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Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel

Nature volume 481, pages 94–97 (2012)Cite this article

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Abstract

High-conductance voltage- and Ca2+-activated K+ channels function in many physiological processes that link cell membrane voltage and intracellular Ca2+ concentration, including neuronal electrical activity, skeletal and smooth muscle contraction, and hair cell tuning1,2,3,4,5,6,7,8. Like other voltage-dependent K+ channels, Ca2+-activated K+ channels open when the cell membrane depolarizes, but in contrast to other voltage-dependent K+ channels, they also open when intracellular Ca2+ concentrations rise. Channel opening by Ca2+ is made possible by a structure called the gating ring, which is located in the cytoplasm. Recent structural studies have defined the Ca2+-free, closed, conformation of the gating ring, but the Ca2+-bound, open, conformation is not yet known9. Here we present the Ca2+-bound conformation of the gating ring. This structure shows how one layer of the gating ring, in response to the binding of Ca2+, opens like the petals of a flower. The degree to which it opens explains how Ca2+ binding can open the transmembrane pore. These findings present a molecular basis for Ca2+ activation of K+ channels and suggest new possibilities for targeting the gating ring to treat conditions such as asthma and hypertension.

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Figure 1: The BK channel and the gating ring.
Figure 2: The flexible interface and the assembly interface.
Figure 3: A Ca 2+ -gating model for the BK channel.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the reported crystal structure have been deposited into the Protein Data Bank under accession code 3U6N.

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Acknowledgements

We thank staff members at NSLS X29, Brookhaven National Laboratory, for beamline assistance, and members of the MacKinnon laboratory for discussion. We thank P. Hoff and members of the Gadsby laboratory for help with oocyte preparation. R.M. is an investigator in the Howard Hughes Medical Institute. The research is supported by the American Asthma Foundation grant 07-0127.

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Authors and Affiliations

  1. Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA ,

    Peng Yuan, Manuel D. Leonetti, Yichun Hsiung & Roderick MacKinnon

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  1. Peng Yuan
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  2. Manuel D. Leonetti
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  3. Yichun Hsiung
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  4. Roderick MacKinnon
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Contributions

P.Y. purified and crystallized the protein, collected the X-ray diffraction data, determined the structure and conducted electrophysiology recordings. M.D.L. aided in initial crystallization and electrophysiology experiments. Y.H. provided assistance with protein expression. P.Y. and R.M. designed the research and analysed data. P.Y., M.D.L. and R.M. prepared the manuscript.

Corresponding author

Correspondence to Roderick MacKinnon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Table 1 and Supplementary Figures 1-5 with legends. (PDF 3949 kb)

Supplementary Movie 1

This movie shows a morph between the Ca2+-free, closed and Ca2+-bound, open conformations of the BK channel gating ring (RCK1 in blue and RCK2 in red). At 20 seconds, a close-up view at the assembly interface around the Ca2+ bowl is started. At 30 seconds, the pore domain is shown on top of the gating ring. The modeling of the closed and the open conformations of the pore and the gating ring is described in the paper. The N-terminal residues Lys 343 from the RCK1 domains and the last residues from the inner helices are shown as black spheres. The linkers connecting the inner helices to the gating ring are illustrated as dashed lines colored in black. (MPG 16218 kb)

Supplementary Movie 2

This movie shows a morph between the closed (PDB 2FY8) and the open (PDB 1LNQ) conformations of the MthK channel gating ring. (MPG 3686 kb)

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Yuan, P., Leonetti, M., Hsiung, Y. et al. Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel. Nature 481, 94–97 (2012). https://doi.org/10.1038/nature10670

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