator full-text judgment; abstract-only cache)

Proposed NEW: GO:1903565 negative regulation of protein localization to cilium (ciliary gate; RPI-2/TRAM-1a/MKS-3 exclusion) — mirrors mks-2 review, directly supported in the mksr-1 single mutant.

Deep research

Falcon deep research launched via just deep-research-falcon worm mksr-1 --fallback perplexity-lite. The wrapper reported a 600s timeout and the perplexity-lite fallback failed with a 401 quota error, but the underlying falcon (Edison) client actually completed at 1120s and wrote a genuine 50KB report (mksr-1-deep-research-falcon.md, 32 citations, artifacts folder). I read it: it independently confirms MKSR-1 = B9D1, a soluble single-B9-domain protein, obligate B9 complex with MKS-1/MKSR-2, TZ/basal-body localization and MKS-module/ciliopathy role — fully consistent with this review. It cites some additional non-cached sources (okazaki2020, zhang2010); I did NOT add those as citations since they are not in the publications cache and the review is anchored to verified cached PMIDs. This is a genuine late falcon file (kept per ground rules).
Review grounded primarily on cached primary literature (PMID:21422230 full text; PMID:19208769, 18337471, 26595381 abstracts) and UniProt/GOA.

📄 View Raw YAML

id: Q21191
gene_symbol: mksr-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  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.
existing_annotations:
  - term:
      id: GO:0036038
      label: MKS complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: part_of
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6
  - term:
      id: GO:0060271
      label: cilium assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      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.
      action: MODIFY
      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.
      proposed_replacement_terms:
        - id: GO:1905515
          label: non-motile cilium assembly
      propagation_review:
        root_cause: TERM_SCOPING_PROBLEM
        failure_modes:
          - GRANULARITY_MISMATCH
        source_entities:
          - source_id: PANTHER:PTN000311628
            source_label: PANTHER PTHR12968 B9 domain-containing family node
            source_status: SUPPORTS_TRANSFER
            comment: >-
              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.
      supported_by:
        - reference_id: PMID:18337471
          supporting_text: >-
            regulate the formation and/or maintenance of cilia and dendrites in the
            amphid and phasmid ciliated sensory neurons
  - term:
      id: GO:0005929
      label: cilium
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    qualifier: located_in
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0035869
          label: ciliary transition zone
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            This is evident for MKS-1, MKS-1 related-1 (MKSR-1)/B9D1
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14704431
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19123269
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            MKS/MKSR module ... consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IGI
    original_reference_id: PMID:18337471
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:18337471
          supporting_text: >-
            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
  - term:
      id: GO:1904491
      label: protein localization to ciliary transition zone
    evidence_type: IMP
    original_reference_id: PMID:26595381
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:26595381
          supporting_text: >-
            TZ-localized MKS module by organizing recruitment of the ciliopathy
            proteins
  - term:
      id: GO:1904491
      label: protein localization to ciliary transition zone
    evidence_type: IMP
    original_reference_id: PMID:21422230
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            disrupting MKSR-1, MKSR-2, or MKS-5 results in TZ delocalization of MKS-6
        - reference_id: PMID:21422230
          supporting_text: >-
            MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane
  - term:
      id: GO:1905515
      label: non-motile cilium assembly
    evidence_type: IGI
    original_reference_id: PMID:21422230
    qualifier: involved_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            Phenotypes nearly identical to mks-6;nphp-4 mutants were observed in the
            mksr-1;nphp-4 strain
  - term:
      id: GO:0035869
      label: ciliary transition zone
    evidence_type: IDA
    original_reference_id: PMID:21422230
    qualifier: located_in
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            This is evident for MKS-1, MKS-1 related-1 (MKSR-1)/B9D1
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IGI
    original_reference_id: PMID:19208769
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:19208769
          supporting_text: >-
            increased lifespan phenotype, which is due to abnormal insulin-IGF-I
            signaling
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18337471
    qualifier: enables
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:18337471
          supporting_text: >-
            the C. elegans B9 proteins form a complex that localizes to the base of
            cilia
  - term:
      id: GO:0008104
      label: intracellular protein localization
    evidence_type: IMP
    original_reference_id: PMID:18337471
    qualifier: involved_in
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:1904491
          label: protein localization to ciliary transition zone
      supported_by:
        - reference_id: PMID:18337471
          supporting_text: >-
            the C. elegans B9 proteins form a complex that localizes to the base of
            cilia
  - term:
      id: GO:0035177
      label: larval foraging behavior
    evidence_type: IGI
    original_reference_id: PMID:18337471
    qualifier: involved_in
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:18337471
          supporting_text: >-
            regulate the formation and/or maintenance of cilia and dendrites in the
            amphid and phasmid ciliated sensory neurons
  - term:
      id: GO:1903565
      label: negative regulation of protein localization to cilium
    evidence_type: IMP
    original_reference_id: PMID:21422230
    qualifier: involved_in
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:21422230
          supporting_text: >-
            accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and
            nphp-4 mutants
        - reference_id: PMID:21422230
          supporting_text: >-
            TZ proteins normally function to maintain a boundary at the cilium base,
            establishing the TZ as a bona fide ciliary gate
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: PMID:14704431
    title: A map of the interactome network of the metazoan C. elegans.
    findings: []
    reference_review:
      relevance: MEDIUM
      correctness: VERIFIED
      review_notes: >-
        Li et al 2004 (Science), the large-scale C. elegans yeast two-hybrid
        interactome map. Source (via IntAct) of an MKSR-1-MKSR-2 (Q21191-Q9N423)
        binary interaction underlying an IPI 'protein binding' annotation. Cached
        record is abstract-only; the specific interaction is corroborated by the
        UniProt binary-interaction record (NbExp=3) and by the independent
        interactome study PMID:19123269. Interaction is real but the GO term it
        supports is uninformative.
  - id: PMID:18337471
    title: Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis
      elegans ciliogenesis.
    findings:
      - statement: >-
          The C. elegans B9 proteins (MKS-1/MKSR-1/MKSR-2) form a complex at the base
          of cilia and function redundantly with the nephrocystins (nph-1/nph-4);
          B9-gene mutations do not overtly affect cilia unless combined with a nph
          mutation.
        supporting_text: >-
