ArticleScience advances2017
Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy.
Article in Science advances, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 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 mutation G768R makes cardiac myosin a high duty ratio motor.bioRxiv : the preprint server for biology · 2026Article
- Multi-omics Insight into Cardiac Myofibril Remodeling in Post-Prandial Burmese Pythons.bioRxiv : the preprint server for biology · 2026Article
- Early Cytoskeletal Remodeling Drives Hypertrophic Cardiomyopathy Pathogenesis inJournal of cardiovascular development and disease · 2025Article
- Hypertrophic cardiomyopathy.Nature reviews. Disease primers · 2025Review
- Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states.The Journal of biological chemistry · 2025Article
- Biochemical characterization of cardiac α-actin mutations A21V and D26N implicated in hypertrophic cardiomyopathy.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.The EMBO journal · 2024Review
- Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release.PNAS nexus · 2024Article
- Cost-Efficient Expression of Human Cardiac Myosin Heavy Chain in C2C12 Cells with a Non-Viral Transfection Reagent.International journal of molecular sciences · 2024Article
- Incomplete-penetrant hypertrophic cardiomyopathyProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Homologous mutations in human β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- From amoeboid myosin to unique targeted medicines for a genetic cardiac disease.Frontiers in physiology · 2024Review
- Motility Assay to Probe the Calcium Sensitivity of Myosin and Regulated Thin Filaments.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues.Communications biology · 2023Article
- Cryo-EM structure of the folded-back state of human β-cardiac myosin.bioRxiv : the preprint server for biology · 2023Article
- Virus-free transfection, transient expression, and purification of human cardiac myosin in mammalian muscle cells for biochemical and biophysical assays.Scientific reports · 2023Article
- Article
- Recent drug discovery success signals renaissance in biophysics.Biophysics reviews · 2022Article
- Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the β-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human β-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production.
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