Instability in the central region of tropomyosin modulates the function of its overlapping ends

The causal link between disparate tropomyosin (Tm) functions and the structural instability in Tm is unknown. To test the hypothesis that the structural instability in the central region of Tm modulates the function of the overlapping ends of contiguous Tm dimers, we used transgenic mice (Tm(DM)) that expressed a mutant α-Tm in the heart; S229E and H276N substitutions induce structural instability in the central region and the overlapping ends of Tm, respectively. In addition, two mouse cardiac troponin T mutants (TnT(1-44Δ) and TnT(45-74Δ)) that have a divergent effect on the overlapping ends of Tm were employed. The S229E-induced instability in the central region of Tm(DM) altered the overlapping ends of Tm(DM), thereby it negated the attenuating effect of H276N on Ca(2+)-activated maximal tension. The rate of cross-bridge detachment (g) decreased in Tm(DM)+TnT(WT) and Tm(H276N)+TnT(WT) fibers but increased in Tm(DM)+TnT(45-74Δ) fibers; however, TnT(45-74Δ) did not alter g, demonstrating that S229E in Tm(DM) had divergent effects on g. The S229E substitution in Tm(DM) ablated the H276N-induced desensitization of myofilament Ca(2+) sensitivity in Tm(DM)+TnT(1-44Δ) fibers. To our knowledge, novel findings from this study show that the structural instability in the central region of Tm modifies cardiac contractile function via its effect on the overlapping ends of contiguous Tm.