期刊
JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY
卷 21, 期 7, 页码 609-620出版社
KLUWER ACADEMIC PUBL
DOI: 10.1023/A:1005678905119
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- NHLBI NIH HHS [HL51126, HL59408] Funding Source: Medline
Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere. In the beta -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 (nu (actin)). At the single molecule level, nu (a)ctin similar tod/t(on), where d is the myosin unitary step displacement and t(on) is the step duration. Laser trap studies were performed at 10 muM MgATP to estimate d and t(on) for the normal and mutant myosin molecules. The increase in nu (actin) can be explained by a significant decrease in the average t(on)'s in both the R403Q and L908V mutants (similar to 30 ms) compared to controls (similar to 40 ms), while d was not different for all myosins tested (similar to7 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.
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