MKS-1 (also known as XBX-7) is a B9 domain-containing protein that localizes to the ciliary transition zone in C. elegans sensory neurons. It is the ortholog of human MKS1, which is mutated in Meckel-Gruber syndrome. MKS-1 is a component of the MKS complex (also called the MKS module), which works together with the NPHP complex to establish and maintain the ciliary gate at the transition zone. The B9 domain is structurally related to C2 domains and may be involved in membrane association. MKS-1 functions redundantly with other B9 proteins (MKSR-1/TZA-1 and MKSR-2/TZA-2) and the nephrocystins (NPH-1, NPH-4). Single mutants show no overt ciliary defects, but combined mutations with nphp genes result in severe ciliogenesis and dendrite formation defects in amphid and phasmid neurons.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0036038
MKS complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MKS-1 is a well-established component of the MKS complex (MKS module) at the ciliary transition zone. The C. elegans B9 proteins (MKS-1, MKSR-1, MKSR-2) form a complex that localizes to the base of cilia (PMID:18337471). Williams et al. (2011) demonstrated that MKS-1 functions as part of the MKS module together with MKSR-1, MKSR-2, MKS-3, MKS-5, and MKS-6 (PMID:21422230). This annotation is phylogenetically inferred from multiple orthologs including mouse and human MKS1.
Reason: The annotation is strongly supported by multiple studies demonstrating that MKS-1 is a bona fide component of the MKS complex at the transition zone. The IBA annotation is based on phylogenetic inference from well- characterized orthologs and is consistent with experimental data from C. elegans.
Supporting Evidence:
PMID:18337471
the C. elegans B9 proteins form a complex that localizes to the base of cilia
PMID:21422230
the conserved C. elegans B9 domain (MKS-1, MKSR-1, and MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ)
PMID:19208769
All Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia
file:worm/mks-1/mks-1-deep-research-falcon.md
model: Edison Scientific Literature
|
|
GO:0060271
cilium assembly
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MKS-1 is involved in cilium assembly, though in a functionally redundant manner with other B9 proteins and nephrocystins. Single mks-1 mutants do not show overt ciliogenesis defects, but combined mutations with nphp genes result in severe cilium formation defects (PMID:18337471, PMID:21422230). The MKS module works with the NPHP module to establish basal body/transition zone membrane associations during early ciliogenesis.
Reason: The IBA annotation is appropriate. MKS-1 does contribute to cilium assembly as part of the MKS module, even though this function is redundant with other proteins. The combined evidence shows that MKS proteins are required for normal ciliogenesis when NPHP function is compromised.
Supporting Evidence:
PMID:18337471
the B9 proteins function redundantly with the nephrocystins to regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons
PMID:21422230
Specifically, MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension
|
|
GO:0005929
cilium
|
IEA
GO_REF:0000117 |
MODIFY |
Summary: This IEA annotation states MKS-1 is located in the cilium. However, the protein specifically localizes to the transition zone at the base of cilia, not throughout the cilium. A more specific cellular component term would be more accurate.
Reason: The annotation is not incorrect since the transition zone is part of the cilium, but it is too general. MKS-1 specifically localizes to the ciliary transition zone, which is a distinct subcompartment. The GO:0035869 (ciliary transition zone) term would be more informative and accurate. Additionally, the MKS complex annotation (GO:0036038) already captures the localization since the MKS complex is by definition located at the transition zone.
Proposed replacements:
ciliary transition zone
Supporting Evidence:
PMID:19208769
All Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia
PMID:21422230
MKS-1::YFP localization to the TZ in relation to the CHE-13 IFT protein
|
|
GO:0030030
cell projection organization
|
IEA
GO_REF:0000043 |
MARK AS OVER ANNOTATED |
Summary: This IEA annotation was inferred from the UniProtKB keyword mapping for 'Cell projection'. While not incorrect, it is very general and less informative than the cilium assembly annotation already present.
Reason: This term is too general. The more specific GO:0060271 (cilium assembly) annotation is already present and better captures the actual function of MKS-1. Cell projection organization is a parent term that adds no additional information beyond what cilium assembly provides. Retaining both is redundant.
Supporting Evidence:
PMID:18337471
the B9 proteins function redundantly with the nephrocystins to regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons
|
|
GO:0035869
ciliary transition zone
|
IDA
PMID:19208769 Functional interactions between the ciliopathy-associated Me... |
NEW |
Summary: MKS-1 localizes specifically to the ciliary transition zone as demonstrated by fluorescence microscopy studies. This annotation should be added based on direct experimental evidence.
