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

E244 D-和K247 R-肌钙蛋白-T（TnT）突变体可引起家族性肥厚型心肌病，已被证明可增强心肌的钙依赖性收缩。为了阐明这种增强的机制，我们进行了肌钙蛋白分子的分子动力学模拟，以及与心肌纤维的X-射线衍射实验，其中野生型/E244 D/K247 R突变体TnT已被引入在缺乏肌钙蛋白I（TnI）。当E244 D-TnT被引入心脏纤维时，与引入野生型TnT的那些相比，反映相互作用的肌球蛋白与肌动蛋白的量的赤道反射的强度比（1，1/1，0）增加。另一方面，分子动力学模拟结果表明，K247 R-TnT突变体中TnT和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，增强的张力发展将通过完全不同的机制来引发心肌肥大。

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.