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The structure of the native CNGA1/CNGB1 CNG channel from bovine retinal rods

Nature Structural & Molecular Biology volume 29, pages 32–39 (2022)Cite this article

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Abstract

In rod photoreceptors of the retina, the cyclic nucleotide-gated (CNG) channel is composed of three CNGA and one CNGB subunits, and it closes in response to light activation to generate an electrical signal that is conveyed to the brain. Here we report the cryo-EM structure of the closed state of the native rod CNG channel isolated from bovine retina. The structure reveals differences between CNGA1 and CNGB1 subunits. Three CNGA1 subunits are tethered at their C terminus by a coiled-coil region. The C-helix in the cyclic nucleotide-binding domain of CNGB1 features a different orientation from that in the three CNGA1 subunits. The arginine residue R994 of CNGB1 reaches into the ionic pathway and blocks the pore, thus introducing an additional gate, which is different from the central hydrophobic gate known from homomeric CNGA channels. These results address the long-standing question of how CNGB1 subunits contribute to the function of CNG channels in visual and olfactory neurons.

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Fig. 1: The rod CNG channel from bovine retina.
Fig. 2: Architecture of the rod CNG channel.
Fig. 3: The ion conduction pathway.
Fig. 4: Conservation of the CNGB gate in rod and cone CNG channels.

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Data availability

Atomic coordinates and density map have been deposited at the wwPDB and the EMDB under accession numbers PDB 7O4H and EMD-12718, respectively. Source data are provided with this paper.

Change history

  • 22 November 2022

    In the version of this article initially published, author U. Benjamin Kaupp’s name was tagged incorrectly in the article XML, and has now been corrected.

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Acknowledgements

J.M. received funding from Holcim Stiftung (Holderbank, Switzerland), Promedica Stiftung (no. 1461/M), Swiss National Science Foundation (SNSF) (no. 19082) and from Novartis Stiftung for Biomedical Research (no. 20C198). G.F.X.S. acknowledges SNSF grants no. 173335 and no. 192760. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are indebted to M. Peterek at the Scientific Center for Optical and Electron Microscopy (ScopeM) of ETH Zurich, who has provided training and support during acquisition of the datasets on the Titan Krios. We are grateful to our colleagues at the Paul Scherrer Institut who maintain the Merlin HPC cluster.

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Authors and Affiliations

  1. Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland

    Diane C. A. Barret, Gebhard F. X. Schertler & Jacopo Marino

  2. Department of Biology, ETH-Zurich, Zurich, Switzerland

    Gebhard F. X. Schertler

  3. Center for Advanced European Studies and Research (CAESAR), Bonn, Germany

    U. Benjamin Kaupp

  4. Life and Medical Sciences Institute LIMES, University of Bonn, Bonn, Germany

    U. Benjamin Kaupp

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Contributions

G.F.X.S., U.B.K. and J.M. conceived the project. D.C.A.B. and J.M. purified the sample and prepared grids for cryo-EM. D.C.A.B. and J.M. collected data at the microscope. J.M. performed single-particle analysis. D.C.A.B. modeled the atomic model. D.C.A.B. and J.M. analyzed the structure. J.M. performed bioinformatic analysis on protein sequences. J.M. and U.B.K. wrote the manuscript and made figures, with contributions from all coauthors.

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Correspondence to Jacopo Marino.

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G.F.X.S. is a co-founder and scientific advisor of the company leadXpro AG and InterAx Biotech AG. The remaining authors declare no competing interests.

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Nature Structural and Molecular Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Florian Ullrich was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Cryo-EM single-particle analysis.

a, Representative micrograph from one of the three datasets. b, Summary of the single-particle pipeline used to obtain the final density map used for model building.

Extended Data Fig. 2 FSC curves and details of the density map.

a, On the left, gold-standard FSC curves of the final 3D reconstruction, and on the right, FSC curve for validation of map and model. b, Euler angle distribution of the set of particles that contribute to the final density map. c, Local resolution of the final density map shown at different threshold values (as displayed in Chimera) and different orientations.

