caa a22 4500 475744942 CHVBK 20180406123510.0 cr unu---uuuuu 170329e20001001xx s 000 0 eng 10.1023/A:1005678905119 doi (NATIONALLICENCE)springer-10.1023/A:1005678905119 R403Q and L908V mutant β-cardiac myosin from patients with familial hypertrophic cardiomyopathy exhibit enhanced mechanical performance at the single molecule level [Elektronische Daten] [Kimberly Palmiter, Matthew Tyska, Joe Haeberle, Norman Alpert, Lameh Fananapazir, David Warshaw] Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere. In the β-myosin heavy chain gene, which codes for the mechanical enzyme myosin, greater than 40 point mutations have been found that are causal for this disease. We have studied the effect of two mutations, the R403Q and L908V, on myosin molecular mechanics. In the in vitro motility assay, the mutant myosins produced a 30% greater velocity of actin filament movement (νactin). At the single molecule level, νactin ∼d/t on, where d is the myosin unitary step displacement and t on is the step duration. Laser trap studies were performed at 10 μM MgATP to estimate d and t on for the normal and mutant myosin molecules. The increase in νactin can be explained by a significant decrease in the average t on's in both the R403Q and L908V mutants (∼30 ms) compared to controls (∼40 ms), while d was not different for all myosins tested (∼7 nm). Thus the mutations affect the kinetics of the cross-bridge cycle without any effect on myosin's inherent motion and force generating capacity. Based on these studies, the primary signal for the hypertrophic response appears to be an apparent gain in function of the individual mutant myosin molecules. Kluwer Academic Publishers, 2000 Palmiter Kimberly Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut Tyska Matthew Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut Haeberle Joe Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut Alpert Norman Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut Fananapazir Lameh Division of Cardiology, National Institutes of Health, Bethesda, MD aut Warshaw David E-mail: warshaw@salus.med.uvm.edu aut Journal of Muscle Research & Cell Motility Kluwer Academic Publishers 21/7(2000-10-01), 609-620 0142-4319 21:7<609 2000 21 10974 https://doi.org/10.1023/A:1005678905119 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1005678905119 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Palmiter Kimberly Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut NATIONALLICENCE 700 1- Tyska Matthew Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut NATIONALLICENCE 700 1- Haeberle Joe Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut NATIONALLICENCE 700 1- Alpert Norman Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT aut NATIONALLICENCE 700 1- Fananapazir Lameh Division of Cardiology, National Institutes of Health, Bethesda, MD aut NATIONALLICENCE 700 1- Warshaw David E-mail: warshaw@salus.med.uvm.edu aut NATIONALLICENCE 773 0- Journal of Muscle Research & Cell Motility Kluwer Academic Publishers 21/7(2000-10-01), 609-620 0142-4319 21:7<609 2000 21 10974 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer