CM01 beamline. European Synchrotron Radiation Facility (ESRF), Grenoble, France.
Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, F-75005, Paris, France.
Nat Commun. 2023 May 31;14(1):3166. doi: 10.1038/s41467-023-38698-w.
To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the 'off' state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the 'off' state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability.
为了节能并精确调节心肌收缩力，心肌肌球蛋白头部处于“关闭”状态，当需要增加收缩力时可转换为“开启”状态。“关闭”状态等同于一种称为“相互作用头部模体（IHM）”的折叠结构，这是所有 2 类肌球蛋白和非肌球蛋白的调节特征。我们在此报告通过冷冻电子显微镜以 3.6 Å 分辨率确定的人类β-心脏肌球蛋白 IHM 结构，提供了稳定“关闭”状态的所有界面的详细信息。该结构表明，这些界面是肥厚型心肌病突变的热点，这些突变被认为通过破坏“关闭”状态而导致过度收缩力。重要的是，心脏和平滑肌肌球蛋白 IHM 结构差异很大，为这些肌肉类型的不同生理调节提供了结构证据。心脏 IHM 结构将有助于开发具有临床应用价值的新型调节 IHM 稳定性的分子。
