Myosin-2 is essential for processes as diverse as cell division and muscle contraction. Dephosphorylation of its regulatory light chain promotes an inactive, ‘shutdown’ state with the filament-forming tail folded onto the two heads 1 , which prevents filament formation and inactivates the motors 2 . The mechanism by which this happens is unclear. Here we report a cryo-electron microscopy structure of shutdown smooth muscle myosin with a resolution of 6 Å in the head region. A pseudo-atomic model, obtained by flexible fitting of crystal structures into the density and molecular dynamics simulations, describes interaction interfaces at the atomic level. The N-terminal extension of one regulatory light chain interacts with the tail, and the other with the partner head, revealing how the regulatory light chains stabilize the shutdown state in different ways and how their phosphorylation would allow myosin activation. Additional interactions between the three segments of the coiled coil, the motor domains and the light chains stabilize the shutdown molecule. The structure of the lever in each head is competent to generate force upon activation. This shutdown structure is relevant to all isoforms of myosin-2 and provides a framework for understanding their disease-causing mutations. The structure of myosin-2 in the shutdown state reveals how the shutdown state is stabilized and how phosphorylation of light chains allows myosin to be activated.

中文翻译：

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myosin-2关闭状态的结构

肌球蛋白 2 对细胞分裂和肌肉收缩等多种过程至关重要。其调节轻链的去磷酸化促进了一种不活跃的“关闭”状态，形成长丝的尾巴折叠在两个头部 1 上，这会阻止长丝的形成并使马达 2 失活。发生这种情况的机制尚不清楚。在这里，我们报告了头部区域分辨率为 6 Å 的关闭平滑肌肌球蛋白的冷冻电子显微镜结构。通过将晶体结构灵活地拟合到密度和分子动力学模拟中而获得的伪原子模型描述了原子级的相互作用界面。一条调节轻链的 N 端延伸与尾部相互作用，另一个与伙伴头相互作用，揭示调节性轻链如何以不同方式稳定关闭状态，以及它们的磷酸化如何激活肌球蛋白。卷曲线圈的三个部分、电机域和轻链之间的额外相互作用稳定了关闭分子。每个头部的杠杆结构都能在激活时产生力。这种关闭结构与肌球蛋白 2 的所有同工型相关，并为了解其致病突变提供了框架。关闭状态下肌球蛋白 2 的结构揭示了关闭状态如何稳定以及轻链的磷酸化如何使肌球蛋白被激活。运动域和轻链稳定关闭分子。每个头部的杠杆结构都能在激活时产生力。这种关闭结构与肌球蛋白 2 的所有同工型相关，并为了解其致病突变提供了框架。关闭状态下肌球蛋白 2 的结构揭示了关闭状态如何稳定以及轻链的磷酸化如何使肌球蛋白被激活。运动域和轻链稳定关闭分子。每个头部的杠杆结构都能在激活时产生力。这种关闭结构与肌球蛋白 2 的所有同工型相关，并为了解其致病突变提供了框架。关闭状态下肌球蛋白 2 的结构揭示了关闭状态如何稳定以及轻链的磷酸化如何使肌球蛋白被激活。