Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution

Zhen Yan, Xiao-chen Bai, Chuangye Yan, Jianping Wu, Zhangqiang Li, Tian Xie, Wei Peng, Chang-cheng Yin, Xueming Li, Sjors H. W. Scheres (), Yigong Shi () and Nieng Yan ()
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Zhen Yan: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University
Xiao-chen Bai: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK
Chuangye Yan: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University
Jianping Wu: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University
Zhangqiang Li: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University
Tian Xie: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University
Wei Peng: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University
Chang-cheng Yin: the Health Science Center & Center for Protein Science, Peking University
Xueming Li: Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK
Yigong Shi: Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University
Nieng Yan: State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University

Nature, 2015, vol. 517, issue 7532, 50-55

Abstract: Abstract The ryanodine receptors (RyRs) are high-conductance intracellular Ca2+ channels that play a pivotal role in the excitation–contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 Å, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities.

Date: 2015
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DOI: 10.1038/nature14063

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