MKSR-2 (MKS1-related protein 2) is a B9 domain-containing protein that functions as a component of the MKS (Meckel syndrome) module at the ciliary transition zone. It is the C. elegans ortholog of mammalian B9D2. MKSR-2 forms a complex with MKS-1 and MKSR-1 and localizes specifically to the transition zone/basal body of sensory cilia. The protein functions redundantly with nephrocystins (NPHP-1, NPHP-4) to regulate cilia formation and maintenance in amphid and phasmid ciliated sensory neurons. The MKS module, together with the NPHP module, establishes basal body/ transition zone membrane attachments and a ciliary gate that restricts entry of non-ciliary components. Loss of mksr-2 in combination with other MKS/NPHP pathway mutations leads to ciliogenesis defects and altered lifespan via abnormal insulin-IGF-I signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036038 MKS complex | IBA GO_REF:0000033 | ACCEPT | Summary: MKSR-2 is a core component of the MKS complex at the ciliary transition zone. The B9 proteins (MKS-1, MKSR-1, MKSR-2) form a complex that localizes to the base of cilia and functions as part of the MKS module (PMID:18337471, PMID:21422230). Reason: This is a well-established core function of MKSR-2. Multiple studies demonstrate that the B9 proteins including MKSR-2 form the MKS complex and function together at the transition zone. IBA annotation from phylogenetic analysis is consistent with experimental data. Supporting Evidence: PMID:18337471 we report that 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 file:worm/mksr-2/mksr-2-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | MODIFY | Summary: MKSR-2 participates in cilium assembly as part of the MKS/NPHP transition zone machinery. The B9 proteins function redundantly with nephrocystins in ciliogenesis (PMID:18337471, PMID:21422230). Reason: While MKSR-2 is involved in cilium assembly, the annotation should be more specific. In C. elegans sensory neurons, these are non-motile primary cilia. The term GO:1905515 (non-motile cilium assembly) is more accurate for this organism and cell type context. Proposed replacements: non-motile cilium assembly 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 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: IEA annotation based on ARBA prediction. While MKSR-2 functions in ciliated neurons, it specifically localizes to the transition zone rather than the cilium proper (PMID:21422230). Reason: MKSR-2 specifically localizes to the ciliary transition zone, not the cilium proper. The IEA annotation is too broad. The protein is found at the base of cilia (transition zone/basal body region). Proposed replacements: ciliary transition zone Supporting Evidence: PMID:21422230 MKS/MKSR and NPHP proteins localize specifically to the ciliary TZ |
| GO:0030030 cell projection organization | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping. This is a very general term that captures the overall role in organizing ciliary/dendritic structures. Reason: While this is a broad term, it is not incorrect. MKSR-2 functions in organizing the ciliary transition zone and participates in dendritic organization. This can be kept as a general annotation, though more specific terms (cilium assembly, ciliary transition zone) are more informative. |
| GO:0005515 protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | MARK AS OVER ANNOTATED | Summary: High-throughput Y2H screen showing interaction with MKSR-1 (Q21191). While the interaction is real, the term 'protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is too generic and uninformative per GO curation guidelines. The interaction with MKSR-1 is biologically relevant (they function together in the MKS complex), but a more specific binding term should be used. The MKS complex annotation captures this functional relationship better. Supporting Evidence: PMID:14704431 more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | MARK AS OVER ANNOTATED | Summary: Another high-throughput Y2H study confirming interaction with MKSR-1 (Q21191). Reason: Same as above - 'protein binding' is too generic. The interaction data is valid but better captured by the MKS complex component annotation. Supporting Evidence: PMID:19123269 We present an expanded Caenorhabditis elegans protein-protein interaction network, or "interactome" map derived from testing a matrix of ~ 10,000 × ~ 10,000 proteins using a highly specific high-throughput yeast two-hybrid system |
| GO:0036064 ciliary basal body | IDA PMID:27623382 A Conserved Role for Girdin in Basal Body Positioning and Ci... | ACCEPT | Summary: IDA annotation showing localization to the ciliary basal body. This study on Girdin showed MKSR-2 localization in this context (PMID:27623382). Reason: Direct localization evidence. MKSR-2 localizes to the proximal region including the basal body. This is consistent with its role at the transition zone which is immediately distal to the basal body. Both basal body and transition zone localizations are valid. Supporting Evidence: PMID:27623382 Primary cilia are ubiquitous sensory organelles that mediate diverse signaling pathways. Cilia position on the cell surface is determined by the location of the basal body (BB) that templates the cilium |
| GO:1905515 non-motile cilium assembly | IGI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | ACCEPT | Summary: IGI evidence with genetic interaction with nph-1 (NPHP1 ortholog). B9 proteins function redundantly with nephrocystins in ciliogenesis (PMID:18337471). Reason: This is the appropriate specific term for MKSR-2's role in cilium assembly in C. elegans sensory neurons, which are non-motile cilia. The genetic interaction data supports this 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:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: IMP evidence showing MKSR-2 is required for proper localization of proteins to the transition zone. The MKS module proteins show co-dependent localization (PMID:21422230). Reason: This is a core function of MKSR-2 as part of the MKS module. The transition zone proteins have mutually dependent localization and collectively establish the ciliary gate that controls protein access to the cilium. Supporting Evidence: PMID:21422230 These TZ proteins functionally interact as members of two distinct modules, which together contribute to an early ciliogenic event PMID:19208769 Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins |
