Gravett Molly S C, Klebl David P, Harlen Oliver G, Read Daniel J, Muench Stephen P, Harris Sarah A, Peckham Michelle
Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT Leeds, UK; School of Molecular and Cellular Biology, University of Leeds, LS2 9JT Leeds, UK; School of Physics and Astronomy, University of Leeds, LS2 9JT Leeds, UK.
Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT Leeds, UK; School of Biomedical Sciences, University of Leeds, LS2 9JT Leeds, UK.
Structure. 2024 Dec 5;32(12):2316-2324.e6. doi: 10.1016/j.str.2024.09.025. Epub 2024 Oct 24.
Myosin 5a (Myo5a) is a dimeric processive motor protein that transports cellular cargos along filamentous actin (F-actin). Its long lever is responsible for its large power-stroke, step size, and load-bearing ability. Little is known about the levers' structure and physical properties, and how they contribute to walking mechanics. Using cryoelectron microscopy (cryo-EM) and molecular dynamics (MD) simulations, we resolved the structure of monomeric Myo5a, comprising the motor domain and full-length lever, bound to F-actin. The range of its lever conformations revealed its physical properties, how stiffness varies along its length and predicts a large, 35 nm, working stroke. Thus, the newly released trail head in a dimeric Myo5a would only need to perform a small diffusive search for its new binding site on F-actin, and stress would only be generated across the dimer once phosphate is released from the lead head, revealing new insight into the walking behavior of Myo5a.
肌球蛋白5a（Myo5a）是一种二聚体持续性运动蛋白，它沿着丝状肌动蛋白（F-肌动蛋白）运输细胞货物。其长杠杆负责其大的动力冲程、步长和承载能力。关于杠杆的结构和物理性质，以及它们如何影响行走机制，我们知之甚少。利用冷冻电子显微镜（cryo-EM）和分子动力学（MD）模拟，我们解析了与F-肌动蛋白结合的单体Myo5a的结构，该结构包括运动结构域和全长杠杆。其杠杆构象范围揭示了其物理性质、刚度如何沿其长度变化，并预测了一个35纳米的大工作冲程。因此，二聚体Myo5a中新释放的尾部头部只需对其在F-肌动蛋白上的新结合位点进行小范围的扩散搜索，并且只有当磷酸从领先头部释放时，二聚体才会产生应力，这为Myo5a的行走行为提供了新的见解。
