Potassium dependent structural changes in the selectivity filter of HERG potassium channels

Carus H. Y. Lau, Emelie Flood, Mark J. Hunter, Billy J. Williams-Noonan, Karen M. Corbett, Chai-Ann Ng, James C. Bouwer, Alastair G. Stewart, Eduardo Perozo, Toby W. Allen () and Jamie I. Vandenberg ()
Additional contact information
Carus H. Y. Lau: Victor Chang Cardiac Research Institute
Emelie Flood: RMIT University
Mark J. Hunter: Victor Chang Cardiac Research Institute
Billy J. Williams-Noonan: RMIT University
Karen M. Corbett: RMIT University
Chai-Ann Ng: Victor Chang Cardiac Research Institute
James C. Bouwer: University of Wollongong
Alastair G. Stewart: UNSW Sydney
Eduardo Perozo: The University of Chicago
Toby W. Allen: RMIT University
Jamie I. Vandenberg: Victor Chang Cardiac Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K+ sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.

Date: 2024
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DOI: 10.1038/s41467-024-51208-w

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