Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA.
Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA
J Gen Physiol. 2019 Mar 4;151(3):316-327. doi: 10.1085/jgp.201812266. Epub 2019 Feb 6.
Our senses of touch and hearing are dependent on the conversion of external mechanical forces into electrical impulses by the opening of mechanosensitive channels in sensory cells. This remarkable feat involves the conversion of a macroscopic mechanical displacement into a subnanoscopic conformational change within the ion channel. The mechanosensitive channel NOMPC, responsible for hearing and touch in flies, is a homotetramer composed of four pore-forming transmembrane domains and four helical chains of 29 ankyrin repeats that extend 150 Å into the cytoplasm. Previous work has shown that the ankyrin chains behave as biological springs under extension and that tethering them to microtubules could be involved in the transmission of external forces to the NOMPC gate. Here we combine normal mode analysis (NMA), full-atom molecular dynamics simulations, and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. NMA reveals that the lowest-frequency modes of motion correspond to fourfold symmetric compression/extension along the channel, and the lowest-frequency symmetric mode for the isolated channel domain involves rotations of the TRP domain, a putative gating element. Finite element modeling reveals that the ankyrin chains behave as a soft spring with a linear, effective spring constantof 22 pN/nm for deflections ≤15 Å. Force-balance analysis shows that the entire channel undergoes rigid body rotation during compression, and more importantly, each chain exerts a positive twisting moment on its respective linker helices and TRP domain. This torque is a model-independent consequence of the bundle geometry and would cause a clockwise rotation of the TRP domain when viewed from the cytoplasm. Force transmission to the channel for compressions >15 Å depends on the nature of helix-helix contact. Our work reveals that compression of the ankyrin chains imparts a rotational torque on the TRP domain, which potentially results in channel opening.
我们的触觉和听觉依赖于感觉细胞中机械敏感通道的打开，将外部机械力转换为电脉冲。这一非凡的壮举涉及将宏观机械位移转换为离子通道内亚纳米级构象变化。机械敏感通道诺莫匹克（NOMPC）负责苍蝇的听觉和触觉，它由四个形成孔的跨膜结构域和四个延伸到细胞质 150 Å 的 29 个锚蛋白重复的螺旋链组成，是一个同源四聚体。以前的工作表明，在拉伸下，锚蛋白链表现为生物弹簧，将它们系在微管上可能涉及将外部力传递到 NOMPC 门。在这里，我们将正常模式分析（NMA）、全原子分子动力学模拟和连续体力学相结合，以表征链条在极端压缩和拉伸下的材料特性。NMA 表明，运动的最低频率模式对应于沿通道的四元对称压缩/拉伸，并且孤立通道域的最低频率对称模式涉及 TRP 结构域的旋转，TRP 结构域是一个潜在的门控元件。有限元建模表明，锚蛋白链表现为软弹簧，在 15 Å 以内的挠度下具有线性、有效弹簧常数为 22 pN/nm。力平衡分析表明，整个通道在压缩过程中经历刚体旋转，更重要的是，每个链在其各自的接头螺旋和 TRP 结构域上施加正扭转力矩。当从细胞质观察时，这种扭矩是束几何形状的模型独立结果，会导致 TRP 结构域的顺时针旋转。对于压缩超过 15 Å 的情况，力传递到通道取决于螺旋-螺旋接触的性质。我们的工作表明，锚蛋白链的压缩会在 TRP 结构域上施加旋转扭矩，这可能导致通道打开。
