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-cardiac myosin in the laser trap assay
1 Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States
2 University of Würzburg, Institute of Pharmacology and Toxicology, Würzburg, Germany
3 Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States
4 Department of Molecular Physiology, University of Vermont, Colchester, United States
5 Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States
6 Harvard Medical School, Department of Genetics, Boston, Massachusetts, United States; Harvard Medical School, Dept. of Genetics, 77 Ave. Louis Pasteur, Boston, Massachusetts, 02115, United States
* To whom correspondence should be addressed. E-mail: warshaw{at}physiology.med.uvm.edu.
Point mutations in cardiac myosin, the heart’s molecular motor, produce distinct clinical phenotypes; hypertrophic (HCM) and dilated cardiomyopathy (DCM). Do mutations alter myosin's molecular mechanics in a manner that is predictive of the clinical outcome? We have directly characterized the maximal force-generating capacity (Fmax) of two HCM- (R403Q, R453C) and two DCM-(S532P, F764L) mutant myosins isolated from homozygous mouse models using a novel load-clamped laser trap assay. Fmax was 50% (R403Q) and 80% (R453C) greater for the HCM mutants compared to wild-type (WT), whereas Fmax was severely depressed for one of the DCM mutants (75% S532P). Although Fmax was normal for the F764L DCM mutant, its actin-activated ATPase activity and actin filament velocity (Vactin) in a motility assay were significantly reduced (Schmitt et al., 2006). These Fmax data combined with previous Vactin measurements suggest that HCM and DCM result from alterations to one or more of myosin's fundamental mechanical properties, with HCM-causing mutations leading to enhanced while DCM-causing mutations lead to depressed function. These mutation-specific changes in mechanical properties must initiate distinct signaling cascades that ultimately lead to the disparate phenotypic responses observed in HCM and DCM.
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