          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
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        Williams et al 2008 (Mol Biol Cell). Establishes B9-protein/nephrocystin
        redundancy in worm ciliogenesis and the B9 complex at the ciliary base;
        source of the IGI non-motile-cilium-assembly, larval-foraging, IMP protein
        localization, and one IPI annotation. Cached record is abstract-only; uses the
        older names XBX-7/TZA-1/TZA-2 for the B9 proteins (TZA-2 = B9D1 = mksr-1),
        while the annotations use current WormBase naming.
  - id: PMID:19123269
    title: Empirically controlled mapping of the Caenorhabditis elegans protein-protein
      interactome network.
    findings: []
    reference_review:
      relevance: MEDIUM
      correctness: VERIFIED
      review_notes: >-
        Simonis et al 2009 (Nat Methods), the empirically-controlled C. elegans
        interactome (Worm Interactome 2007). Independent source (via IntAct) of the
        MKSR-1-MKSR-2 binary interaction supporting an IPI 'protein binding'
        annotation. Real interaction, uninformative GO term.
  - id: PMID:19208769
    title: Functional interactions between the ciliopathy-associated Meckel syndrome
      1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.
    findings:
      - statement: >-
          The B9 domain defines a family of three proteins (MKS-1, MKSR-1, MKSR-2) in
          ciliated organisms; all three localize co-dependently to transition
          zones/basal bodies of C. elegans sensory cilia. Double mks/mksr mutants show
          an increased-lifespan phenotype due to abnormal insulin-IGF-I signaling.
        supporting_text: >-
          increased lifespan phenotype, which is due to abnormal insulin-IGF-I
          signaling
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        Bialas et al 2009 (J Cell Sci); the paper that named MKSR-1/MKSR-2 and
        established the B9 family, co-dependent TZ/basal-body localization, and the
        insulin-IGF-I-dependent lifespan phenotype of double mutants. Source of the
        determination-of-adult-lifespan IGI annotations. Cached record is
        abstract-only.
  - 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: >-
          MKSR-1/B9D1 localizes to the ciliary transition zone and is a member of the
          MKS/MKSR module (with MKS-1, MKSR-2, MKS-3, MKS-6); the mksr-1;nphp-4 double
          mutant disrupts TZ membrane anchoring and Y-links.
        supporting_text: >-
          Phenotypes nearly identical to mks-6;nphp-4 mutants were observed in the
          mksr-1;nphp-4 strain
      - statement: >-
          MKSR-1 is required for the transition-zone localization of other MKS-module
          proteins (MKS-6 and MKS-3), restricting MKS-3 to the TZ membrane.
        supporting_text: >-
          MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane
      - statement: >-
          MKSR-1 contributes to ciliary-gate function; in mksr-1 mutants the
          normally-excluded membrane proteins TRAM-1a and RPI-2 accumulate inside
          cilia.
        supporting_text: >-
          accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and
          nphp-4 mutants
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        Williams et al 2011 (J Cell Biol); full text cached and MKSR-1 is extensively
        assayed (TZ localization, mksr-1;nphp-4 TEM phenotype, requirement for MKS-6/
        MKS-3 TZ localization, and ciliary-gate leak of TRAM-1a/RPI-2/MKS-3). Anchors
        the IDA TZ localization, the IMP/IGI cilium-assembly and protein-localization
        annotations, and the NEW ciliary-gate annotation.
  - 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 ciliopathy proteins to
          subdomains of the ciliary transition zone; MKS-module membrane proteins are
          immobile and periodically arranged within the TZ.
        supporting_text: >-
          TZ-localized MKS module by organizing recruitment of the ciliopathy
          proteins
    reference_review:
      relevance: MEDIUM
      correctness: VERIFIED
      review_notes: >-
        Lambacher et al 2016 (Nat Cell Biol). Cached record is abstract-only; the
        abstract supports the MKS-module TZ recruitment/architecture framing. The
        WormBase IMP for MKSR-1 protein-localization-to-TZ draws on the full text;
        deferring to the curator for that experimental evidence.
core_functions:
  - description: >-
      MKSR-1/B9D1 acts as a structural/scaffolding subunit of the MKS module of the
      ciliary transition zone. As a soluble B9/C2-domain protein it localizes to the
      TZ (dependent on MKS-5) and contributes to assembly and integrity of the TZ
      (Y-link connectors and basal body/TZ membrane anchoring) and to the ciliary
      gate - the membrane diffusion barrier that restricts non-ciliary membrane
      proteins (e.g. TRAM-1a, RPI-2) from entering the cilium. It is required to
      recruit/retain other MKS-module proteins (MKS-6, MKS-3) at the TZ and forms a
      heterodimer with MKSR-2/B9D2. There is no GO molecular-function term that
      precisely describes a transition-zone diffusion-barrier scaffold subunit;
      'structural molecule activity' is used here as the closest available placeholder.
    molecular_function:
      id: GO:0005198
      label: structural molecule activity
    in_complex:
      id: GO:0036038
      label: MKS complex
    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
      - id: GO:1903565
        label: negative regulation of protein localization to cilium
    supported_by:
      - reference_id: PMID:21422230
        supporting_text: >-
          MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane
      - reference_id: PMID:21422230
        supporting_text: >-
          accumulates within cilia of mksr-1, mksr-2, mks-5, mks-6, nphp-1, and
          nphp-4 mutants
knowledge_gaps:
  - gap_statement: >-
      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.
    boundary: >-
      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.
    gap_kind:
      - ONTOLOGY
      - CURATION
    dark_aspect: MF_DARK
    status: OPEN
    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.
    resolution: >-
      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:
      - reference_id: PMID:21422230
        supporting_text: >-
          MKSR-1, MKSR-2, and MKS-5 restrict MKS-3 to the TZ membrane
        reference_section_type: RESULTS
    proposed_terms:
      - proposed_name: structural constituent of ciliary transition zone
        proposed_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.
        proposed_parent:
          id: GO:0005198
          label: structural molecule activity
  - gap_statement: >-
      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.
    boundary: >-
      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.
    gap_kind:
      - BIOLOGY
    dark_aspect: RESIDUAL_SUBGAP
    status: OPEN
    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.
    resolution: >-
      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:
      - reference_id: PMID:21422230
        supporting_text: >-
          This motif is predicted to bind Ca2+/lipids and participate—similar to
          synaptotagmin—in membrane/vesicle trafficking and fusion
        reference_section_type: RESULTS
proposed_new_terms:
  - proposed_name: structural constituent of ciliary transition zone
    proposed_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.
    proposed_parent:
      id: GO:0005198
      label: structural molecule activity
suggested_questions:
  - question: >-
      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?
    experts: []
  - question: >-
      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?
    experts: []
suggested_experiments:
  - description: >-
      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.
  - description: >-
      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.
tags:
  - caeel-ciliopathy

