Muscle contraction is initiated by the release of calcium (Ca2+) 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.
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Electron Microscopy Data Bank
Protein Data Bank
The coordinates and electron microscopy density maps for closed and open states have been deposited in the RCSB Protein Data Bank under the accession codes 4UWA and 4UWE, and in the Electron Microscopy Data Bank under the accession codes EMD-2751 and EMD-2752, respectively.
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We are grateful to O. Hofnagel for assistance with electron microscopy facilities and R. S. Goody for continuous support and useful comments on the manuscript. R.G.E. thanks R. Chaves and K. Willegems for assistance with particle selection. We gratefully acknowledge R. Matadeen and S. de Carlo (FEI Company) for image acquisition at the National Center for Electron Nanoscopy in Leiden (NeCEN) which is co-financed by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (project 175.010.2009.001) and by the European Union’s Regional Development Fund through ‘Kansen voor West’ (project 21Z.014). This work was funded by Humboldt Foundation (to R.G.E.), by the ‘Deutsche Forschungsgemeinschaft’ Grant RA 1781/1-1 (to S.R.), the Max Planck Society (to S.R. and R.G.E.), VIB and Vrij Universiteit Brussel (to R.G.E.).
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 Quality of electron microscopy data.
a–j, Data collected on a FEI Titan Krios in 1 mM EGTA (a–e) and on a JEOL 3200 microscope in 10 mM CaCl2 (f–j). a, f, Typical low dose cryo-EM micrographs of RyR1 vitrified in holey carbon grid recorded at an accelerating voltage of 300 kV (a) and 200 kV (f). b, g, Power spectra of the low dose micrographs. Thon rings are visible up to a resolution of 5 Å (b) and 10 Å (g). c, h, Representative two-dimensional class averages calculated in SPARX (c) and RELION (h) show characteristic views of RyR1. d, i, FSC curves between two independently refined half data sets (gold standard) shown for a set of all particles (solid black) and different conformational states (coloured curves). FSC between the volume calculated from all particles and the molecular model of RyR1 are shown as dotted black curves. FSC levels of 0.143 and 0.5 corresponding to the resolution cut off for density maps and the model are indicated. According to the 0.5 criterion the resolution of the model is 8.0 and 9.0 Å for the RyR1 reconstructions of closed and open states. The resolution is slightly lower than that of the map because of incompleteness of the model (the polyalanine model accounts for only about half of all the atoms of RyR1). e, j, Three-dimensional map of RyR1 coloured according to the local resolution calculated in ResMap from two unmasked volumes calculated from independently refined halves of the data sets. The resolution of the electron micoscropy map is heterogeneous with the highest resolution close to the centre of the molecule and the lowest resolution at the periphery. k, Statistics of single particle data.
Extended Data Figure 2 Consensus secondary structure prediction for rabbit RyR1 generated in SABLE.
Extension of domains is indicated by rectangles colour-coded as in Fig. 1. Except for the N-terminal AB domain and the three SPRY domains located in the first 1,650 residues, RyR1 is predicted to fold mainly in α-helices connected with coiled structures. The 165 amino acid sequence between residues 4,375 and 4,540, connecting the amphipathic region with the transmembrane domain, is glycine- and proline-rich and predicted to be disordered.
Extended Data Figure 3 Positions of transmembrane helices.
a, The probability for the formation of transmembrane helices calculated by the program TMHMM is shown for the C-terminal region of RyR1. Red bars indicate α-helices predicted in SABLE. The consensus transmembrane (TM) helices are unambiguously recognized and clearly separated, except of TM3 and TM4, which have nearly no solvent exposed loop in between. The amphipathic and pore helices are also clearly indicated, but have lower hydrophobicity scores than the transmembrane helices. b, Experimental mapping and prediction of transmembrane helices. Sequence ranges of computationally predicted, annotated and experimentally mapped transmembrane helices. Consensus helices between experimental mapping and computational prediction are indicated in bold. Although computational methods suggest just one TM3 helix instead of TM3/4, the width of the hydrophobic region corresponding to helix TM3 is consistent with the presence of two joint transmembrane helices as observed in the topology mapping experiments14.
