Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Nat Commun. 2020 Feb 17;11(1):922. doi: 10.1038/s41467-020-14573-w.
Ryanodine receptors (RyR) are ion channels responsible for the release of Ca from the sarco/endoplasmic reticulum and play a crucial role in the precise control of Ca concentration in the cytosol. The detailed permeation mechanism of Ca through RyR is still elusive. By using molecular dynamics simulations with a specially designed Ca model, we show that multiple Ca ions accumulate in the upper selectivity filter of RyR1, but only one Ca can occupy and translocate in the narrow pore at a time, assisted by electrostatic repulsion from the Ca within the upper selectivity filter. The Ca is nearly fully hydrated with the first solvation shell intact during the whole permeation process. These results suggest a remote knock-on permeation mechanism and one-at-a-time occupation pattern for the hydrated Ca within the narrow pore, uncovering the basis underlying the high permeability and low selectivity of the RyR channels.
Ryanodine 受体（RyR）是一种离子通道，负责从肌浆/内质网释放 Ca，并在精确控制细胞质中 Ca 浓度方面发挥着关键作用。Ca 通过 RyR 的详细渗透机制仍难以捉摸。通过使用专门设计的 Ca 模型进行分子动力学模拟，我们表明多个 Ca 离子在 RyR1 的上选择性过滤器中积累，但只有一个 Ca 可以在静电排斥的辅助下一次占据并在狭窄的孔中转运，来自上选择性过滤器中的 Ca。在整个渗透过程中，Ca 几乎完全水合，第一溶剂化壳完整。这些结果表明，在狭窄的孔内，水合 Ca 具有远程碰撞渗透机制和逐个占据模式，揭示了 RyR 通道高渗透性和低选择性的基础。