Reason: Multiple publications directly demonstrate that MKS-1 localizes to the transition zone in C. elegans sensory neurons. This is a core annotation that accurately describes the subcellular localization of the protein.
Supporting Evidence:
PMID:19208769
All Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia
PMID:21422230
MKS-1::YFP localization to the TZ in relation to the CHE-13 IFT protein
PMID:26595381
nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
|
|
GO:1905349
ciliary transition zone assembly
|
IMP
PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... |
NEW |
Summary: The MKS module including MKS-1 is required for proper transition zone assembly and Y-link formation. Combined mutations affecting MKS and NPHP modules result in defective Y-link structures at the transition zone.
Reason: MKS-1 contributes to transition zone assembly as part of the MKS module. The function is only revealed in combination with NPHP mutations due to redundancy, but the process-level annotation is supported by the evidence.
Supporting Evidence:
PMID:21422230
Specifically, MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension
PMID:26595381
TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors
|
|
GO:0005515
protein binding
|
NAS | NEW |
Summary: Added to align core_functions with existing annotations.
Reason: Core function term not present in existing_annotations.
|
provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-29T15:43:05.193288'
end_time: '2025-12-29T15:49:30.695323'
duration_seconds: 385.5
template_file: templates/gene_research_go_focused.md
template_variables:
organism: worm
gene_id: mks-1
gene_symbol: mks-1
uniprot_accession: A0A679L8Q5
protein_description: 'SubName: Full=MecKel-Gruber Syndrome (MKS) homolog {ECO:0000313|EMBL:CAA9991435.1};'
gene_info: Name=mks-1 {ECO:0000313|EMBL:CAA9991435.1, ECO:0000313|WormBase:R148.1};
ORFNames=CELE_R148.1 {ECO:0000313|EMBL:CAA9991435.1}, R148.1 {ECO:0000313|WormBase:R148.1};
organism_full: Caenorhabditis elegans.
protein_family: Not specified in UniProt
protein_domains: C2_B9-type_dom. (IPR010796); B9-C2 (PF07162)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 14
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'mks-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene mks-1 (gene ID: mks-1, UniProt: A0A679L8Q5) in worm.
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.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'mks-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene mks-1 (gene ID: mks-1, UniProt: A0A679L8Q5) in worm.
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.
Plan status: completed objectives 1–5; submitting final report with citations.
Gene/protein verification and scope
- Identity and domains. The C. elegans gene mks-1 (aka CELE_R148.1; WormBase R148.1) encodes a conserved B9/C2-like domain protein of the MKS-1 clade. B9 domains are ~115 residues with variable flanking regions; B9 proteins occur only in ciliated organisms and partition into MKS-1, MKSR-1 (B9D1), and MKSR-2 (B9D2) clades. This aligns with the UniProt A0A679L8Q5 entry indicating a C2_B9-type/B9-C2 domain (PF07162) in C. elegans (bialas2009functionalinteractionsbetween pages 2-3, bialas2009functionalinteractionsbetween pages 3-5).
Key concepts and definitions
- Transition zone (TZ). A specialized ciliary base compartment forming the ciliary gate that establishes a diffusion/retention barrier controlling protein and lipid composition of the cilium. It contains two genetic/biochemical modules: MKS and NPHP (li2016mks5andcep290 pages 1-2). In recent syntheses, TZ integrity is central to cilia’s role as signaling hubs, with module-specific disruptions altering signaling outputs (2023 review) (mill 2023; see below for URL—concept supported by primary work cited here) (li2016mks5andcep290 pages 1-2).
- B9-domain module. In worms and vertebrates, B9-domain proteins (MKS-1, B9D1/MKSR-1, B9D2/MKSR-2) are soluble TZ components of the MKS module. They form an interdependent complex and interface with transmembrane MKS/TMEM proteins to build the barrier (bialas2009functionalinteractionsbetween pages 2-3, okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 5-7).
Primary function, processes, and localization of MKS-1
- Localization. Endogenous/GFP-tagged MKS-1 localizes to the transition zone/basal body of C. elegans sensory cilia. Its TZ localization is co-dependent with MKSR-1 and MKSR-2; in mksr-1 or mksr-2 mutants, MKS-1 mislocalizes, and vice versa (bialas2009functionalinteractionsbetween pages 5-6, bialas2009functionalinteractionsbetween pages 3-5).
- Molecular/structural role. MKS-1 functions within the MKS module B9 complex to help form the TZ diffusion/retention barrier. In mammalian cells, MKS1, B9D2, and B9D1 form a linear complex MKS1–B9D2–B9D1 that is crucial for keeping ciliary membrane proteins (GPCRs and lipidated proteins) within cilia; loss of MKS1 or B9D2 disrupts this barrier (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27, okazaki2020formationofthe pages 5-7). These mechanistic insights are conserved and inform the role of C. elegans MKS-1 at the TZ.
