title: The Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening.
abstract: The ryanodine receptors (RyRs) are intracellular calcium channels responsible for rapid release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum (SR/ER) to the cytoplasm, which is essential for the excitation-contraction (E-C) coupling of cardiac and skeletal muscles. The near-atomic resolution structure of closed RyR1 revealed the molecular details of this colossal channel, while the long-range allosteric gating mechanism awaits elucidation. Here, we report the cryo-EM structures of rabbit RyR1 in three closed conformations at about 4 Å resolution and an open state at 5.7 Å. Comparison of the closed RyR1 structures shows a breathing motion of the cytoplasmic platform, while the channel domain and its contiguous Central domain remain nearly unchanged. Comparison of the open and closed structures shows a dilation of the S6 tetrahelical bundle at the cytoplasmic gate that leads to channel opening. During the pore opening, the cytoplasmic "O-ring" motif of the channel domain and the U-motif of the Central domain exhibit coupled motion, while the Central domain undergoes domain-wise displacement. These structural analyses provide important insight into the E-C coupling in skeletal muscles and identify the Central domain as the transducer that couples the conformational changes of the cytoplasmic platform to the gating of the central pore.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Xiao-Chen
authors.initials: XC
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China.|Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.|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: State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China.|Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.|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 Membrane Biology, Tsinghua University, Beijing 100084, China.|Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.|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: State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China.|Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.|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: D000494:Allosteric Regulation; D000818:Animals; D020285:Cryoelectron Microscopy; D003593:Cytoplasm / Q000378:metabolism; D056966:Excitation Contraction Coupling; D015640:Ion Channel Gating; 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