Extended Data Fig. 3 Cryo-EM density map of CNGA1 and relative atomic model of selected regions.

The density map relative to one of the CNGA1 subunits (chain C) is shown. The map was contoured at threshold values ranging between 0.03 and 0.065 in Chimera.

Extended Data Fig. 4 Cryo-EM density map of CNGB1 and relative atomic model of selected regions.

The density map relative to the CNGB1 subunits (chain D) is shown. The map was contoured at threshold values ranging between 0.03 and 0.065 in Chimera.

Extended Data Fig. 5 Details of the ab-initio model shown with two different contour levels and two orientations.

In a, the cytoplasmic region of the CNGB1 subunit, and transmembrane region of neighboring CNGA1 is indicated. In b, the transmembrane region of the CNGB1 subunit is indicated. Here, the S2-S3 loop of CNGB1 is visible only at lower threshold. The map thresholds indicated in a are also applied to the density maps shown in b.

Extended Data Fig. 6 Structural alignment between the four chains composing the rod CNG channel.

Model chain A, B, and C belong to the CNGA1 subunit, and chain D belongs to the CNGB1 subunit.

Extended Data Fig. 7 Intersubunit interfaces at contact distance within the cytoplasmic region.

On top, overview of the CNGA1/CNGB1 structure, with the areas of the interfaces making contacts indicated within boxes. On the bottom, close-up of the interactions taking place between neighboring subunits, with distances between chosen residues indicated (in Å). The structures of TAX-4 in closed (PDB: 6WEJ) and open state (PDB: 6WEK) are shown for comparison.

Extended Data Fig. 8 Structural alignment between this structure, hCNGA1, and TAX-4 structures.

a, Superposition of single subunits of bovine CNGA1 (chain A, this structure) with TAX-4 in closed-state (PDB: 6WEJ) and human CNGA1 (hCNGA1) in closed-state (PDB: 7LFT). Superposition of the cytoplasmic domains of CNGA1 and CNGB1 (this structure), with TAX-4 in closed (b, d) (PDB: 6WEJ), and TAX-4 in open state (PDB: 6WEK) (c, e).

Extended Data Fig. 9 Details of the distance between the S4-S5 loop and the C-linker.

a, Overview of the CNGA1/CNGB1 structure, with region indicated for the S4-S5 loop and the C-linker of two neighboring CNGA1, and CNGA1/CNGB1 subunits. On the left, panels contain details of model and map and distance (in Å) of selected residues on the S4-S5 loop and on the A’ helix of the C-linker. b, The distance between the S4-S5 loop and the A’ helix of the C-linker of hCNGA1 in closed state (PDB: 7LFT), in open state (PDB: 7LFX), and for TAX-4 in closed state (PDB: 6WEJ).

Extended Data Fig. 10 Details of the loop C-terminal to the P-helix in the CNBD.

a, Structural alignment of CNGA1, CNGB1, TAX-4 in closed state (PDB: 6WEJ), HCN1 in closed state (PDB: 5U6O), and SthK (PDB: 6CJQ). The region of the CNBD is shown, with emphasis on the loop that follows the P-helix. b, Details of the density map at the loop connecting the C-helix and the coiled-coiled region in one of the CNGA1 subunits. K554 and D608 are indicated as possible electrostatic interaction c, Sequence alignment of the loop region among CNG subunits (Bos taurus) and other CNG channels. d, The last C-terminal125 residues of the indicated sequences were used as input for DeepCoil for calculating the propensity of the C-terminus to form a coiled-coil.

Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2.

Reporting Summary

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Supplementary Data 1

Sequence alignment of CNGB1 protein sequences at the S6 segment region.

Supplementary Data 2

Sequence alignment of CNGB3 protein sequences at the S6 segment region.

Source data

Source Data Fig. 1

Unprocessed gel of Fig. 1b

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Barret, D.C.A., Schertler, G.F.X., Kaupp, U.B. et al. The structure of the native CNGA1/CNGB1 CNG channel from bovine retinal rods. Nat Struct Mol Biol 29, 32–39 (2022). https://doi.org/10.1038/s41594-021-00700-8

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