Architecture and conformational switch mechanism of the ryanodine receptor

Muscle contraction is initiated by the release of calcium (Ca 2+ ) from the sarcoplasmic reticulum into the cytoplasm of myocytes through ryanodine receptors (RyRs). RyRs are homotetrameric channels with a molecular mass of more than 2.2 megadaltons that are regulated by several factors, including ions, small molecules and proteins. Numerous mutations in RyRs have been associated with human diseases. The molecular mechanism underlying the complex regulation of RyRs is poorly understood. Using electron cryomicroscopy, here we determine the architecture of rabbit RyR1 at a resolution of 6.1 Å. We show that the cytoplasmic moiety of RyR1 contains two large α-solenoid domains and several smaller domains, with folds suggestive of participation in protein–protein interactions. The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. We identify the calcium-binding EF-hand domain and show that it functions as a conformational switch allosterically gating the channel. Using electron cryomicroscopy, the structure of the rabbit RyR1 calcium channel is determined at 6.1 Å resolution in the closed state and 8.5 Å in the open state, revealing how calcium binding to the EF-hand of RyR1 regulates channel opening and facilitates calcium-induced calcium release. Ryanodine receptor structure Muscle contraction is regulated by the concentration of calcium ions in the cytoplasm of muscle cells. Ryanodine receptors (RyR) release Ca 2+ from the sarcoplasmic reticulum to induce muscle contraction. Dysfunction of these channels contributes to the pathophysiology of important human diseases including muscular dystrophy. Three papers in this issue of Nature report high-resolution electron cryomicroscopy structures of the 2.2 MDa ryanodine receptor RyR1. Efremov et al . report the structure of rabbit RyR1 at 8.5 Å resolution the presence of Ca 2+ in a 'partly open' state, and at 6.1 Å resolution in the absence of Ca 2+ in a closed state. Zalk et al . report the rabbit RyR1 structure at 4.8 Å in the absence of Ca 2+ in a closed state. And third, Yan et al . report the structure of rabbit RyR1 bound to its modulator FKBP12 at a near-atomic resolution of 3.8 Å. These papers reveal how calcium binding to the EF-hand domain of RyR1 regulates channel opening and facilitates calcium-induced calcium release. The authors also note that disease-causing mutations are clustered in regions of the channel that appear to be critical for normal channel f