title: Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin.
abstract: 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.
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA jspudich@stanford.edu kruppel@stanford.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Spudich
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tural
authors.initials: T
authors.lastname: Aksel
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sadie R
authors.initials: SR
authors.lastname: Bartholomew
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Nag
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kawana
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Elizabeth Choe
authors.initials: EC
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Saswata S
authors.initials: SS
authors.lastname: Sarkar
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Sung
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Sommese
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Sutton
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Arjun S
authors.initials: AS
authors.lastname: Adhikari
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Darshan
authors.initials: D
authors.lastname: Trivedi
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA jspudich@stanford.edu kruppel@stanford.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ruppel
mesh_terms: D001696:Biomechanical Phenomena / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics*
chemical_list: D024723:Ventricular Myosins
keywords: Cardiac myosin; Cardiomyopathy mutations; Force–velocity curves