title: Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.
abstract: 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.
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Risheng
authors: R
authors: Wei
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xue
authors: X
authors: Wang
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Yan
authors: Y
authors: Zhang
authors: Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors: Saptarshi
authors: S
authors: Mukherjee
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.|Electron Microscopy Analysis Laboratory, The Health Science Center, Peking University, Beijing 100191, China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Qiang
authors: Q
authors: Chen
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Xinrui
authors: X
authors: Huang
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Shan
authors: S
authors: Jing
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Congcong
authors: C
authors: Liu
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Shuang
authors: S
authors: Li
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Guangyu
authors: G
authors: Wang
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Yaofang
authors: Y
authors: Xu
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.
authors: Sujie
authors: S
authors: Zhu
authors: Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors: Alan J
authors: AJ
authors: Williams
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China.|Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Fei
authors: F
authors: Sun
authors: Department of Biophysics, The Health Science Center, Peking University, Beijing 100191, China.|Electron Microscopy Analysis Laboratory, The Health Science Center, Peking University, Beijing 100191, China.|Center for Protein Science, Peking University, Beijing 100871, China.
authors: Chang-Cheng
authors: CC
authors: Yin
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D020832:EF Hand Motifs; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D000072417:Protein Domains; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium