Division of Cell Biology and Imaging, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Physiology and Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA.
Nature. 2023 Nov;623(7988):853-862. doi: 10.1038/s41586-023-06691-4. Epub 2023 Nov 1.
Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state; how titin and cMyBP-C may contribute to length-dependent activation; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
心脏的泵血功能是由肌球蛋白丝提供动力的，肌球蛋白丝拉动肌动蛋白丝产生心脏收缩。除了肌球蛋白，这些细丝还包含肌球蛋白结合蛋白 C（cMyBP-C），它可以响应生理刺激调节收缩性，以及titin，它作为细丝组装的支架。肌球蛋白、cMyBP-C 和 titin 都可能发生突变，从而导致心力衰竭。尽管心肌丝对于生命至关重要，但它们的分子结构在 60 年来一直是个谜。在这里，我们使用冷冻电子显微镜解决了人类心肌丝主要（包含 cMyBP-C）区域的结构问题。重建结果揭示了 titin 和 cMyBP-C 的结构，并展示了肌球蛋白的马达结构域（头部）如何形成三种不同类型的基序（提供功能灵活性），这些基序相互作用，与 titin 和 cMyBP-C 相互作用，从而决定了细丝的结构和功能。肌球蛋白尾部在细丝骨架中的包装也得到了解决。该结构表明了 cMyBP-C 如何帮助产生心脏超松弛状态；titin 和 cMyBP-C 如何有助于长度依赖性激活；以及肌球蛋白和 cMyBP-C 的突变如何可能干扰相互作用，导致疾病。该重建解决了过去的不确定性，并整合了先前关于心肌结构和功能的研究数据。它为解释结构、生理和临床观察以及潜在治疗药物的设计提供了一个新的范例。