Extended Data Figure 4 Cross-links identified within RyR1.
a, b, Graphical representation (a) and table (b) summarizing cross-links identified in cross-linking mass spectrometry experiments. a, Schematic representation of RyR1 domains colour-coded similar to domains in Fig. 1. The repeat 3–4 and EF-hand domains are shown as inserts into the α-solenoid 1.1 and α-solenoid 1.2 domains, respectively. The cross-links are shown by red lines. The approximate length of linkers joining domains is indicated by ‘Δ’ followed by the number of residues. Disordered regions of linking fragments are shown as fat dotted lines and their positions in the amino acid sequence are indicated. Domains containing β-sheets are depicted as circles, α-helical domains are shown as squares. b, Cross-linked residues are shown with ID score and their distances in the built model (see Supplementary Table 1 for complete list of identified cross-links).
Extended Data Figure 5 Cryo-EM density map of RyR1 at 6.1 Å resolution.
a–f, Backbone of the model in ribbon representation coloured as in Fig. 1 and cryo-EM density map from different regions of the structure are shown. a, Transmembrane region showing the inner helix and the helices of the voltage-sensor-like domain. The cytoplasmic part of the inner helix (in red) is resolved as good as the transmembrane helices indicating that the resolution inside the lipid nanodisc is similar to the nearby cytoplasmic regions. b, Pore helix and pore loops showing the absence of the second pore helix found in structurally homologous Nav channels. c, d, Helices of α-solenoid domains 1 (c) and 2 (d). e, Fit of the SPRY2 domain in the density. f, One of the least resolved domains, repeat 1–2, rod-shaped densities corresponding to α-helices are visible. g, Structure and density maps of individual domains. Segments of the 6.1 Å RyR1 density map corresponding to individual domains of RyR1 are shown together with the ribbon models of the domains in rainbow colouring from the N terminus (blue) to the C terminus (red). The excellent fitting of the crystallographic model of the N-terminal AB domain (residues 12–532)11 into the density, even revealing conformation of loops that were disordered in the crystal structure, indicates the high quality of our electron microscopy map. The density segment for FKBP bound to RyR1 was extracted from the 8.5 Å cryo-EM map of RyR1 in its open state.
Extended Data Figure 6 Details of the RyR1 structure.
a, The α-helical protrusion in α-solenoid 1 (contoured) includes an 80-Å-long α-helix and a bundle of helices exposed to solvent and represents a potential CaM-binding site. b, The phosphorylation loop (shown schematically since it was not resolved in the crystal structure) of repeat 3–4 (shown in rainbow colouring from N to C terminus) is exposed to solvent. Mutations of seven residues (four of which are shown as blue spheres) close to the potential phosphorylation site cause human diseases suggesting functional importance of this region and its potential involvement in the interaction with Cav1.1 channels. c, FKBP (red) bound to RyR1 resolved in the cryo-EM map of RyR1 in presence of 10 mM Ca2+. It interacts with the SPRY2 and the α-solenoid 1 domains. d, e, Comparison of the backbone of the RyR1 (coloured in red, yellow, green and blue) membrane domain with the TRPV1 channel (grey). Views perpendicular to (d) and parallel to (e) the membrane plane are shown. The tilt of transmembrane helices in the voltage-sensor domain (S1–S4) is different between the two proteins, while positions of inner helices (S6) in the gate region and architecture of the pore region shown as insert in e are similar.
