title: Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution.
abstract: The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) 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.
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Bai
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Chuangye
authors.initials: C
authors.lastname: Yan
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Zhangqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Biophysics, the Health Science Center & Center for Protein Science, Peking University, Beijing 100191, China.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Yin
authors.affiliation: Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Li
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Sjors H W
authors.initials: SHW
authors.lastname: Scheres
authors.affiliation: Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.|Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Nieng
authors.initials: N
authors.lastname: Yan
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D000818:Animals; D020285:Cryoelectron Microscopy; D015640:Ion Channel Gating; D008958:Models, Molecular; D008970:Molecular Weight; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D012519:Sarcoplasmic Reticulum / Q000737:chemistry; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016335:Zinc Fingers
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A