Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.
Department of Biological Sciences, University of Massachusetts-Lowell, Lowell, MA, USA.
J Muscle Res Cell Motil. 2020 Mar;41(1):23-38. doi: 10.1007/s10974-019-09501-5. Epub 2019 Feb 15.
Tropomyosin, best known for its role in the steric regulation of muscle contraction, polymerizes head-to-tail to form cables localized along the length of both muscle and non-muscle actin-based thin filaments. In skeletal and cardiac muscles, tropomyosin, under the control of troponin and myosin, moves in a cooperative manner between blocked, closed and open positions on filaments, thereby masking and exposing actin-binding sites necessary for myosin crossbridge head interactions. While the coiled-coil signature of tropomyosin appears to be simple, closer inspection reveals surprising structural complexity required to perform its role in steric regulation. For example, component α-helices of coiled coils are typically zippered together along a continuous core hydrophobic stripe. Tropomyosin, however, contains a number of anomalous, functionally controversial, core amino acid residues. We argue that the atypical residues at this interface, including clusters of alanines and a charged aspartate, are required for preshaping tropomyosin to readily fit to the surface of the actin filament, but do so without compromising tropomyosin rigidity once the filament is assembled. Indeed, persistence length measurements of tropomyosin are characteristic of a semi-rigid cable, in this case conducive to cooperative movement on thin filaments. In addition, we also maintain that tropomyosin displays largely unrecognized and residue-specific torsional variance, which is involved in optimizing contacts between actin and tropomyosin on the assembled thin filament. Corresponding twist-induced stiffness may also enhance cooperative translocation of tropomyosin across actin filaments. We conclude that anomalous core residues of tropomyosin facilitate thin filament regulatory behavior in a multifaceted way.
原肌球蛋白，以其在肌肉收缩的空间调节中的作用而闻名，通过头尾聚合形成电缆，定位于肌肉和非肌肉肌动蛋白细纤维的长度上。在骨骼肌和心肌中，原肌球蛋白在肌钙蛋白和肌球蛋白的控制下，以协作的方式在细丝的封闭、关闭和开放位置之间移动，从而掩盖和暴露肌球蛋白横桥头相互作用所需的肌动蛋白结合位点。虽然原肌球蛋白的卷曲螺旋特征似乎很简单，但仔细观察发现，为了执行其在空间调节中的作用，需要惊人的结构复杂性。例如，卷曲螺旋的组成α-螺旋通常沿着连续的核心疏水区段拉链在一起。然而，原肌球蛋白包含许多异常的、功能上有争议的核心氨基酸残基。我们认为，该界面处的非典型残基，包括丙氨酸簇和带电荷的天冬氨酸，对于原肌球蛋白的预成型以适应肌动蛋白丝的表面是必需的，但在组装细丝后不会影响原肌球蛋白的刚性。事实上，原肌球蛋白的持久长度测量值是半刚性电缆的特征，在这种情况下有利于细纤维上的协作运动。此外，我们还认为原肌球蛋白显示出很大程度上未被识别的和残基特异性的扭转变化，这涉及到在组装的细纤维上优化肌动蛋白和原肌球蛋白之间的接触。相应的扭曲诱导的刚度也可以增强原肌球蛋白在肌动蛋白丝上的协同易位。我们的结论是，原肌球蛋白的异常核心残基以多方面的方式促进细纤维的调节行为。
