CALM1 — biological evidence notes

Calcium sensing and distinct target activities

Human CALM1, CALM2 and CALM3 share the canonical calmodulin protein sequence. Experiments on that protein establish biochemical capabilities but do not by themselves identify which gene supplies it in a cell. Calmodulin binds calcium through EF-hand sites; the KCNQ-associated structure reports PMID:27564677. Calcium sensing enables several distinct target-regulatory activities rather than making calmodulin the target enzyme or channel pore.

The CaMKII structural study explains activation through the regulatory segment and active-site configuration: PMID:20668654. Its complete available Results and Methods were read; experimental construct numbering is not evidence for an additional human product. Calmodulin activates the kinase, which performs phosphate transfer. A separate human-calmodulin disulfide-mutant study reports PMID:8631777; reduction restores regulatory activity. That abstract supports phosphatase activation without assigning calcineurin's dephosphorylation chemistry to calmodulin.

Channel regulation is target dependent. The CaV1.2 study reports PMID:26969752 for disease-associated variants. RyR2 studies independently support modulation of cardiac calcium release, whereas the complete human Reactome R-HSA-9865670 narrative describes TRPV4 potentiation. These results support a broad calcium-channel-regulator activity, not universal channel inhibition. The three functional units remain kinase activation, phosphatase activation and channel regulation, with calcium binding as their enabling sensing mechanism.

Nuclear location and reaction-specific uncertainty

The complete cached human Reactome R-HSA-2730867 and R-HSA-4551465 records explicitly name CaM-containing calcineurin:NFAT complexes translocating to the nucleus. They corroborate a nucleoplasmic calmodulin pool. All six existing nucleoplasm assertions are therefore retained as ACCEPT. The three CaMKK-linked records require separate caveats: R-HSA-442749 leaves the kinase reaction compartment unresolved; R-NUL-9618916 combines mouse Camkk1 with human calmodulin; R-NUL-9619177 combines rat Camkk2 with human CAMK4 and assumes recombinant-calmodulin species identity from sequence conservation. Those experiments do not independently locate the particular reaction in a human nucleus. Their uncertainty does not negate the independently supported target-location assertion. The underlying primary localization experiments and structured Reactome participant graphs were not inspected.

Gene-specific disease attribution and residue numbering

The CALM1 arrhythmia study directly reports PMID:23040497. Its N53I/N97S names use mature-protein numbering. UniProt P0DP23 records initiator-methionine removal from the 149-residue precursor and a chain spanning residues 2–149, so the corresponding precursor names are N54I/N98S. Three paralog genes must not be interpreted as three CALM1 alternative products.

The later calmodulinopathy report explicitly separates PMID:31454269. CALM1-E141V must be distinguished from CALM3-E141K and CALM3-D130G; the two mosaic pedigrees concern CALM3. Its cardiomyocyte experiments overexpress mutant or wild-type calmodulin, and detailed Methods reside in an unavailable supplement. The CALM3-A103V study (PMID:27516456) also compares known CALM1 variants, so its title alone does not invalidate CALM1 biochemical evidence. The PMID:26969752 abstract and cached author narrative give differing cohort counts; no prevalence or cohort-size claim is made here.

Contextual functions and limits of the available evidence

Anthrax edema factor is a real calmodulin-activated target: calmodulin PMID:11807546. This pathogen context does not establish a mammalian GPCR-linked cyclase core. The mu-opioid-receptor work supplies a separate GPCR regulatory context. CP110 binding-defective experiments and bacterial OspC/CaMKII signaling experiments support their specific cellular contexts without establishing universal cell-cycle or CALM1-gene-specific mechanisms.

Supported generic interactions are retained as non-core when no finer activity is justified. Directly supported refinements include IDH1 enzyme binding, KIF1A kinesin binding, EPB41 cytoskeletal binding and channel/transporter binding. Association alone does not transfer a partner's catalysis or establish its activation. LYST and tau target-interaction assertions remain unresolved because the relevant original target evidence was not recovered; the tau abstract is truncated. Other remaining uncertainties concern G2/M transition, sperm midpiece, calyx of Held, presynaptic endocytosis, calcium export and substantia nigra development.

The primary reading comprises complete cached abstracts and the specifically identified available Methods, Results or narrative sections. A full-text metadata flag does not establish that target tables, images or supplements are present. The PMID:19855925 erratum corrects Figure 5 panels and an axis unit; correction prose, not images, was inspected. PAINT node evidence supports conserved activities, without a claim to have reanalyzed every donor or the complete alignment. These access boundaries remain recorded per reference.

Current follow-up assessment

The focused follow-up changes only the three nucleoplasm decisions and the question that distinguished their reaction compartments: 106 ACCEPT, 48 KEEP_AS_NON_CORE, 14 MODIFY and 8 UNDECIDED across the same 176 source assertions. All references, source fields, existing evidence quotations and three functional cores remain unchanged; no new annotation or product is introduced. The original dated journal below is preserved verbatim as historical provenance. Its earlier action counts and nuclear uncertainty classification are superseded by this section.