cmd-1 encodes the single Caenorhabditis elegans calmodulin, a small EF-hand calcium sensor with four functional calcium-binding sites. The conserved core function is calcium-dependent binding and regulation of target proteins, including enzymes and spindle-associated factors. Experimental work in worms additionally places CMD-1 at spindle poles, centrosomes, the interphase nuclear membrane, and cell-cell boundaries in early embryos, and supports context-specific roles in meiotic spindle orientation, embryonic morphogenesis, apoptosis-related phenotypes, and neuronal chemotaxis. Falcon deep research further documents concrete downstream effector contexts: CMD-1 is the Ca2+/CaM activator component of the calcineurin phosphatase complex (with TAX-6 and CNB-1), it sets a transcriptionally controlled, limiting level of neuronal excitability, and it couples intestinal epithelial Ca2+ influx to NHX-6 activation in a gut-to-neuron host-defense pathway. Current GOA for cmd-1 contains no ISO annotations; the transfer-style annotations are IBA/IEA rather than ISO, so this ISO-focused pass mainly evaluates whether those orthology- derived calls are appropriately conservative.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: This phylogenetically inferred annotation matches the defining biochemical property of calmodulin family proteins. cmd-1 is the sole worm calmodulin, UniProt records four functional calcium-binding sites, and no conflicting evidence exists. Reason: Calcium ion binding is a conserved and central calmodulin activity, so the orthology-based transfer is well supported and represents core function. Supporting Evidence: file:worm/cmd-1/cmd-1-uniprot.txt This protein has four functional calcium-binding sites. file:worm/cmd-1/cmd-1-deep-research-falcon.md encoding the Ca2+-binding messenger protein **CMD-1** |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization is consistent with cmd-1 being a broadly acting soluble calcium sensor. Experimental work in embryos also places CMD-1 on spindle/centrosomal structures and other non-nuclear sites, which is compatible with a general cytoplasmic annotation. Reason: Cytoplasm is a correct high-level cellular location for calmodulin and is sufficiently general to retain as a core localization term. Supporting Evidence: file:worm/cmd-1/cmd-1-uniprot.txt DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. |
| GO:0030234 enzyme regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Calmodulin-Ca2+ complexes regulate multiple enzyme classes, including kinases and phosphatases, and UniProt explicitly describes cmd-1 as a mediator of enzyme control. The term is broad, but it captures a genuine conserved molecular role. Reason: Although general, enzyme regulator activity is an appropriate conserved summary term for calmodulin and reflects core function rather than a lineage-specific phenotype. Falcon deep research identifies a concrete worm enzyme target: CMD-1 is the Ca2+/CaM activator subunit of the calcineurin phosphatase complex (TAX-6 catalytic, CNB-1 regulatory). Supporting Evidence: file:worm/cmd-1/cmd-1-uniprot.txt Calmodulin mediates the control of a large number of enzymes, ion channels and other proteins by Ca(2+). file:worm/cmd-1/cmd-1-deep-research-falcon.md CMD-1 is part of the calcineurin activation complex (TAX-6/CNB-1/CMD-1) |
| GO:0000226 microtubule cytoskeleton organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The transfer is plausible because worm experiments support CMD-1 roles in spindle organization and spindle orientation. However, the specific evidence is tied to cell-division contexts rather than to a universally defining calmodulin function. Reason: Retain the annotation as valid but non-core because it reflects a real, experimentally supported spindle phenotype without being the central conserved biochemical identity of the gene. Falcon deep research confirms this is a recurring spindle-pole module function spanning multiple studies. Supporting Evidence: PMID:19219036 ASPM-1, together with calmodulin (CMD-1), promotes meiotic spindle organization file:worm/cmd-1/cmd-1-deep-research-falcon.md CMD-1 acts with ASPM-1/LIN-5 to recruit dynein and drive meiotic spindle rotation |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-derived calcium ion binding agrees with the IBA call and with the well-established EF-hand architecture of calmodulin. Reason: This is a correct electronic annotation for a canonical EF-hand calcium- binding protein and matches core function. Supporting Evidence: file:worm/cmd-1/cmd-1-uniprot.txt This protein has four functional calcium-binding sites. |
| GO:0072686 mitotic spindle | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The ARBA localization is consistent with direct experimental embryo data showing CMD-1 accumulation on spindle structures. It is a correct but context-specific localization. Reason: Mitotic spindle localization is supported, but it is not a universal core localization for calmodulin across all contexts. Supporting Evidence: file:worm/cmd-1/cmd-1-deep-research-falcon.md CMD-1 acts with ASPM-1/LIN-5 to recruit dynein and drive meiotic spindle rotation |
