The E59D/D75Y double mutation in cardiac troponin C reduced the number of myosin S-1 binding sites on regulated thin filaments by approximately 23% (from 4.8 to 3.7 mol per mol filament).
The E59D/D75Y mutation in cardiac troponin C likely causes dilated cardiomyopathy by altering thin filament conformation and reducing accessible myosin binding sites, thereby lowering contractile force.
Effect estimate: 23% reduction
Absolute Event Rate: 3.7% vs 4.8%
In this study we explore the mechanisms by which a double mutation (E59D/D75Y) in cardiac troponin C (CTnC) associated with dilated cardiomyopathy reduces the Ca(2+)-activated maximal tension of cardiac muscle. Studying the single mutants (i.e. E59D or D75Y) indicates that D75Y, but not E59D, causes a reduction in the calcium affinity of CTnC in troponin complex, regulated thin filaments (RTF), and the Ca(2+) sensitivity of contraction and ATPase in cardiac muscle preparations. However, both D75Y and E59D are required to reduce the actomyosin ATPase activity and maximal force in muscle fibers, indicating that E59D enhances the effects of D75Y. Part of the reduction in force/ATPase may be due to a defect in the interactions between CTnC and cardiac troponin T, which are known to be necessary for ATPase activation. An additional mechanism for the reduction in force/ATPase comes from measurements of the binding stoichiometry of myosin subfragment-1 (S-1) to the RTF. Using wild type RTFs, 4.8 mol S-1 was bound per mol filament (seven actins), whereas with E59D/D75Y RTFs, the number of binding sites was reduced by approximately 23% to 3.7. Altogether, these results suggest that the reduction in force and ATPase activation is possibly due to a thin filament conformation that promotes fewer accessible S-1-binding sites. In the absence of any family segregation data, the functional results presented here support the concept that this is likely a dilated cardiomyopathy-causing mutation.
Dweck et al. (Wed,) conducted a other in Dilated cardiomyopathy. E59D/D75Y double mutation in cardiac troponin C vs. Wild type cardiac troponin C was evaluated on Binding stoichiometry of myosin subfragment-1 (S-1) to regulated thin filaments (23% reduction). The E59D/D75Y double mutation in cardiac troponin C reduced the number of myosin S-1 binding sites on regulated thin filaments by approximately 23% (from 4.8 to 3.7 mol per mol filament).
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