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Cell Res. 2016 Sep;26(9):977-94. doi: 10.1038/cr.2016.99. Epub 2016 Aug 30.

Structural insights into Ca(2+)-activated long-range allosteric channel gating of RyR1.

Author information

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.

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.

PMID:
27573175
PMCID:
PMC5034117
DOI:
10.1038/cr.2016.99
[Indexed for MEDLINE]
Free PMC Article

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