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

E244D和K247R-肌钙蛋白-T(TNT)突变可导致家族性肥厚型心肌病，已被证明可增强心肌钙依赖的收缩。为了阐明这种增强的机制，我们对肌钙蛋白分子进行了分子动力学模拟，并对心肌纤维进行了X射线衍射实验，在没有肌钙蛋白I(TnI)的情况下，野生型/E244D/K247R突变体TNT被引入到心肌纤维中。当将E244D-TNT引入心肌纤维时，反映肌球蛋白与肌动蛋白相互作用的赤道反射强度比(1，1/1，0)比加入野生型TNT时增加。另一方面，分子动力学模拟表明K247R-TnT突变体中TnT与TnI之间的相互作用发生了变化。这些结果表明，在这两个突变体中，张力发育增强可能是由完全不同的触发心肌肥大的机制引起的。

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.