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Structure of the Ryanodine Receptor/Calcium Release Channel

Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca2+) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation–contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle cryo-electron microscopy at an overall resolution of 4.8A° We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended a-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+.

Ryanodine receptor

The architecture of RyR1 at 4.8A° . (a) View from the plane of the sarcoplasmic reticulum membrane of a slab of density (blue mesh) coinciding with the channel axis. (b) Colour-coded schematic representation of the RyR1. B-sol, bridge solenoid; C-sol, core solenoid; N-sol, N-terminus solenoid. (c) Viewin the plane of the sarcoplasmic reticulummembrane. (d) View from the cytosol. (e) View from the lumen of the density map of skeletal muscle RyR1 at 5.0° resolution, with one protomer segmented according to the domains assigned in the model, coloured as follows: blue, N-terminal domain; cyan, SPRY1, SPRY2 and SPRY3; salmon, clamp region (RY12 repeats), and phosphorylation domain (RY34 repeats); yellow, calstabin; green, the bridge solenoid scaffold; red, the core solenoid; and orange, transmembrane and C-terminal domains; purple, putative Ca2+-binding domain (EF). Dashed lines represent major disordered segments. LINK TO ARTICLE