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. 2011 Dec 4;481(7379):94-7.
doi: 10.1038/nature10670.

Open Structure of the Ca2+ Gating Ring in the High-Conductance Ca2+-activated K+ Channel

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Free PMC article

Open Structure of the Ca2+ Gating Ring in the High-Conductance Ca2+-activated K+ Channel

Peng Yuan et al. Nature. .
Free PMC article

Abstract

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

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1. The BK channel and the gating ring
a, Domain topology of the BK channel. Only two opposing subunits are shown for clarity. b, Crystal structure of the Ca2+-bound open gating ring with RCK1 in blue and RCK2 in red. Ca2+ ions are shown as yellow spheres. The N-termini of RCK1 that connect to the C-termini of the inner helices are indicated as green asterisks. c, Structure of the Ca2+-free closed gating ring with RCK1 in blue and RCK2 in red (PDB: 3NAF). d, The RCK1 N-terminal lobes (blue) and the Ca2+-bowls (red) from the Ca2+-bound open gating ring. The diagonal distance between the Cα atoms of the N-terminal residues (Lys 343) is indicated. e, The corresponding region to that shown in d from the closed gating ring (PDB: 3NAF).
Figure 2
Figure 2. The flexible and the assembly interfaces
a, The flexible interface from the open gating ring structure with RCK1 in blue and RCK2 in red. The Ca2+ ions are shown as yellow spheres. The N-and C-terminal lobes of RCK1 and RCK2 are labeled. Large disordered regionsare indicated by dashed lines. b, The flexible interface from the closed gating ring with RCK1 in blue and RCK2 in red (PDB: 3NAF). c, Superposition of the assembly interfaces from the open and the closed gating ring structures.
Figure 3
Figure 3. A Ca2+-gating model for the BK channel
a, Views of the BK channel model with an open gating ring and an open pore. Structure of the Ca2+-bound BK gating ring is docked onto the open MthK channel (PDB: 1LNQ) by aligning the gating rings. Yellow spheres represent Ca2+ ions. The N-terminal residues of RCK1 and the C-terminal residues of the inner helices are shown as black spheres. b, Views of the BK channel model with a Ca2+-free gating ring and a closed pore. Here, the Ca2+-bound gating ring in a is replaced by the Ca2+-free gating ring (PDB: 3NAF) and the open MthK pore in a is replaced by the closed KcsA pore (PDB: 1K4C). The innerhelix from KcsA is truncated to match the length in MthK. See Supplementary Movie 1.

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