Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers
Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers
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DOI：
10.1073/pnas.1809540115
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发表时间：
2018-08-28
影响因子：
11.1
通讯作者：
Spudich, James A.
中科院分区：
文献类型：
--
作者：
Anderson, Robert L.;Trivedi, Darshan V.;Spudich, James A.
β-心肌肌球蛋白是人类心脏收缩的主要运动蛋白，其突变可改变功率输出并导致心肌病。然而，肌球蛋白的内力、速度和ATP酶活性的测量还没有提供一个一致的机制来将突变与肌肉病理联系起来。另一种模型假定肌球蛋白的突变影响了蛋白质的隔离超松弛状态（SRX）的稳定性，ATP水解非常缓慢，从而改变了肌动蛋白可接近的肌球蛋白头的数量。在这里，我们表明，纯化的人β-心肌肌球蛋白部分存在于SRX，并可能在一定程度上对应于一个折返构象的肌球蛋白头周围的粗丝骨干肌纤维中观察到。导致肥厚型心肌病的突变破坏了这种状态，而小分子mavacamten促进了这种状态。这些发现提供了心肌病遗传学和生理学之间的生化和结构联系，并对治疗策略产生了影响。
Mutations in beta-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human beta-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.