| GO:0010629 negative regulation of gene expression | IMP PMID:34499028 Neuronal calmodulin levels are controlled by CAMTA transcrip... | MARK AS OVER ANNOTATED | Summary: PMID:34499028 supports a specific autoregulatory loop in which high CMD-1 levels repress expression from the cmd-1 promoter through CAMT-1. That is more limited than generic negative regulation of gene expression. Reason: The paper supports context-specific feedback on cmd-1 transcription, not a broad generic role in repressing gene expression across targets. Supporting Evidence: PMID:34499028 high levels of CMD-1 can repress expression from the cmd-1 promoter |
| GO:0050918 positive chemotaxis | IMP PMID:34499028 Neuronal calmodulin levels are controlled by CAMTA transcrip... | KEEP AS NON CORE | Summary: Neuronal reduction of cmd-1 contributes to chemotaxis defects, and supplementing neuronal CMD-1 rescues attraction to several cues in the CAMT-1 regulatory context examined in the paper. Reason: The phenotype is real but represents a specialized neuronal/behavioral context rather than the core conserved role of calmodulin. Falcon deep research underscores that neuronal CMD-1 abundance is a limiting, transcriptionally controlled determinant of sensory-neuron excitability and chemotaxis behavior. Supporting Evidence: PMID:34499028 restored normal chemotaxis toward salt, benzaldehyde, and diacetyl file:worm/cmd-1/cmd-1-deep-research-falcon.md reduced CaM levels are associated with hyperexcitable Ca2+ responses in sensory neurons |
| GO:0009792 embryo development ending in birth or egg hatching | IMP PMID:14703012 Functional analysis of the single calmodulin gene in the nem... | KEEP AS NON CORE | Summary: cmd-1 RNAi causes severe embryonic lethality with disturbed morphogenesis, so the gene clearly contributes to successful embryogenesis. Reason: This broad developmental phenotype is supported experimentally, but it is a pleiotropic consequence of depleting a global calcium sensor and should not be treated as core function. Falcon deep research quantifies the strong essentiality (~95% embryonic lethality by dsRNA injection) while framing it as downstream of CMD-1's global Ca2+-sensor role. Supporting Evidence: PMID:14703012 RNAi microinjection approach results in a severe embryonic lethal phenotype file:worm/cmd-1/cmd-1-deep-research-falcon.md cmd-1 knockdown produced **~95% embryonic lethality** |
| GO:0005813 centrosome | IDA PMID:17716666 Cytokinesis is not controlled by calmodulin or myosin light ... | KEEP AS NON CORE | Summary: Full-text evidence from PMID:17716666 shows GFP-tagged CMD-1 accumulation at centrosomes in early embryos. Reason: The localization is directly observed and valid, but it is a cell-division context rather than a core pan-context localization. |
| GO:0031965 nuclear membrane | IDA PMID:17716666 Cytokinesis is not controlled by calmodulin or myosin light ... | KEEP AS NON CORE | Summary: The same embryo localization study reports CMD-1 at the interphase nuclear membrane. Reason: The annotation is experimentally supported but context-specific and not a primary summary of calmodulin function. |
| GO:0071944 cell periphery | IDA PMID:17716666 Cytokinesis is not controlled by calmodulin or myosin light ... | KEEP AS NON CORE | Summary: PMID:17716666 reports CMD-1 at the borders of abutting cells in embryos, which justifies a general cell periphery term. Reason: Direct localization supports the term, but this is again a non-core, context-dependent localization. |
| GO:0072686 mitotic spindle | IDA PMID:17716666 Cytokinesis is not controlled by calmodulin or myosin light ... | KEEP AS NON CORE | Summary: Direct imaging shows CMD-1 on spindle structures and not at the cleavage furrow in early embryos. Reason: Correct experimental localization, but specialized to embryonic cell division rather than a core location. |
| GO:0005515 protein binding | IPI PMID:19219036 NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote me... | MODIFY | Summary: PMID:19219036 places CMD-1 in an ASPM-1/LIN-5 spindle-pole complex, so a physical interaction claim is credible. However, protein binding is too generic for calmodulin and loses the informative calcium-dependent nature of its target interactions. Reason: The interaction evidence should be retained, but the annotation should use a more informative calmodulin-appropriate term rather than generic protein binding. Proposed replacements: calcium-dependent protein binding |