Extended Data Figure 7 Conserved architecture of RyR and IP3R channels.
a, Conserved core between RyRs and IP3Rs. The evolutionarily most conserved and likely functionally important core includes part of the AB domain bridging the C-terminal regions of the α-solenoid 1 (blue), the C terminus of α-solenoid 1 (orange), which is in direct contact with the C-terminal domain (red). To indicate better the extent of the C-terminal domain the corresponding density segments are shown. The helices of the membrane domain are shown in dark blue. In the side view the density of the nanodisc is shown in light grey. The colour coding is identical to Fig. 1. b, c Fit of RyR1 domains in the IP3R1 density map. b, Rigid body fit of the RyR1 domains conserved between IP3Rs and RyRs into the 17 Å resolution cryo-EM density map of IP3R1 (ref. 34) shows a high correlation coefficient of 0.90. c, Positions of the individual domains in RyR1 (grey) compared to their positions in IP3R1 (coloured). The colour coding is the same as in Fig. 1. Although the middle part of the α-solenoid 1 domain is not conserved, the secondary structure prediction of this region in IP3R1 is similar to RyR1 containing mainly α-helices. We therefore included it in the fit and it agrees well with the density. The complete transmembrane region was included in the fit as the architecture of the ion-channel domain is extremely conserved even between more distant channels. With the exception of RIH2 (2155–2477), which shifted by ∼70 Å (this domain for RyR1 corresponds to the α-solenoid 2 domain and is omitted from the figure), all other domains had only minor shifts. The large shift of RIH might be caused by the actual shift that occurred as α-solenoid 2 evolved or by reverse directionality of the solenoid domain (Supplementary Information). d, Conserved sequence regions between RyR1 and IP3R1. Numbering corresponds to rabbit RyR1 and human IP3R1, respectively. The most conserved regions are highlighted in bold.
Extended Data Figure 8 Sequence conservation between RyRs and IP3Rs.
a, b, The most conserved regions between RyRs and IP3Rs are in the N-terminal (a, residues 1–432 rabbit RyR1) and C-terminal (b, residues 3,796–5,037 rabbit RyR1) sequence regions. Amino acid sequences were aligned in CLUSTALW2, the amino acids with conservation >50% were coloured in clustalw colour scheme. Domains with the highest conservation are indicated with black bars. Aligned sequences from top to bottom are: rabbit RyR1, human RyR1, rabbit RyR2, human RyR2, rabbit RyR3, human RyR3, Oikopleura dioica RyR, Caenorhabditis elegans RyR, Drosophila melanogaster RyR, Drosophila melanogaster IP3R and human IP3R1, 2 and 3.
Extended Data Figure 9 Conformational dynamics of RyR1 in closed and open states.
a–c, Collective motions, changes in the gate region and relative domain movements between different conformations in the closed (a) and open (b, c) states. Left panels: on the right, protomers of the respective two states are shown in cartoon representation, on the left, the conformational changes between them are depicted as vector field. Second panel from left: top view on the pore region depicting the S4–S5 linker and the inner pore helices. Third panel form left: membrane domain, C-terminal domain, α-solenoid 1, and EF-hand of two different conformations in solid-cylinder representation. As in Fig. 3c the structures were aligned to the core of the α-solenoid 1 domain preceding the helices that embed the EF-hand. Similarities between the structures point towards an absence of the specific conformational changes between the conformers from the same data set. Right panels show densities of RyR1 dimers corresponding to different conformations with fitted RyR1 models.
This file contains Supplementary Text, Supplementary Table 1 and additional references. (PDF 456 kb)
Conformational changes between open and closed states
The video shows morphs of cryo-EM maps and structures of RyR1 between closed and open states of the channel. First an overview of conformational changes is shown for a dimer. Then the video zooms on conformational changes at the cytoplasmic surface of the membrane where the ion gate is formed by a bundle of four inner helices (the structure is coloured similar to Figure 1) and conformational changes around EF-hand (purple). To better visualize conformational changes around the EF-hand the density maps and structures of a fragment of a RyR1 protomer were aligned to the α-solenoid 1 region preceding the EF-hand (orange, left from the EF-hand), see also Figure 3. (MOV 20666 kb)
Multiple conformations of RyR1 in closed and open states
Morphs of cryo-EM density maps between two extreme conformations of RyR1 in the closed state and between two conformational transition modes identified in the open state. See also Extended Data Figure 9. (MOV 12085 kb)
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Efremov, R., Leitner, A., Aebersold, R. et al. Architecture and conformational switch mechanism of the ryanodine receptor. Nature 517, 39–43 (2015). https://doi.org/10.1038/nature13916
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