Title | The Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Bai, X-C, Yan, Z, Wu, J, Li, Z, Yan, N |
Journal | Cell Res |
Volume | 26 |
Issue | 9 |
Pagination | 995-1006 |
Date Published | 2016 Sep |
ISSN | 1748-7838 |
Keywords | Allosteric Regulation, Animals, Cryoelectron Microscopy, Cytoplasm, Excitation Contraction Coupling, Ion Channel Gating, Models, Molecular, Protein Domains, Rabbits, Ryanodine Receptor Calcium Release Channel, Structure-Activity Relationship |
Abstract | <p>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.</p> |
DOI | 10.1038/cr.2016.89 |
Alternate Journal | Cell Res |
PubMed ID | 27468892 |
PubMed Central ID | PMC5034110 |
Grant List | MC_UP_A025_1013 / MRC_ / Medical Research Council / United Kingdom / HHMI / Howard Hughes Medical Institute / United States |