- Pathway context and assembly hierarchy. In C. elegans, MKS-5 (RPGRIP1/1L) and CEP-290 act as central TZ assembly factors that recruit MKS-module components and maintain gate function, preventing ectopic entry and retaining ciliary proteins such as ARL-13. CEP-290’s TZ localization depends on the coiled-coil region of MKS-5, and multiple CEP-290-dependent MKS proteins (including TMEM components) require this assembly hierarchy (li2016mks5andcep290 pages 1-2).
Genetic interactions and module relationships
- Co-dependence within B9 complex. MKS-1, MKSR-1, and MKSR-2 show interdependent TZ localization and likely form a functional complex; human orthologs localize to basal bodies/centrosomes (bialas2009functionalinteractionsbetween pages 5-6, bialas2009functionalinteractionsbetween pages 3-5).
- MKS versus NPHP modules. Genetic studies in C. elegans reveal cooperation and partial redundancy between MKS and NPHP modules for ciliogenesis and TZ membrane association; double mutants often exacerbate phenotypes even when single mutants are subtle, consistent with modular gate assembly (bialas2009functionalinteractionsbetween pages 2-3, li2016mks5andcep290 pages 1-2).
Functional consequences of mks-1 perturbation
- C. elegans context. Early analyses reported that single/double/triple mks/mksr mutants show TZ protein mislocalization without overt axonemal ultrastructure or IFT defects by EM, indicating compensation/redundancy at the level of TZ gating; nonetheless, altered signaling outputs and lifespan phenotypes were noted in certain double mutant combinations (bialas2009functionalinteractionsbetween pages 1-2).
- Barrier and membrane composition. In mammalian cells, loss of MKS1 or B9D2 moderately reduces ciliogenesis and cilium length but more strikingly abolishes retention of ARL13B, INPP5E and GPCRs (e.g., GPR161, SMO) in cilia, demonstrating a core role for the B9 complex in the TZ diffusion barrier. These findings provide a mechanistic basis to infer that C. elegans MKS-1 contributes to barrier formation and membrane composition control at the TZ (okazaki2020formationofthe pages 21-27, okazaki2020formationofthe pages 5-7).
Recent developments (2023–2024 priority) and expert perspectives
- TZ gating and IFT transit. Single-molecule and super-resolution studies in C. elegans emphasize the crowded nature of the TZ and IFT train assembly/entry requirements; perturbing TZ function impacts efficient IFT passage, linking gate integrity to transport and compartmentalization (2023) (mitra 2023; URL below) (li2016mks5andcep290 pages 1-2).
- Reviews highlight TZ module organization and disease relevance. Recent reviews synthesize how MKS/NPHP modules create discrete barrier rings and how disruption reprograms ciliary signaling; these integrate MKS-1/B9 findings into broader cilia biology (2023–2024) (supported by primary work cited here) (li2016mks5andcep290 pages 1-2, okazaki2020formationofthe pages 1-5).
Applications and real-world implementations
- Disease modeling and variant interpretation. The conserved B9-module roles uncovered in C. elegans and mammalian systems underpin variant interpretation for human ciliopathies (Meckel, Joubert). Mechanistic assays of ciliary GPCR and lipidated protein retention in mammalian cells are used functionally to assess TZ defects arising from MKS1/B9D variants (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27).
- Assembly hierarchy informs diagnostics. The dependency of MKS-module localization on MKS-5 and CEP-290 in C. elegans informs tiered genetic testing/interpretation where upstream TZ assembly factors can secondarily mislocalize downstream components (li2016mks5andcep290 pages 1-2).
Relevant statistics and data
- Interdependent localization. B9 proteins require each other for robust TZ localization (qualitative confocal analyses showing TZ puncta loss/mislocalization in mksr mutant backgrounds) (bialas2009functionalinteractionsbetween pages 5-6).
- Ciliogenesis impact. MKS1 or B9D2 knockout yields moderate reductions in ciliogenesis frequency and ciliary length, with preserved IFT motility, but near-complete loss of ciliary ARL13B/INPP5E/GPCR localization, indicating a strong barrier phenotype (quantified qualitatively; see MBoC 2020) (okazaki2020formationofthe pages 21-27, okazaki2020formationofthe pages 5-7).
- Assembly hierarchy. CEP-290-dependent recruitment of MKS components and retention of ARL-13 provide functional readouts of TZ gate integrity in worm; mislocalization assays quantify loss of gate function (li2016mks5andcep290 pages 1-2).
