Volume 26, No 9, Sep 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 9, September 2016: 977-994 | Open Access
ORIGINAL ARTICLES
Structural insights into Ca2+-activated long-range allosteric channel gating of RyR1
Risheng Wei1,*, Xue Wang2,3,*, Yan Zhang2, Saptarshi Mukherjee4, Lei Zhang1,5, Qiang Chen1, Xinrui Huang1, Shan Jing1, Congcong Liu1, Shuang Li1, Guangyu Wang1, Yaofang Xu1, Sujie Zhu1, Alan J Williams4, Fei Sun2,3,6 and Chang-Cheng Yin1,5,7
1Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China
2National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
3College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
4Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
5Electron Microscopy Analysis Laboratory, The Health Science Center, Peking University, Beijing 100191, China
6Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
7Center for Protein Science, Peking University, Beijing 100871, China
Correspondence: Chang-Cheng Yin, E-mail: ccyin@hsc.pku.edu.cn; Fei Sun,(feisun@ibp.ac.cn)
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.
10.1038/cr.2016.99
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