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

TitleThe Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening.
Publication TypeJournal Article
Year of Publication2016
AuthorsBai, X-C, Yan, Z, Wu, J, Li, Z, Yan, N
JournalCell Res
Date Published2016 Sep
KeywordsAllosteric Regulation, Animals, Cryoelectron Microscopy, Cytoplasm, Excitation Contraction Coupling, Ion Channel Gating, Models, Molecular, Protein Domains, Rabbits, Ryanodine Receptor Calcium Release Channel, Structure-Activity Relationship

<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>

Alternate JournalCell Res
PubMed ID27468892
PubMed Central IDPMC5034110
Grant ListMC_UP_A025_1013 / MRC_ / Medical Research Council / United Kingdom
/ HHMI / Howard Hughes Medical Institute / United States