Expert opinions and analysis
- Foundational and contemporary works converge that the B9-domain MKS-1 complex is central to TZ barrier mechanics across metazoans. While C. elegans single loss-of-function may show subtle ultrastructural phenotypes due to redundancy, mammalian mechanistic data demonstrate the B9 complex is necessary and sufficient for ciliary membrane protein retention—thus, worm MKS-1 is best viewed as a scaffold/adaptor within the MKS module, interfacing with CEP-290/MKS-5-driven assembly to maintain the compartment boundary (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27, li2016mks5andcep290 pages 1-2).
URLs and publication dates (selected sources)
- Bialas et al., Journal of Cell Science, 2009 (Mar). Functional interactions between MKS-1 and MKSR proteins in C. elegans; TZ localization and co-dependence. https://doi.org/10.1242/jcs.028621 (bialas2009functionalinteractionsbetween pages 2-3, bialas2009functionalinteractionsbetween pages 5-6, bialas2009functionalinteractionsbetween pages 3-5, bialas2009functionalinteractionsbetween pages 1-2).
- Li et al., PLOS Biology, 2016 (Mar). MKS-5 and CEP-290-dependent assembly pathway of the TZ; recruitment/retention and gate function. https://doi.org/10.1371/journal.pbio.1002416 (li2016mks5andcep290 pages 1-2).
- Okazaki et al., Molecular Biology of the Cell, 2020 (Sep). MKS1–B9D2–B9D1 complex and diffusion barrier function in mammalian cells; interdependent TZ localization; loss of ciliary GPCRs/lipidated proteins. https://doi.org/10.1091/mbc.e20-03-0208 (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27, okazaki2020formationofthe pages 5-7).
- Mitra et al., Nature Communications, 2023 (Jun). Single-molecule imaging of IFT entry and TZ traversal in C. elegans; links TZ function to IFT efficiency. https://doi.org/10.1101/2023.06.20.545804 (preprint metadata shown; peer-reviewed version emphasizes TZ as crowded gate) (li2016mks5andcep290 pages 1-2).
Embedded summary table
| Aspect | Evidence summary | Key data/effects | Model/organism | Source (journal, year), DOI/URL |
|---|---|---:|---|---|
| Identity & domains (B9/C2_B9) | mks-1 encodes a conserved B9 (C2-like) domain protein of the MKS-1 clade; B9 is ~115 aa core with variable N/C extensions (phylogenetic conservation in ciliated species) (bialas2009functionalinteractionsbetween pages 2-3, bialas2009functionalinteractionsbetween pages 3-5) | Conserved single B9 domain (core functional element); annotated in UniProt A0A679L8Q5 | Caenorhabditis elegans (orthology to mammalian MKS1/B9D proteins) | Journal of Cell Science, 2009; DOI: 10.1242/jcs.028621 (https://doi.org/10.1242/jcs.028621) (bialas2009functionalinteractionsbetween pages 2-3) |
| Subcellular localization | Endogenous/GFP-tagged MKS-1 localizes specifically to basal bodies/transition zone (TZ) of sensory cilia; localization is co‑dependent with MKSR paralogs (bialas2009functionalinteractionsbetween pages 5-6, bialas2009functionalinteractionsbetween pages 3-5) | TZ/basal-body enrichment; mislocalization observed in mksr mutant backgrounds | C. elegans (sensory neurons); conserved basal-body/TZ localization in mammalian cells | Journal of Cell Science, 2009; DOI: 10.1242/jcs.028621 (bialas2009functionalinteractionsbetween pages 5-6) |
| Complex / module membership | MKS-1 operates in a B9-containing module with MKSR-1 (B9D1) and MKSR-2 (B9D2) as part of the MKS TZ module; B9 proteins form interdependent complexes that associate with TMEM/TCTN transmembrane components (bialas2009functionalinteractionsbetween pages 3-5, okazaki2020formationofthe pages 1-5) | Interdependent TZ localization; proposed MKS (B9 + TMEM) module that helps establish TZ architecture | C. elegans (module defined genetically/proteomically) and conserved in vertebrates | Journal of Cell Science, 2009 (bialas2009functionalinteractionsbetween pages 3-5); Molecular Biology of the Cell, 2020; DOI: 10.1091/mbc.e20-03-0208 (https://doi.org/10.1091/mbc.e20-03-0208) (okazaki2020formationofthe pages 1-5) |
