ArticleThe Journal of biological chemistry2018
Dilated cardiomyopathy myosin mutants have reduced force-generating capacity.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Cardiomyopathy phenotypes in human-induced pluripotent stem cell-derived cardiomyocytes-a systematic review.Pflugers Archiv : European journal of physiology · 2019Pooled it
- The hypertrophic cardiomyopathy myosin variant G256E prolongs cardiac muscle relaxation via altered nucleotide handling.Communications chemistry · 2026Article
- Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.Science advances · 2026Article
- Emerging Mechanisms and Therapeutic Strategies in Dilated Cardiomyopathy.Biomedicines · 2026Review
- S2Tag, a novel affinity tag for the capture and immobilization of coiled-coil proteins: Application to the study of human β-cardiac myosin.The Journal of biological chemistry · 2025Article
- Cryo-EM Reveals How Cardiomyopathy Therapeutic Drugs Modulate the Myosin Motors of the Heart.bioRxiv : the preprint server for biology · 2025Article
- The G256E HCM mutation prolongs cardiac muscle relaxation via altered nucleotide handling.Research square · 2025Article
- Unraveling Mutation-Induced Protein Communication Pathways in the Actomyosin Complex: Insights from Comprehensive Metadynamics Simulations.The journal of physical chemistry. B · 2025Article
- Mechanistic insights into effects of the cardiac myosin activator omecamtiv mecarbil from mechanokinetic modelling.Frontiers in physiology · 2025Article
- The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum.Journal of cardiovascular translational research · 2024Review
- Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release.PNAS nexus · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Protocols for Myosin and Actin-Myosin Assays Using Rapid, Stopped-Flow Kinetics.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.Genome medicine · 2023Article
- Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies.Current cardiology reports · 2023Review
- Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.medRxiv : the preprint server for health sciences · 2023Article
- Virus-free transfection, transient expression, and purification of human cardiac myosin in mammalian muscle cells for biochemical and biophysical assays.Scientific reports · 2023Article
- Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies.Frontiers in cardiovascular medicine · 2023Review
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Corrections and comments
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
Abstract
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human β-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force-holding capacity due to the reduced occupancy of the force-holding state.
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Registered trials
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