ArticleProceedings of the National Academy of Sciences of the United States of America2013
Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers, 1 of them a synthesis that pooled it.
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121 citing papers in PubMed, 1 synthesis or guideline pooled it, 179 citations in OpenAlex.
- Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.Circulation. Genomic and precision medicine · 2024Pooled it
- The hypertrophic cardiomyopathy mutation G768R makes cardiac myosin a high duty ratio motor.bioRxiv : the preprint server for biology · 2026Article
- Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling.Circulation research · 2026Article
- A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unraveling Mutation-Induced Protein Communication Pathways in the Actomyosin Complex: Insights from Comprehensive Metadynamics Simulations.The journal of physical chemistry. B · 2025Article
- A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states.The Journal of biological chemistry · 2025Article
- A FRET assay to quantitate levels of the human β-cardiac myosin interacting heads motif based on its near-atomic resolution structure.bioRxiv : the preprint server for biology · 2024Article
- Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.European journal of cell biology · 2024Article
- Probing actin-activated ATP turnover kinetics of human cardiac myosin II by single molecule fluorescence.Cytoskeleton (Hoboken, N.J.) · 2024Article
- 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
- Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice.European heart journal · 2024Review
- Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.Nature cardiovascular research · 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
- MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways.Open biology · 2024Article
- Myosin-Catalyzed ATP Hydrolysis in the Presence of Disease-Causing Mutations: Mavacamten as a Way to Repair Mechanism.The journal of physical chemistry. B · 2024Article
- Incomplete-penetrant hypertrophic cardiomyopathyProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Modeling thick filament activation suggests a molecular basis for force depression.Biophysical journal · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
61 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including β-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human β-cardiac myosin. We found that this mutation causes a ∼30% decrease in the maximum ATPase of the human β-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human β-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle.
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