| GO:1905515 non-motile cilium assembly | IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: IGI evidence with genetic interaction with nphp-4 (WB:WBGene00007490). Combined mutations show ciliogenesis defects (PMID:21422230). Reason: Redundant with the other non-motile cilium assembly annotation but from a different genetic interaction. Both are valid and support the functional role of MKSR-2 in ciliogenesis through interaction with the NPHP module. Supporting Evidence: PMID:21422230 MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension |
| GO:0044292 dendrite terminus | IDA PMID:25335890 Ciliopathy proteins establish a bipartite signaling compartm... | ACCEPT | Summary: IDA localization to dendrite terminus in the AFD thermosensory neuron (PMID:25335890). This study showed ciliopathy proteins at the base of cilia in AFD neurons. Reason: Valid localization data. In C. elegans sensory neurons, the cilium extends from the dendrite terminus. MKSR-2 localization to this region is consistent with its role at the transition zone. Supporting Evidence: PMID:25335890 ciliary proteins help establish two contiguous, yet distinct cyclic GMP (cGMP) signaling compartments in Caenorhabditis elegans thermosensory AFD neurons |
| GO:0035869 ciliary transition zone | IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: IDA localization to the ciliary transition zone. This is the primary localization site for MKSR-2 (PMID:21422230). Reason: This is the canonical localization for MKSR-2 and represents its core functional compartment. The transition zone is where the MKS complex establishes the ciliary gate. Supporting Evidence: PMID:21422230 MKS/MKSR and NPHP proteins localize specifically to the ciliary 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 |
| GO:0008340 determination of adult lifespan | IGI PMID:19208769 Functional interactions between the ciliopathy-associated Me... | KEEP AS NON CORE | Summary: IGI evidence showing increased lifespan in double/triple mks/mksr mutant combinations due to abnormal insulin-IGF-I signaling (PMID:19208769). Reason: This is a secondary phenotype arising from ciliary dysfunction rather than a direct core function of MKSR-2. The lifespan extension in mutants results from abnormal insulin-IGF signaling, which is an indirect consequence of sensory cilium defects affecting DAF-2/ insulin signaling. This is biologically valid but represents a downstream consequence rather than a direct molecular function. Supporting Evidence: PMID:19208769 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 |
| GO:0005515 protein binding | IPI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | MARK AS OVER ANNOTATED | Summary: IPI evidence for interaction with MKS-1 (WB:WBGene00019364). The B9 proteins form a complex (PMID:18337471). Reason: Same issue as other protein binding annotations - the term is too generic. The interaction with MKS-1 is biologically meaningful (they form the B9/MKS complex together) but better captured by the MKS complex annotation. Supporting Evidence: PMID:18337471 we report that 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: IMP evidence for role in protein localization based on mutant phenotype. Reason: This term is too generic. MKSR-2 specifically functions in localizing proteins to the ciliary transition zone. The more specific term GO:1904491 (protein localization to ciliary transition zone) is already annotated and is more appropriate. Proposed replacements: protein localization to ciliary transition zone 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:0030425 dendrite | IDA PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | ACCEPT | Summary: IDA localization to dendrites of ciliated sensory neurons (PMID:18337471). Reason: Valid localization data. MKSR-2 is expressed in ciliated sensory neurons and localizes to the distal dendrite region where the ciliary base is located. 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:0035177 larval foraging behavior | IGI PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i... | KEEP AS NON CORE | Summary: IGI evidence showing defects in larval foraging behavior in genetic interaction with nph-1. Reason: Foraging behavior defects are a downstream consequence of sensory cilium dysfunction. C. elegans uses ciliated sensory neurons for chemosensation, which is required for proper foraging. This is not a direct molecular function but rather a phenotypic consequence of loss of ciliary function in the sensory neurons. Supporting Evidence: PMID:18337471 Our data indicate that 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:0005198 structural molecule activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. |
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Download this section (compressed HTML)Q: What is the precise molecular mechanism by which MKSR-2 contributes to ciliary gate function?
Q: Does MKSR-2 directly interact with membrane components at the transition zone or function through other adaptor proteins?
Q: What are the specific cargo proteins whose localization is regulated by MKSR-2?
Experiment: Proximity labeling (BioID/TurboID) to identify direct interaction partners of MKSR-2 at the transition zone
Hypothesis: MKSR-2 interacts with specific membrane and cytoskeletal proteins to anchor the MKS complex at the transition zone
Experiment: Structure-function analysis to determine which domains are required for localization vs complex formation vs gate function
Hypothesis: The B9 domain mediates complex formation while other regions control membrane association
Experiment: Systematic analysis of ciliary protein localization in mksr-2 mutants to identify cargo affected by loss of gate function
Hypothesis: Loss of MKSR-2 results in abnormal accumulation or exclusion of specific ciliary membrane proteins
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