Structural basis for the regulation of muscle contraction by troponin and tropomyosin
Structural basis for the regulation of muscle contraction by troponin and tropomyosin
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DOI：
10.1016/j.jmb.2008.04.062
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发表时间：
2008-06-20
影响因子：
5.6
通讯作者：
Lehman, William
中科院分区：
文献类型：
--
作者：
Galinska-Rakoczy, Agnieszka;Engel, Patti;Lehman, William
控制骨骼肌和心肌收缩的分子开关机制将肌钙蛋白上的Ca 2+结合到肌动蛋白丝上的原肌球蛋白的运动。尽管多年的研究，这种机制仍然不清楚，因为它还没有能够直接评估肌钙蛋白对原肌球蛋白的结构影响，导致肌动蛋白丝，因此肌球蛋白-横桥循环和收缩，打开和关闭。肌钙蛋白I的C-末端结构域被认为与诱导原肌球蛋白运动到抑制位置密切相关，该抑制位置阻断肌球蛋白-跨桥相互作用。在Ca 2+与TnC（肌钙蛋白的Ca 2+传感器，可解除抑制作用）结合后，肌动蛋白释放这种调节性闭锁结构域，可能使原肌球蛋白运动离开肌动蛋白上的抑制位置，从而启动收缩。然而，TnI（肌钙蛋白的“抑制性”亚基）的调节结构域与引起原肌球蛋白运动的原肌球蛋白和肌动蛋白的结构相互作用是未知的，因此，调节过程没有很好地定义。在这里，用代表C-末端TnI的工程结构标记细丝，然后，使用3D电子显微镜来解析肌钙蛋白锚定在肌动蛋白原肌球蛋白上的位置。电子显微镜重建显示，肌钙蛋白I bindin的肌动蛋白和原肌球蛋白在低钙竞争与原肌球蛋白的一个共同的网站上的肌动蛋白和驱动原肌球蛋白运动到一个受约束的，放松的位置，以抑制肌球蛋白交联协会。因此，报告的观察结果揭示了肌钙蛋白-原肌球蛋白介导的肌动蛋白-肌球蛋白相互作用的空间干扰调节肌肉收缩的结构机制。(C)2008爱思唯尔有限公司保留所有权利。
The molecular switching mechanism governing skeletal and cardiac muscle contraction couples the binding of Ca2+ on troponin to the movement of tropomyosin on actin filaments. Despite years of investigation, this mechanism remains unclear because it has not yet been possible to directly assess the structural influence of troponin on tropomyosin that causes actin filaments, and hence myosin-crossbridge cycling and contraction, to switch on and off. A C-terminal domain of troponin I is thought to be intimately involved in inducing tropomyosin movement to an inhibitory position that blocks myosin-crossbridge interaction. Release of this regulatory, latching domain from actin after Ca2+ binding to TnC (the Ca2+ sensor of troponin that relieves inhibition) presumably allows tropomyosin movement away from the inhibitory position on actin, thus initiating contraction. However, the structural interactions of the regulatory domain of TnI (the "inhibitory" subunit of troponin) with tropomyosin and actin that cause tropomyosin movement are unknown, and thus, the regulatory process is not well defined. Here, thin filaments were labeled with an engineered construct representing C-terminal TnI, and then, 3D electron microscopy was used to resolve where troponin is anchored on actin-tropomyosin. Electron microscopy reconstruction showed how TnI bindin to both actin and tropomyosin at low Ca2+ competes with tropomyosin for a common site on actin and drives tropomyosin movement to a constrained, relaxing position to inhibit myosin-crossbridge association. Thus, the observations reported reveal the structural mechanism responsible for troponin-tropomyosin-mediated steric interference of actin-myosin interaction that regulates muscle contraction. (C) 2008 Elsevier Ltd. All rights reserved.