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Mapping the sequence of conformational changes underlying selectivity filter gating in the Kv11.1 potassium channel

Nature Structural & Molecular Biology volume 18, pages 35–41 (2011)Cite this article

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Abstract

The potassium channel selectivity filter both discriminates between K+ and sodium ions and contributes to gating of ion flow. Static structures of conducting (open) and nonconducting (inactivated) conformations of this filter are known; however, the sequence of protein rearrangements that connect these two states is not. We show that closure of the selectivity filter gate in the human Kv11.1 K+ channel (also known as hERG, for ether-a-go-go–related gene), a key regulator of the rhythm of the heartbeat, is initiated by K+ exit, followed in sequence by conformational rearrangements of the pore domain outer helix, extracellular turret region, voltage sensor domain, intracellular domains and pore domain inner helix. In contrast to the simple wave-like sequence of events proposed for opening of ligand-gated ion channels, a complex spatial and temporal sequence of widespread domain motions connect the open and inactivated states of the Kv11.1 K+ channel.

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Figure 1: Schematic representation of topology and energetics of gating in Kv11.1 channels.
Figure 2: Measurement of inactivation in Kv11.1 channels.
Figure 3: Mutations in the outer turret affect energetics of Kv11.1 inactivation.
Figure 4: Mutations adjacent to the selectivity filter affect a late step in Kv11.1 inactivation.
Figure 5: Mutations in transmembrane and cytoplasmic domains affect dynamics of Kv11.1 inactivation.
Figure 6: External K+ concentration affects energetics of K+ channel inactivation.
Figure 7: Japanese puzzle box model of allosteric control of selectivity filter gating.

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Acknowledgements

We thank E. Perozo for providing preprints of papers in press; R.M Graham, A. Husain, L. Lee, B. Martinac, E. Perozo and M. Sunde for participating in critical discussions and for reading the manuscript; and K. Wyse and T. Marciniec for making technical contributions. This research was supported by project grants from the National Health and Medical Research Council of Australia (NHMRC, grants 459402 and 635520) and fellowships to J.V. (NHMRC grant 459401) and to A.H. (National Heart Foundation of Australia grant PF 08S 3956).

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  1. David T Wang and Adam P Hill: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Cardiology and Biophysics Division, Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, New South Wales, Australia

    David T Wang, Adam P Hill, Stefan A Mann, Peter S Tan & Jamie I Vandenberg

  2. St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales, Australia

    David T Wang, Adam P Hill, Stefan A Mann & Jamie I Vandenberg

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Correspondence to Jamie I Vandenberg.

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Wang, D., Hill, A., Mann, S. et al. Mapping the sequence of conformational changes underlying selectivity filter gating in the Kv11.1 potassium channel. Nat Struct Mol Biol 18, 35–41 (2011). https://doi.org/10.1038/nsmb.1966

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