Wei Risheng, Wang Xue, Zhang Yan, Mukherjee Saptarshi, Zhang Lei, Chen Qiang, Huang Xinrui, Jing Shan, Liu Congcong, Li Shuang, Wang Guangyu, Xu Yaofang, Zhu Sujie, Williams Alan J, Sun Fei, Yin Chang-Cheng
Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Cell Res. 2016 Sep;26(9):977-94. doi: 10.1038/cr.2016.99. Epub 2016 Aug 30.
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 Ca(2+)-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 Ca(2+) 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.
兰尼碱受体（RyRs）是一类分子量超过220万道尔顿的巨型离子通道。这些通道介导多种细胞中的钙信号传导。由于超过80%的RyR蛋白折叠成细胞质组装体，其余残基形成跨膜结构域，因此有人推测，RyR通道的激活和调节是通过一种尚未明确的长程变构机制实现的。在此，我们报告了通过冷冻电子显微镜对Ca(2+)激活的开放状态RyR1结构的表征。该结构的整体分辨率为4.9 Å，核心区域的分辨率为4.2 Å。与先前确定的无钙/关闭状态结构相比，我们观察到Ca(2+)激活后通道的长程变构门控。深入的结构分析阐明了RyR1的一种新型通道门控机制和一种新型离子选择性机制。我们的工作不仅为RyRs通道门控和调节的分子机制提供了结构见解，也为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提供了线索。