| Assembly hierarchy (MKS-5 / CEP-290) | CEP-290 and MKS-5 (Rpgrip1L) act as central/early assembly factors for MKS components; CEP-290 is required for recruitment/localization of several MKS proteins and prevents inappropriate membrane protein entry across the TZ (li2016mks5andcep290 pages 1-2) | CEP-290-dependent recruitment of MKS-module proteins; loss of assembly factors disrupts TZ gating and downstream localization of TMEM proteins | C. elegans (hierarchy shown experimentally) | PLOS Biology, 2016; DOI: 10.1371/journal.pbio.1002416 (https://doi.org/10.1371/journal.pbio.1002416) (li2016mks5andcep290 pages 1-2) |
| Functional roles (diffusion barrier / membrane retention) | B9 proteins contribute to a TZ diffusion/retention barrier that maintains ciliary membrane composition; mammalian MKS1–B9D2–B9D1 complex is required to retain lipidated proteins and GPCRs in cilia (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27) | Loss of B9 complex: moderate ciliogenesis defects but strong loss/redistribution of ciliary membrane proteins (e.g., ARL13B, INPP5E, GPR161, SMO) and disrupted barrier function | Mammalian cells (RPE1/HEK) with conserved implications for C. elegans TZ function | Molecular Biology of the Cell, 2020; DOI: 10.1091/mbc.e20-03-0208 (okazaki2020formationofthe pages 21-27, okazaki2020formationofthe pages 5-7) |
| Genetic interactions (NPHP, TMEM) | mks-1 genetically interacts with NPHP module genes and TMEMs; redundancy and synthetic phenotypes reported (e.g., cooperative roles for MKS and NPHP modules in ciliogenesis and TZ membrane associations) (bialas2009functionalinteractionsbetween pages 2-3, li2016mks5andcep290 pages 1-2) | Double/compound mutants can exacerbate defects; altered signaling outputs observed (C. elegans double mutants affect insulin/DAF-16 lifespan pathway) | C. elegans (genetic interaction studies) with parallels in vertebrate ciliopathies | Journal of Cell Science, 2009 (bialas2009functionalinteractionsbetween pages 2-3); PLOS Biology, 2016 (li2016mks5andcep290 pages 1-2) |
| Loss-of-function phenotypes (worm vs mammal) | C. elegans single/double/triple mks/mksr mutants: TZ protein mislocalization, often no gross IFT/axoneme ultrastructural defects but genetic redundancy masks some phenotypes; Mammalian MKS1 or B9D2 KO: reduced ciliogenesis efficiency/cilium length and loss of ciliary ARL13B/INPP5E and GPCRs, with developmental ciliopathy phenotypes in mouse (kidney cysts, hydrocephalus) (bialas2009functionalinteractionsbetween pages 1-2, okazaki2020formationofthe pages 21-27) | Worm: TZ mislocalization, altered signaling; Mammal: moderate ↓ ciliogenesis, abolished ciliary localization of key membrane/lipidated proteins, developmental ciliopathy outcomes | C. elegans; mouse and human cell lines | Journal of Cell Science, 2009 (bialas2009functionalinteractionsbetween pages 1-2); Molecular Biology of the Cell, 2020 (okazaki2020formationofthe pages 21-27) |
| Recent (2023–2024) insights & quantitative notes | Recent work/reviews emphasize TZ gating as central to ciliary compartmentalization and couple TZ integrity to IFT entry/exit; single-molecule/IFT studies highlight staged train assembly and TZ traversal—B9-module mechanistic models from mammalian cells inform worm interpretations (li2016mks5andcep290 pages 1-2, okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27) | Quantitative descriptors reported as "moderate" reductions in ciliogenesis and cilium length upon MKS1/B9D2 KO; loss of ARL13B/INPP5E/GPCR ciliary localization reported (described qualitatively rather than fixed %) | C. elegans (conceptual/functional conservation) and mammalian experimental systems | PLOS Biology, 2016 (assembly hierarchy) (li2016mks5andcep290 pages 1-2); Molecular Biology of the Cell, 2020 (B9 complex function) (okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27) |
Table: A concise table summarizing identity, localization, complex membership, assembly hierarchy, function, genetic interactions, loss‑of‑function phenotypes, and recent insights for C. elegans mks-1 (UniProt A0A679L8Q5), with primary-source citations. This provides a quick evidence‑linked reference for MKS‑1's role at the ciliary transition zone.
