|Title||Architecture and conformational switch mechanism of the ryanodine receptor.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Efremov, R. G., A. Leitner, R. Aebersold, and S. Raunser|
|Date Published||2015 Jan 01|
|Keywords||Allosteric Regulation, Animals, Calcium, Cryoelectron Microscopy, Cytoplasm, Hydrogen-Ion Concentration, Inositol 1,4,5-Trisphosphate Receptors, Ion Channel Gating, Models, Molecular, Protein Binding, Protein Structure, Tertiary, Rabbits, Ryanodine Receptor Calcium Release Channel, Tacrolimus Binding Protein 1A|
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.
Architecture and conformational switch mechanism of the ryanodine receptor.