Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution

• Published in: Nature (London) 2015-01, Vol.517 (7532), p.50-55
• Main Authors: Yan, Zhen, Bai, Xiao-chen, Yan, Chuangye, Wu, Jianping, Li, Zhangqiang, Xie, Tian, Peng, Wei, Yin, Chang-cheng, Li, Xueming, Scheres, Sjors H. W., Shi, Yigong, Yan, Nieng
• Format: Article
• Language: English
• Subjects: 101/28; 147/28; 631/535/1258/1259; 631/92/269/1146; Algorithms; Allosteric Regulation; Animals; Chemical compounds; Cryoelectron Microscopy; Disease; Humanities and Social Sciences; Ion Channel Gating; Ion channels; Microscopy; Models, Molecular; Molecular structure; Molecular Weight; multidisciplinary; Muscles; Mutation; Physiological aspects; Protein Multimerization; Protein Structure, Tertiary; Rabbits; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine Receptor Calcium Release Channel - ultrastructure; Sarcoplasmic Reticulum - chemistry; Science; Structure; Tacrolimus Binding Protein 1A - chemistry; Tacrolimus Binding Protein 1A - metabolism; Tacrolimus Binding Protein 1A - ultrastructure; Zinc Fingers
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14063

The ryanodine receptors (RyRs) are high-conductance intracellular Ca 2+ channels that play a pivotal role in the excitation–contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 Å, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities. Using electron cryomicroscopy, the structure of the closed-state rabbit ryanodine receptor RyR1 in complex with its modulator FKBP12 is solved at 3.8 Å; in addition to determining structural details of the ion-conducting channel domain, three previously uncharacterized domains help to reveal a molecular scaffold that allows long-range allosteric regulation of channel activities. 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 rab