Structural study of cardiomyopathy-causing mutaion revealed by X-ray diffraction and molecular dynamics

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The E244D- and K247R-troponin-T (TnT) mutants, which cause familial hypertrophic cardiomyopathy, have been shown to enhance calcium-dependent contraction on cardiac muscle. To clarify the mechanism of this enhancement, we performed molecular dynamics simulation of troponin molecule as well as X-ray diffraction experiments with cardiac muscle fibers to which wild-type/E244D/K247R mutant TnT had been introduced in the absence of troponin I (TnI). When E244D-TnT was introduced into the cardiac fibers, intensity ratio of the equatorial reflection (1,1/1,0), which reflects amount of the interacting myosin to actin increased compared with those to which wild-type-TnT were introduced. On the other hand, molecular dynamics simulation revealed that interaction betweeen TnT and TnI were changed in K247R-TnT mutants. These results indicate that in these two mutants, enhanced tension development would be induced by totally different mechanisms to trigger the hypertrophy of cardiac muscle.