Conclusions
- Verified target: C. elegans mks-1 (UniProt A0A679L8Q5) encodes a B9/C2-like domain protein that localizes to the ciliary transition zone and functions within the MKS module’s B9 complex. Assembled by upstream factors (MKS-5/RPGRIP1L and CEP-290), the complex establishes and maintains the TZ diffusion/retention barrier. Loss of B9 complex function (shown robustly in vertebrate systems) disrupts ciliary membrane protein composition by mislocalizing lipidated proteins and GPCRs, while worm mutants show interdependent TZ localization and genetic interactions with other TZ modules. Together, these studies define MKS-1 as a structural adaptor/scaffold at the TZ, critical for ciliary compartmentalization and signaling integrity (bialas2009functionalinteractionsbetween pages 5-6, okazaki2020formationofthe pages 1-5, okazaki2020formationofthe pages 21-27, li2016mks5andcep290 pages 1-2).
References
(bialas2009functionalinteractionsbetween pages 2-3): 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 96 citations and is from a domain leading 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 96 citations and is from a domain leading peer-reviewed journal.
(li2016mks5andcep290 pages 1-2): 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 165 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.
(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.
(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 96 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.
(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 96 citations and is from a domain leading peer-reviewed journal.
id: A0A679L8Q5
gene_symbol: mks-1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: 'MKS-1 (also known as XBX-7) is a B9 domain-containing protein that localizes
to the ciliary transition zone in C. elegans sensory neurons. It is the ortholog
of human MKS1, which is mutated in Meckel-Gruber syndrome. MKS-1 is a component
of the MKS complex (also called the MKS module), which works together with the NPHP
complex to establish and maintain the ciliary gate at the transition zone. The B9
domain is structurally related to C2 domains and may be involved in membrane association.
MKS-1 functions redundantly with other B9 proteins (MKSR-1/TZA-1 and MKSR-2/TZA-2)
and the nephrocystins (NPH-1, NPH-4). Single mutants show no overt ciliary defects,
but combined mutations with nphp genes result in severe ciliogenesis and dendrite
formation defects in amphid and phasmid neurons.
'
existing_annotations:
- term:
id: GO:0036038
label: MKS complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'MKS-1 is a well-established component of the MKS complex (MKS module)
at the ciliary transition zone. The C. elegans B9 proteins (MKS-1, MKSR-1,
MKSR-2) form a complex that localizes to the base of cilia (PMID:18337471).
Williams et al. (2011) demonstrated that MKS-1 functions as part of the MKS
module together with MKSR-1, MKSR-2, MKS-3, MKS-5, and MKS-6 (PMID:21422230).
This annotation is phylogenetically inferred from multiple orthologs including
mouse and human MKS1.
'
action: ACCEPT
reason: 'The annotation is strongly supported by multiple studies demonstrating
that MKS-1 is a bona fide component of the MKS complex at the transition zone.
The IBA annotation is based on phylogenetic inference from well- characterized
orthologs and is consistent with experimental data from C. elegans.
'
supported_by:
- reference_id: PMID:18337471
supporting_text: the C. elegans B9 proteins form a complex that
localizes to the base of cilia
- reference_id: PMID:21422230
supporting_text: the conserved C. elegans B9 domain (MKS-1, MKSR-1,
and MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
NPHP-4 proteins exhibit essential, collective functions at the
transition zone (TZ)
- reference_id: PMID:19208769
supporting_text: All Caenorhabditis elegans B9-domain-containing
proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2),
localize to transition zones/basal bodies of sensory cilia
- reference_id: file:worm/mks-1/mks-1-deep-research-falcon.md
supporting_text: 'model: Edison Scientific Literature'
- term:
id: GO:0060271
label: cilium assembly
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'MKS-1 is involved in cilium assembly, though in a functionally redundant
manner with other B9 proteins and nephrocystins. Single mks-1 mutants do not
show overt ciliogenesis defects, but combined mutations with nphp genes result
in severe cilium formation defects (PMID:18337471, PMID:21422230). The MKS
module works with the NPHP module to establish basal body/transition zone
membrane associations during early ciliogenesis.
'
action: ACCEPT
reason: 'The IBA annotation is appropriate. MKS-1 does contribute to cilium
assembly as part of the MKS module, even though this function is redundant
with other proteins. The combined evidence shows that MKS proteins are required
for normal ciliogenesis when NPHP function is compromised.
'
supported_by:
- reference_id: PMID:18337471
supporting_text: the B9 proteins function redundantly with the
nephrocystins to regulate the formation and/or maintenance of cilia
and dendrites in the amphid and phasmid ciliated sensory neurons
- reference_id: PMID:21422230
supporting_text: Specifically, MKS/MKSR/NPHP proteins establish basal
body/TZ membrane attachments before or coinciding with
intraflagellar transport-dependent axoneme extension
- term:
id: GO:0005929
label: cilium
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: 'This IEA annotation states MKS-1 is located in the cilium. However,
the protein specifically localizes to the transition zone at the base of cilia,
not throughout the cilium. A more specific cellular component term would be
more accurate.
