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首页> 外文期刊>American Journal of Physiology >Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions
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Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions

机译：肌球蛋白调节轻链突变K104e对肌动蛋白 - 肌球蛋白相互作用的影响

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Familial hypertrophic cardiomyopathy (FHC) is the most common cause of sudden cardiac death in young individuals. Molecular mechanisms underlying this disorder are largely unknown; this study aims at revealing how disruptions in actin-myosin interactions can play a role in this disorder. Cross-bridge (XB) kinetics and the degree of order were examined in contracting myofibrils from the ex vivo left ventricles of transgenic (Tg) mice expressing FHC regulatory light chain (RLC) mutation K104E. Because the degree of order and the kinetics are best studied when an individual XB makes a significant contribution to the overall signal, the number of observed XBs in an ex vivo ventricle was minimized to ~20. Autofiuorescence and photobleaching were minimized by labeling the myosin lever arm with a relatively long-lived red-emitting dye containing a chro-mophore system encapsulated in a cyclic macromolecule. Mutated XBs were significantly better ordered during steady-state contraction and during rigor, but the mutation had no effect on the degree of order in relaxed myofibrils. The K104E mutation increased the rate of XB binding to thin filaments and the rate of execution of the power stroke. The stopped-flow experiments revealed a significantly faster observed dissociation rate in Tg-K104E vs. Tg-wild-type (WT) myosin and a smaller second-order ATP-binding rate for the K104E compared with WT myosin. Collectively, our data indicate that the mutation-induced changes in the interaction of myosin with actin during the contraction-relaxation cycle may contribute to altered contractility and the development of FHC.
机译：家族肥厚性心肌病（FHC）是年轻人心脏猝死最常见的原因。这种疾病的分子机制很大程度上是未知的;本研究旨在揭示肌动蛋白 - 肌球蛋白相互作用的破坏如何在这种疾病中发挥作用。在表达FHC调节轻链（RLC）突变K104E的转基因（TG）小鼠的前体内左心室的收缩肌纤维中，检查了跨桥（XB）动力学和顺序程度。因为当单独的XB对整体信号作出显着贡献时，所以顺序和动力学最佳地研究，所以在exvivo心室中观察到的XB的数量最小化至〜20。通过用含有封装在循环大分子中的CHO- Mophore系统的相对长的红发染料标记肌蛋白杆臂，最小化自动偶像和光漂白。在稳态收缩期间和严格期间，突变的XBS显着更好地订购，但突变对松弛肌原纤维的顺序没有影响。 K104E突变增加了XB结合到薄长丝的速率和电力行程的执行速率。停止流动实验揭示了TG-K104E与Tg-野生型（WT）肌球蛋白的显着更快的观察到率和K104e的较小的二阶ATP结合速率。集体，我们的数据表明，收缩 - 松弛循环期间，肌蛋白与肌动蛋白相互作用的突变诱导的变化可能有助于改变收缩性和FHC的发育。

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