| GO:0032880 regulation of protein localization | IMP PMID:19219036 NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote me... | KEEP AS NON CORE | Summary: The meiosis study shows CMD-1 promotes accumulation of LIN-5 at meiotic and mitotic spindle poles, which is an experimentally grounded protein localization phenotype. Reason: This process annotation is valid but reflects a specific spindle-pole context, not cmd-1's central conserved biochemical identity. Falcon deep research reinforces that the CMD-1/LIN-5/ASPM-1 module recruits dynein to spindle poles, and that this recruitment is gated by CDK-1. Supporting Evidence: PMID:19219036 promotes meiotic spindle organization and the accumulation of LIN-5 at meiotic and mitotic spindle poles file:worm/cmd-1/cmd-1-deep-research-falcon.md CDK-1 inhibits spindle rotation by blocking the interaction between the **CMD-1–LIN-5–ASPM-1** module and **DHC-1/dynein** |
| GO:0051296 establishment of meiotic spindle orientation | IMP PMID:19219036 NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote me... | KEEP AS NON CORE | Summary: The paper directly concludes that LIN-5, ASPM-1, CMD-1 and dynein are required for spindle rotation during maternal meiosis. Reason: Strong experimental support exists, but the process is specialized rather than core to calmodulin across contexts. Falcon deep research corroborates this with an independent follow-up study (Ellefson & McNally 2011) showing cmd-1(RNAi) abolishes meiosis I spindle rotation. Supporting Evidence: PMID:19219036 Spindle rotation during maternal meiosis is independent of GPR-1/2 and Galpha, yet requires LIN-5, ASPM-1, CMD-1 and dynein file:worm/cmd-1/cmd-1-deep-research-falcon.md cmd-1(RNAi) abolished meiosis I spindle rotation |
| GO:0051296 establishment of meiotic spindle orientation | IGI PMID:19219036 NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote me... | KEEP AS NON CORE | Summary: The genetic interaction-based version of the same process annotation is consistent with the paper's functional dissection of the spindle-pole complex. Reason: Retain as non-core for the same reason as the IMP entry: direct support, but specialized biology. Supporting Evidence: PMID:19219036 Spindle rotation during maternal meiosis is independent of GPR-1/2 and Galpha, yet requires LIN-5, ASPM-1, CMD-1 and dynein |
| GO:0016477 cell migration | IMP PMID:14703012 Functional analysis of the single calmodulin gene in the nem... | KEEP AS NON CORE | Summary: cmd-1 RNAi embryos show aberrant cell migration patterns according to the abstract, supporting a migration-related phenotype. Reason: This is a pleiotropic developmental phenotype observed after strong loss of a global calcium sensor, so it should be retained only as non-core. Supporting Evidence: PMID:14703012 Embryos show disturbed morphogenesis, aberrant cell migration patterns |
| GO:0042981 regulation of apoptotic process | IMP PMID:14703012 Functional analysis of the single calmodulin gene in the nem... | KEEP AS NON CORE | Summary: The abstract reports multiple defects in apoptosis after cmd-1 depletion, which supports involvement in apoptosis-related regulation. Reason: The phenotype is supported, but it is broad and likely pleiotropic rather than a core defining function of calmodulin. Supporting Evidence: PMID:14703012 multiple defects in apoptosis |
| GO:0043277 apoptotic cell clearance | IMP PMID:14703012 Functional analysis of the single calmodulin gene in the nem... | UNDECIDED | Summary: The accessible abstract supports apoptosis defects, but it does not clearly distinguish cell corpse clearance/engulfment from upstream apoptosis defects. Reason: This specific term may be correct, but the currently accessible evidence is insufficiently specific to review it confidently. |
| GO:0051726 regulation of cell cycle | IMP PMID:14703012 Functional analysis of the single calmodulin gene in the nem... | KEEP AS NON CORE | Summary: Hyperproliferation in cmd-1 RNAi embryos is consistent with cell-cycle dysregulation after depletion of calmodulin. Reason: The phenotype is experimentally supported, but it is a broad developmental consequence rather than a core molecular role. Supporting Evidence: PMID:14703012 a striking hyperproliferation of cells |
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Download this section (compressed HTML)Q: Which direct CMD-1 target proteins at spindle poles are most important for the meiotic spindle orientation phenotype in embryos?
Q: Which apoptosis and cell-migration phenotypes after cmd-1 depletion are direct CMD-1-dependent processes versus secondary consequences of broad calcium signaling collapse?
Q: Should calmodulin-family curation in nematodes explicitly add calcium-dependent protein binding where older annotations still use generic protein binding?
Experiment: Endogenous tagged CMD-1 affinity purification or proximity labeling under Ca2+-bound and Ca2+-free conditions to define direct embryo and neuronal target proteins.
Experiment: Rescue cmd-1 loss with EF-hand calcium-binding mutants to separate calcium sensing from possible scaffolding/localization roles at spindle poles.
Experiment: Tissue-specific depletion or rescue in embryos versus neurons to distinguish direct spindle and chemotaxis functions from pleiotropic systemic effects.
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