Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Institute of Biological Information Processing (IBI-7), Forschungszentrum Jülich, 52425 Jülich, Germany.
Structure. 2021 Jan 7;29(1):50-60.e4. doi: 10.1016/j.str.2020.09.013. Epub 2020 Oct 15.
Heart contraction depends on a complicated array of interactions between sarcomeric proteins required to convert chemical energy into mechanical force. Cyclic interactions between actin and myosin molecules, controlled by troponin and tropomyosin, generate the sliding force between the actin-based thin and myosin-based thick filaments. Alterations in this sophisticated system due to missense mutations can lead to cardiovascular diseases. Numerous structural studies proposed pathological mechanisms of missense mutations at the myosin-myosin, actin-tropomyosin, and tropomyosin-troponin interfaces. However, despite the central role of actomyosin interactions a detailed structural description of the cardiac actomyosin interface remained unknown. Here, we report a cryo-EM structure of a cardiac actomyosin complex at 3.8 Å resolution. The structure reveals the molecular basis of cardiac diseases caused by missense mutations in myosin and actin proteins.
心脏收缩依赖于肌节蛋白之间复杂的相互作用网络，这些蛋白将化学能转化为机械力。肌动蛋白和肌球蛋白分子之间的循环相互作用受肌钙蛋白和原肌球蛋白的控制，产生肌动蛋白丝和肌球蛋白丝之间的滑动力。由于错义突变，这个复杂系统的改变可能导致心血管疾病。大量的结构研究提出了肌球蛋白-肌球蛋白、肌动蛋白-原肌球蛋白和原肌球蛋白-肌钙蛋白界面错义突变的病理机制。然而，尽管肌球蛋白和肌动蛋白的相互作用起着核心作用，但心脏肌球蛋白和肌动蛋白界面的详细结构描述仍然未知。在这里，我们报道了一个分辨率为 3.8Å 的心脏肌球蛋白复合物的冷冻电镜结构。该结构揭示了肌球蛋白和肌动蛋白蛋白中的错义突变导致心脏疾病的分子基础。
