The Experts below are selected from a list of 92454 Experts worldwide ranked by ideXlab platform
James A Spudich - One of the best experts on this subject based on the ideXlab platform.
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effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β cardiac myosin
The Journal of Experimental Biology, 2016Co-Authors: James A Spudich, Masataka Kawana, Tural Aksel, Suman Nag, Shirley Sutton, Ruth F Sommese, Sadie Bartholomew, Saswata S Sarkar, Jongmin Sung, Carol ChoAbstract:Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the Fundamental Force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the Forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.
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molecular consequences of the r453c hypertrophic cardiomyopathy mutation on human β cardiac myosin motor function
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Ruth F Sommese, Shirley Sutton, Kathleen M Ruppel, Jongmin Sung, Leslie A Leinwand, John C Deacon, Elizabeth Choe, James A SpudichAbstract: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.
Kathleen M Ruppel - One of the best experts on this subject based on the ideXlab platform.
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multidimensional structure function relationships in human β cardiac myosin from population scale genetic variation
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Julian R Homburger, Kathleen M Ruppel, Eric M Green, Colleen Caleshu, Margaret S Sunitha, Rebecca E Taylor, Raghu Metpally, Steven D Colan, Michelle Michels, Sharlene M DayAbstract:Myosin motors are the Fundamental Force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces Force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
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multi dimensional structure function relationships in human β cardiac myosin from population scale genetic variation
bioRxiv, 2016Co-Authors: Julian R Homburger, Kathleen M Ruppel, Eric M Green, Colleen Caleshu, Margaret S Sunitha, Rebecca E Taylor, Raghu Metpally, Steven D Colan, Share Investigators, Michelle MichelsAbstract:Myosin motors are the Fundamental Force-generating element of muscle contraction. Variation in the human β-cardiac myosin gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 HCM patients to elucidate novel structure-function relationships within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein three-dimensional space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces Force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified another region enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as a myosin mesa. This surface is prominent in the pre-stroke model, but substantially reduced in size following the power stroke. Notably, HCM patients with variants in the enriched regions have earlier presentation and worse outcome than those with variants in other regions. In summary, this study provides a model for the combination of protein structure, large-scale genetic sequencing and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
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molecular consequences of the r453c hypertrophic cardiomyopathy mutation on human β cardiac myosin motor function
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Ruth F Sommese, Shirley Sutton, Kathleen M Ruppel, Jongmin Sung, Leslie A Leinwand, John C Deacon, Elizabeth Choe, James A SpudichAbstract: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.
Sharlene M Day - One of the best experts on this subject based on the ideXlab platform.
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multidimensional structure function relationships in human β cardiac myosin from population scale genetic variation
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Julian R Homburger, Kathleen M Ruppel, Eric M Green, Colleen Caleshu, Margaret S Sunitha, Rebecca E Taylor, Raghu Metpally, Steven D Colan, Michelle Michels, Sharlene M DayAbstract:Myosin motors are the Fundamental Force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces Force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
Ruth F Sommese - One of the best experts on this subject based on the ideXlab platform.
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effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β cardiac myosin
The Journal of Experimental Biology, 2016Co-Authors: James A Spudich, Masataka Kawana, Tural Aksel, Suman Nag, Shirley Sutton, Ruth F Sommese, Sadie Bartholomew, Saswata S Sarkar, Jongmin Sung, Carol ChoAbstract:Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the Fundamental Force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the Forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.
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molecular consequences of the r453c hypertrophic cardiomyopathy mutation on human β cardiac myosin motor function
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Ruth F Sommese, Shirley Sutton, Kathleen M Ruppel, Jongmin Sung, Leslie A Leinwand, John C Deacon, Elizabeth Choe, James A SpudichAbstract: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.
Carol Cho - One of the best experts on this subject based on the ideXlab platform.
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effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β cardiac myosin
The Journal of Experimental Biology, 2016Co-Authors: James A Spudich, Masataka Kawana, Tural Aksel, Suman Nag, Shirley Sutton, Ruth F Sommese, Sadie Bartholomew, Saswata S Sarkar, Jongmin Sung, Carol ChoAbstract:Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the Fundamental Force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the Forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.
