Structural insights into Ca^2＋-activated long-range allosteric channel gating of RyR1  

作　　者：Risheng Wei Xue Wang Yan Zhang Saptarshi Mukherjee Lei Zhang Qiang Chen Xinrui Huang Shan Jing Congcong Liu Shuang Li Guangyu Wang Yaofang Xu Sujie Zhu Alan J Williams Fei Sun Chang-Cheng Yin 

机构地区：[1]Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China [2]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [3]College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China [4]Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, UK [5]Electron Microscopy Analysis Laboratory, The Health Science Center, Peking University, Beijing 100191, China [6]Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [7]Center for Protein Science, Peking University, Beijing 100871, China

出　　处：《Cell Research》2016年第9期977-994,共18页细胞研究（英文版）

基　　金：Acknowledgments We thank Dr Anthony Lai （Wales Heart Research Institute, Cardiff University School of Medicine, UK） for advice and suggestions during the course of this research and critically reading this manuscript. This research was supported by grants from the Strategic Priority Research Program of Chinese Academy of Sciences （XDB08030202 to FS）, the National Basic Research Program （973 Program）, the Ministry of Science ＆ Technology of China （Programs 2012CB917200 to CCY and 2014CB910700 to FS）, the National Natural Science Foundation of China （31270768 to CCY） and the Ministry of Education of China （111 Program China to CCY）. All the cryo-EM work and all the intensive computations were performed at Centre for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences （CBI, http：//cbi.ibp.ac.cn）, with the help from Drs Xiaojun Huang and Lunjiang Lin.

摘　　要：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 A° and a resolution of 4.2A° 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.

关 键 词：Ca^2＋ activation cryo-electron microscopy channel gating ion selectivity long-range allostery ryanodine receptor single-particle analysis 

分 类 号：Q[生物学]