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

TitleStructure of the rabbit ryanodine receptor RyR1 at near-atomic resolution.
Publication TypeJournal Article
Year of Publication2015
AuthorsYan, Z, Bai, X, Yan, C, Wu, J, Li, Z, Xie, T, Peng, W, Yin, C, Li, X, Scheres, SHW, Shi, Y, Yan, N
JournalNature
Volume517
Issue7532
Pagination50-55
Date Published2015 Jan 01
ISSN1476-4687
KeywordsAlgorithms, Allosteric Regulation, Animals, Cryoelectron Microscopy, Ion Channel Gating, Models, Molecular, Molecular Weight, Protein Multimerization, Protein Structure, Tertiary, Rabbits, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Tacrolimus Binding Protein 1A, Zinc Fingers
Abstract

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.

DOI10.1038/nature14063
Alternate JournalNature
PubMed ID25517095
PubMed Central IDPMC4338550
Grant ListMC_UP_A025_1013 / / Medical Research Council / United Kingdom