Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.
Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.
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Ryanodine受体（RyRs）是一类分子量超过2.2兆道尔顿的巨型离子通道。这些通道在多种细胞中介导钙信号。由于超过80%的RyR蛋白被折叠到细胞质组装体中，剩余的残基形成跨膜结构域，因此假设RyR通道的激活和调节通过尚未表征的长程变构机制发生。在这里，我们报告的Ca 2+激活的开放状态RyR 1结构的低温电子显微镜的表征。该结构的总分辨率为4.9 μ m，核心区域的分辨率为4.2 μ m。在与先前确定的载脂蛋白/封闭状态的结构相比，我们观察到长距离变构门控的通道后，钙激活。深入的结构分析阐明了RyR 1的一种新的通道门控机制和一种新的离子选择性机制。我们的工作不仅为通道门控和RyRs调控的分子机制提供了结构上的见解，而且还揭示了六跨膜螺旋阳离子通道家族的通道门控和离子选择性机制的结构基础。
Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca2+-activated open-state RyR1 structure by cryo-electron microscopy. The structure has an overall resolution of 4.9 Å and a resolution of 4.2 Å for the core region. In comparison with the previously determined apo/closed-state structure, we observed long-range allosteric gating of the channel upon Ca2+ activation. In-depth structural analyses elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism of RyR1. Our work not only provides structural insights into the molecular mechanisms of channel gating and regulation of RyRs, but also sheds light on structural basis for channel-gating and ion selectivity mechanisms for the six-transmembrane-helix cation channel family.
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