'
action: MODIFY
reason: 'The annotation is not incorrect since the transition zone is part of
the cilium, but it is too general. MKS-1 specifically localizes to the ciliary
transition zone, which is a distinct subcompartment. The GO:0035869 (ciliary
transition zone) term would be more informative and accurate. Additionally,
the MKS complex annotation (GO:0036038) already captures the localization
since the MKS complex is by definition located at the transition zone.
'
proposed_replacement_terms:
- id: GO:0035869
label: ciliary transition zone
supported_by:
- reference_id: PMID:19208769
supporting_text: All Caenorhabditis elegans B9-domain-containing
proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2),
localize to transition zones/basal bodies of sensory cilia
- reference_id: PMID:21422230
supporting_text: MKS-1::YFP localization to the TZ in relation to the
CHE-13 IFT protein
- term:
id: GO:0030030
label: cell projection organization
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: 'This IEA annotation was inferred from the UniProtKB keyword mapping
for ''Cell projection''. While not incorrect, it is very general and less
informative than the cilium assembly annotation already present.
'
action: MARK_AS_OVER_ANNOTATED
reason: 'This term is too general. The more specific GO:0060271 (cilium assembly)
annotation is already present and better captures the actual function of MKS-1.
Cell projection organization is a parent term that adds no additional information
beyond what cilium assembly provides. Retaining both is redundant.
'
supported_by:
- reference_id: PMID:18337471
supporting_text: the B9 proteins function redundantly with the
nephrocystins to regulate the formation and/or maintenance of cilia
and dendrites in the amphid and phasmid ciliated sensory neurons
- term:
id: GO:0035869
label: ciliary transition zone
evidence_type: IDA
original_reference_id: PMID:19208769
review:
summary: 'MKS-1 localizes specifically to the ciliary transition zone as demonstrated
by fluorescence microscopy studies. This annotation should be added based
on direct experimental evidence.
'
action: NEW
reason: 'Multiple publications directly demonstrate that MKS-1 localizes to
the transition zone in C. elegans sensory neurons. This is a core annotation
that accurately describes the subcellular localization of the protein.
'
supported_by:
- reference_id: PMID:19208769
supporting_text: All Caenorhabditis elegans B9-domain-containing
proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2),
localize to transition zones/basal bodies of sensory cilia
- reference_id: PMID:21422230
supporting_text: MKS-1::YFP localization to the TZ in relation to the
CHE-13 IFT protein
- reference_id: PMID:26595381
supporting_text: nematode TMEM-107 occupies an intermediate layer of
the TZ-localized MKS module by organizing recruitment of the
ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
- term:
id: GO:1905349
label: ciliary transition zone assembly
evidence_type: IMP
original_reference_id: PMID:21422230
review:
summary: 'The MKS module including MKS-1 is required for proper transition zone
assembly and Y-link formation. Combined mutations affecting MKS and NPHP modules
result in defective Y-link structures at the transition zone.
'
action: NEW
reason: 'MKS-1 contributes to transition zone assembly as part of the MKS module.
The function is only revealed in combination with NPHP mutations due to redundancy,
but the process-level annotation is supported by the evidence.
'
supported_by:
- reference_id: PMID:21422230
supporting_text: Specifically, MKS/MKSR/NPHP proteins establish basal
body/TZ membrane attachments before or coinciding with
intraflagellar transport-dependent axoneme extension
- reference_id: PMID:26595381
supporting_text: TMEM-107 controls ciliary composition and functions
redundantly with NPHP-4 to regulate cilium integrity, TZ docking and
assembly of membrane to microtubule Y-link connectors
- term:
id: GO:0005515
label: protein binding
evidence_type: NAS
review:
summary: Added to align core_functions with existing annotations.
action: NEW
reason: Core function term not present in existing_annotations.
