{"doi":"10.1016/j.jbc.2025.110871","title":"Molecular interactions of the NaV1.5 C-terminal domain: CaM sequestered the IQ motif from the CTD","abstract":"Voltage-gated sodium channels (Na V ) are important for life. Alterations to the synchronized timing of ion conduction can create life-threatening conditions. How Na V conduction responds to changes in intracellular Ca 2+ concentration has been the subject of extensive investigation. Crystal structures of the cardiac Na V (Na V 1.5) cytosolic components were reported as trimeric complexes that are restructured in the presence of Ca 2+ . These results formed the basis for a gating model where two Na V 1.5 molecules interact to alter function in response to Ca 2+ concentration. Here, we investigated the binding site surface of these trimeric interactions in solution. NMR demonstrated that these trimeric complexes do not form in solution. Analysis of the available structural data indicated that the Na V 1.5 IQ motif can only accommodate interaction with one protein at a time. Our NMR data were consistent with the Na V 1.5 C-terminal domain (CTD) and the Ca 2+ - sensing protein calmodulin (CaM) engaging the same binding site surface of the Na V 1.5 IQ motif. Titrations of IQ motif peptide into a 1:1 mixture of 15 N CTD : CaM sample revealed the Na V 1.5 channel is biophysically distinct from neuronal Na V 1.2 as Ca 2+ enhanced CaM's ability to sequester the Na V 1.5 IQ motif from the Na V 1.5 CTD. Stopped-flow kinetic measurements quantified Ca 2+ release rates from the CaM-IQ and CaM-inactivation gate (IGATE) complexes to provide insight into complex lifetimes. Our work advanced understanding the molecular machinery that underlies Na V 1.5 gating (CTD-IGATE and CTD-IQ motif interactions) and provided insight into the structural details of CaM-facilitated Na V 1.5 modification (CaM-IQ motif and CaM-IGATE interactions).","journal":"Journal of Biological Chemistry","year":2025,"id":548101,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":523317,"name":"Torien Beard","orcid":null,"position":1,"is_corresponding":false},{"id":341745,"name":"Svetlana B. Tikunova","orcid":"0000-0002-2101-9996","position":2,"is_corresponding":false},{"id":1386175,"name":"Ali Ulker","orcid":null,"position":3,"is_corresponding":false},{"id":1146171,"name":"Sara A. Garcia","orcid":"0000-0002-6906-7436","position":4,"is_corresponding":false},{"id":1146497,"name":"Garrett M. Knotts","orcid":null,"position":5,"is_corresponding":false},{"id":1146170,"name":"Taylor Agee","orcid":"0000-0002-6179-7653","position":6,"is_corresponding":false},{"id":445581,"name":"Md Nure Alam Afsar","orcid":"0000-0002-7251-7661","position":7,"is_corresponding":false},{"id":258342,"name":"Brett M. Kroncke","orcid":"0000-0001-6215-0803","position":8,"is_corresponding":false},{"id":321391,"name":"Jarrod A. Smith","orcid":"0000-0003-0895-2922","position":9,"is_corresponding":false},{"id":341746,"name":"Jonathan P. Davis","orcid":"0000-0002-5627-1550","position":10,"is_corresponding":false},{"id":278722,"name":"Christopher N. Johnson","orcid":"0000-0002-5307-798X","position":11,"is_corresponding":false},{"id":1146496,"name":"Rita F Gyawu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41173394","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}