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

X 射线衍射和分子动力学揭示心肌病突变的结构研究

• 批准号: 23612005
• 负责人: YAMAGUCHI Maki
• 金额: $ 3.41万
• 依托单位: Jikei University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23612005/
• 关键词: 心筋症; X線回折; 分子動力学; トロポニン; Ｘ線回折

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.

E244D-和K247R-肌钙蛋白-T (TnT) 突变体会​​导致家族性肥厚型心肌病，已被证明可以增强心肌的钙依赖性收缩。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，并对在缺乏肌钙蛋白 I (TnI) 的情况下引入野生型/E244D/K247R 突变体 TnT 的心肌纤维进行了 X 射线衍射实验。当将E244D-TnT引入心脏纤维时，与引入野生型-TnT的那些相比，反映肌球蛋白与肌动蛋白相互作用的量的赤道反射的强度比(1,1/1,0)增加。另一方面，分子动力学模拟表明，K247R-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，在这两种突变体中，将通过完全不同的机制诱导增强的张力发展，从而引发心肌肥大。

项目成果

肥大型心筋症の下人となるトロポニン変異体導入筋の構造・機能解析

引入肌钙蛋白突变体的肌肉的结构和功能分析，该肌肉在肥厚性心肌病中发挥作用

• 发表时间: 2013
• 作者: 小林剛;近藤茂忠;二川健;曽我部正博;山口眞紀
• 通讯作者: 山口眞紀

肥大型心筋症の原因となる変異トロポニン導入筋の構造解析

导致肥厚型心肌病的突变肌钙蛋白转导肌的结构分析

• 发表时间: 2011
• 作者: 山口眞紀;木村雅子;竹森重;大野哲生;渡辺賢;湯本正寿;八木直人
• 通讯作者: 八木直人

Mechanical and structural characteristics of cardiac muscle fibers with tropoin-T mutant causing hypertrophic cardiomyopathy

肌钙蛋白-T突变体导致肥厚型心肌病心肌纤维的力学和结构特征

• 发表时间: 2013
• 作者: Yamaguchi;M.;Kimura M.;Takemori S.;Ohno T;Nakahara N.;Yokomizo S.;and Yagi N.
• 通讯作者: and Yagi N.