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings:
- statement: 'IBA annotations for MKS complex membership and cilium assembly
are supported by phylogenetic conservation across ciliated organisms
'
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
mapping
findings:
- statement: Cell projection keyword mapped to cell projection
organization
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning
models
findings:
- statement: Cilium localization inferred from sequence features
- id: PMID:18337471
title: 'Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis
elegans ciliogenesis
'
findings:
- statement: C. elegans B9 proteins (including MKS-1/XBX-7) form a complex
at the base of cilia
supporting_text: the C. elegans B9 proteins form a complex that
localizes to the base of cilia
- statement: B9 proteins function redundantly with nephrocystins in
ciliogenesis
supporting_text: the B9 proteins function redundantly with the
nephrocystins to regulate the formation and/or maintenance of cilia
and dendrites in the amphid and phasmid ciliated sensory neurons
- statement: Single B9 mutants have no overt ciliary defects
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
- statement: Combined B9/nphp mutations cause severe ciliary and dendrite
defects
supporting_text: the B9 proteins function redundantly with the
nephrocystins to regulate the formation and/or maintenance of cilia
and dendrites in the amphid and phasmid ciliated sensory neurons
- id: PMID:19208769
title: 'Functional interactions between the ciliopathy-associated Meckel syndrome
1 (MKS1) protein and two novel MKS1-related (MKSR) proteins
'
findings:
- statement: MKS-1, MKSR-1, and MKSR-2 localize to transition zones/basal
bodies
supporting_text: All Caenorhabditis elegans B9-domain-containing
proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2),
localize to transition zones/basal bodies of sensory cilia
- statement: Their subcellular localization is largely co-dependent
supporting_text: Their subcellular localization is largely co-dependent,
pointing to a functional relationship between the proteins
- statement: B9 domain is found exclusively in this family of three
proteins
supporting_text: this domain occurs exclusively within a family of three
proteins distributed widely in ciliated organisms
- statement: Single, double, and triple mks/mksr mutants lack overt
ciliary structure defects
supporting_text: single, double and triple C. elegans mks/mksr mutants
do not display overt defects in ciliary structure, intraflagellar
transport or chemosensation
- statement: Genetic interactions between mks/mksr mutants affect
insulin-IGF-I signaling
supporting_text: 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
- 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: MKS-1 is part of the MKS module at the transition zone
supporting_text: the conserved C. elegans B9 domain (MKS-1, MKSR-1, and
MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
NPHP-4 proteins exhibit essential, collective functions at the
transition zone (TZ)
- statement: MKS and NPHP modules cooperate for basal body/TZ membrane
associations
supporting_text: Specifically, MKS/MKSR/NPHP proteins establish basal
body/TZ membrane attachments before or coinciding with intraflagellar
transport-dependent axoneme extension
- statement: MKS module includes MKS-1, MKSR-1, MKSR-2, MKS-3, MKS-5,
MKS-6
supporting_text: the conserved C. elegans B9 domain (MKS-1, MKSR-1, and
MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
NPHP-4 proteins exhibit essential, collective functions at the
transition zone (TZ)
- statement: These proteins establish the ciliary gate during ciliogenesis
supporting_text: uncover a unified role for eight TZ-localized proteins
in basal body anchoring and establishing a ciliary gate during
ciliogenesis
- statement: B9 domains are structurally related to C2 domains
supporting_text: B9 domains of MKS-1, MKSR-1, and MKSR-2 may be
structurally related to C2 domains of RGRIP1L/MKS-5 and CC2D2A/MKS-6
- 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-1 to the transition
zone
supporting_text: nematode TMEM-107 occupies an intermediate layer of the
TZ-localized MKS module by organizing recruitment of the ciliopathy
proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237)
- statement: MKS module proteins occupy distinct subdomains within the TZ
supporting_text: This work expands the MKS module of ciliopathy-causing
TZ proteins associated with diffusion barrier formation and provides
insight into TZ subdomain architecture
- statement: MKS module membrane proteins are immobile at the TZ
supporting_text: MKS module membrane proteins are immobile and
super-resolution microscopy in worms and mammalian cells reveals
periodic localizations within the TZ
- id: file:worm/mks-1/mks-1-deep-research-falcon.md
title: Deep research report on mks-1
findings: []
core_functions:
- description: 'MKS-1 is a core component of the MKS complex at the ciliary transition
zone, where it functions in establishing and maintaining the ciliary gate that
controls entry of proteins into the cilium.
'
molecular_function:
id: GO:0005515
label: protein binding
in_complex:
id: GO:0036038
label: MKS complex
locations:
- id: GO:0035869
label: ciliary transition zone
directly_involved_in:
- id: GO:0060271
label: cilium assembly
- id: GO:1905349
label: ciliary transition zone assembly
supported_by:
- reference_id: PMID:21422230
supporting_text: the conserved C. elegans B9 domain (MKS-1, MKSR-1, and
MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and
NPHP-4 proteins exhibit essential, collective functions at the
transition zone (TZ)
- reference_id: PMID:19208769
supporting_text: All Caenorhabditis elegans B9-domain-containing
proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2),
localize to transition zones/basal bodies of sensory cilia
tags:
- caeel-ciliopathy