mksr-1

Gene Description

Proposed New Ontology Terms

structural constituent of ciliary transition zone

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Tags

Deep Research

Falcon

Comprehensive Research Report: mksr-1 (B9 Domain-Containing Protein 1) in Caenorhabditis elegans

1. Gene and Protein Identity

2. Structural and Domain Features

3. Primary Function: Structural Component of the Ciliary Transition Zone Gate

3.1 The Transition Zone as a Ciliary Gate

3.2 The B9 Protein Complex as a Diffusion Barrier

3.3 Recent Advances: B9 Complex Interactions with TMEM67 and Microtubule Modifications

4. Subcellular Localization

5. Transition Zone Assembly Hierarchy and Module Architecture

6. Genetic Interactions and Functional Redundancy

7. Role in Ciliary Signaling and the Ciliary Zone of Exclusion (CIZE)

8. Evolutionary Conservation and Disease Relevance

9. Summary

Artifacts

Citations

📚 Additional Documentation

Notes

mksr-1 (K03E6.4 / WBGene00019364 / Q21191) — research notes

Identity

Nomenclature caution

What is KNOWN

Family, domain, evolution

Localization (experimental)

The MKS module / complex

Function: transition-zone assembly / Y-links / membrane anchoring

Function: ciliary gate / diffusion barrier

Redundancy / single-mutant subtlety

Lifespan / insulin-IGF phenotype

Larval foraging behavior

Protein interactions

What is NOT known

Annotation review plan (summary)

Deep research

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