{"doi":"10.1085/jgp.202313522","title":"Tail length and E525K dilated cardiomyopathy mutant alter human β-cardiac myosin super-relaxed state","abstract":"Dilated cardiomyopathy (DCM) is a condition characterized by impaired cardiac function, due to myocardial hypo-contractility, and is associated with point mutations in β-cardiac myosin, the molecular motor that powers cardiac contraction. Myocardial function can be modulated through sequestration of myosin motors into an auto-inhibited \"super-relaxed\" state (SRX), which may be further stabilized by a structural state known as the \"interacting heads motif\" (IHM). Here, we sought to determine whether hypo-contractility of DCM myocardium results from reduced function of individual myosin molecules or from decreased myosin availability to interact with actin due to increased IHM/SRX stabilization. We used an established DCM myosin mutation, E525K, and characterized the biochemical and mechanical activity of wild-type and mutant human β-cardiac myosin constructs that differed in the length of their coiled-coil tail, which dictates their ability to form the IHM/SRX state. We found that short-tailed myosin constructs exhibited low IHM/SRX content, elevated actin-activated ATPase activity, and fast velocities in unloaded motility assays. Conversely, longer-tailed constructs exhibited higher IHM/SRX content and reduced actomyosin ATPase and velocity. Our modeling suggests that reduced velocities may be attributed to IHM/SRX-dependent sequestration of myosin heads. Interestingly, longer-tailed E525K mutants showed no apparent impact on velocity or actomyosin ATPase at low ionic strength but stabilized IHM/SRX state at higher ionic strength. Therefore, the hypo-contractility observed in DCM may be attributable to reduced myosin head availability caused by enhanced IHM/SRX stability in E525K mutants.","journal":"The Journal of General Physiology","year":2024,"id":432981,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9629,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":347182,"name":"Shane R. Nelson","orcid":"0000-0002-3032-6314","position":1,"is_corresponding":false},{"id":774932,"name":"David V. Rasicci","orcid":"0000-0003-3891-0694","position":2,"is_corresponding":false},{"id":706056,"name":"Skylar M.L. Bodt","orcid":"0000-0002-5794-6927","position":3,"is_corresponding":false},{"id":713130,"name":"Joseph A. Cirilo","orcid":"0000-0003-2135-5831","position":4,"is_corresponding":false},{"id":424956,"name":"Duha Vang","orcid":"0000-0002-8990-8968","position":5,"is_corresponding":false},{"id":424957,"name":"Sivaraj Sivaramakrishnan","orcid":"0000-0002-9541-6994","position":6,"is_corresponding":false},{"id":577296,"name":"Christopher M. Yengo","orcid":"0000-0003-3987-9019","position":7,"is_corresponding":false},{"id":347184,"name":"David M. Warshaw","orcid":"0000-0002-0071-8798","position":8,"is_corresponding":false},{"id":355531,"name":"Sebastian Duno-Miranda","orcid":"0000-0002-2618-1335","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:59:39.937122Z","pmid":"38709176","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":[]}