CALM3 notes

2026-03-19

• Review scope: the CALM3 GOA file fetched on 2026-03-19 contains no literal ISO evidence-code rows, but it does contain multiple transferred annotations (IBA and IEA). I reviewed those in the spirit of [projects/ISO.md] by asking whether a term is safe to transfer across the human calmodulin paralogs.
• Family identity: humans have three calmodulin genes, CALM1, CALM2, and CALM3, and all three encode an identical 149 aa calmodulin polypeptide PMID:27516456 PMID:31454269.
• Family regulation differs even when protein sequence does not: transcription of the three genes is not equivalent, and in teratoma cells CALM3 was reported to be more highly transcribed than CALM1 or CALM2 PMID:9681195.
• Curation consequence: core protein-level functions that follow directly from the conserved calmodulin sequence are safe to treat as family-wide, especially calcium binding, calcium sensing, kinase/phosphatase activation, and ion-channel regulation PMID:27516456 PMID:23040497.
• Cardiac core function is strong for the protein family and directly relevant to CALM3: defective calmodulin regulation of RyR2 increases spontaneous calcium release events PMID:20226167 and the CALM3 A103V mutation promotes arrhythmogenic calcium waves and sparks PMID:27516456.
• CALM3 also has direct human disease evidence for impaired L-type calcium channel regulation and action potential phenotypes in calmodulinopathy PMID:31454269.
• Cell-division localization/function is supported independently of cardiac biology: calmodulin binds CP110 and loss of that interaction disrupts late cytokinesis PMID:16760425.
• Microbial hijacking papers support genuine calmodulin biochemistry but not necessarily core host biological-process terms. OspC-family effectors bind calmodulin and block CaMKII / IFN signaling PMID:35568036, but those infection-context processes should stay non-core.
• Several GOA terms are too context-specific to distinguish CALM3 from CALM1 / CALM2: synaptic localizations, myelin-associated terms, sperm terms, and specialized membrane-trafficking terms likely reflect cell-type context layered on top of the same calmodulin protein sequence rather than a CALM3-specific biochemical innovation PMID:9681195.
• Some annotations should be removed or down-weighted on evidence quality grounds. substantia nigra development is based on proteomic detection in diseased tissue rather than developmental perturbation PMID:22926577.
• Generic protein binding annotations are not informative for calmodulin and should not be favored when more specific regulator/binding terms are available.
• Current UniProt entries for CALM1, CALM2, and CALM3 all show the same 149 aa sequence summary and I found no ALTERNATIVE PRODUCTS block in these local records, so there is no isoform-specific caveat comparable to the splice-isoform project genes [file:human/CALM1/CALM1-uniprot.txt "SQ SEQUENCE 149 AA"] [file:human/CALM2/CALM2-uniprot.txt "SQ SEQUENCE 149 AA"] [file:human/CALM3/CALM3-uniprot.txt "SQ SEQUENCE 149 AA"].

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

• Moved out of the YAML description: annotations were interpreted at the protein level for this review because CALM1, CALM2, and CALM3 encode identical calmodulin proteins.