Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18425-30. doi: 10.1073/pnas.1212754109. Epub 2012 Oct 22.
Cooperative activation of actin-myosin interaction by tropomyosin (Tm) is central to regulation of contraction in muscle cells and cellular and intracellular movements in nonmuscle cells. The steric blocking model of muscle regulation proposed 40 y ago has been substantiated at both the kinetic and structural levels. Even with atomic resolution structures of the major players, how Tm binds and is designed for regulatory function has remained a mystery. Here we show that a set of periodically distributed evolutionarily conserved surface residues of Tm is required for cooperative regulation of actomyosin. Based on our results, we propose a model of Tm on a structure of actin-Tm-myosin in the "open" (on) state showing potential electrostatic interactions of the residues with both actin and myosin. The sites alternate with a second set of conserved surface residues that are important for actin binding in the inhibitory state in the absence of myosin. The transition from the closed to open states requires the sites identified here, even when troponin + Ca(2+) is present. The evolutionarily conserved residues are important for actomyosin regulation, a universal function of Tm that has a common structural basis and mechanism.
原肌球蛋白（Tm）对肌球蛋白-肌动蛋白相互作用的协同激活是肌肉细胞收缩和非肌肉细胞内和细胞运动调节的核心。40 年前提出的肌肉调节的空间位阻模型在动力学和结构水平上都得到了证实。即使有主要参与者的原子分辨率结构，原肌球蛋白的结合方式和设计用于调节功能仍然是一个谜。在这里，我们表明 Tm 的一组周期性分布的进化上保守的表面残基对于肌球蛋白-肌动蛋白的协同调节是必需的。基于我们的结果，我们提出了一个肌动蛋白-Tm-肌球蛋白的“开放”（on）状态的结构模型，显示了残基与肌动蛋白和肌球蛋白之间潜在的静电相互作用。这些位点与第二个保守的表面残基交替，在没有肌球蛋白的情况下，这些残基在抑制状态下对于肌动蛋白的结合很重要。从关闭状态到开放状态的转变需要这里鉴定的位点，即使存在肌钙蛋白+Ca（2+）也是如此。进化上保守的残基对于肌球蛋白-肌动蛋白的调节很重要，这是 Tm 的一种普遍功能，具有共同的结构基础和机制。
