The Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening

• Published in: Cell research Vol. 26; no. 9; pp. 995 - 1006
• Main Authors: Bai, Xiao-Chen, Yan, Zhen, Wu, Jianping, Li, Zhangqiang, Yan, Nieng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2016; Nature Publishing Group
• Subjects: 631/45/269/1146; 631/57/2270/1140; Allosteric Regulation; Animals; Biomedical and Life Sciences; Calcium channels; Cell Biology; Cryoelectron Microscopy; Cytoplasm - metabolism; Excitation Contraction Coupling; Ion Channel Gating; Life Sciences; Models, Molecular; Muscles; Original; original-article; Protein Domains; Rabbits; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine Receptor Calcium Release Channel - ultrastructure; Structure-Activity Relationship; calcium channel; RyR1; membrane transport; excitation-contraction coupling; voltage-gated calcium channels
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2016.89

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 RyRI 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 A° resolution and an open state at 5.7 A°. 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.