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

Author

Listed:
  • Carus H. Y. Lau

    (Victor Chang Cardiac Research Institute
    UNSW Sydney)

  • Emelie Flood

    (RMIT University)

  • Mark J. Hunter

    (Victor Chang Cardiac Research Institute
    UNSW Sydney)

  • Billy J. Williams-Noonan

    (RMIT University)

  • Karen M. Corbett

    (RMIT University)

  • Chai-Ann Ng

    (Victor Chang Cardiac Research Institute
    UNSW Sydney)

  • James C. Bouwer

    (University of Wollongong)

  • Alastair G. Stewart

    (UNSW Sydney
    Victor Chang Cardiac Research Institute)

  • Eduardo Perozo

    (The University of Chicago)

  • Toby W. Allen

    (RMIT University)

  • Jamie I. Vandenberg

    (Victor Chang Cardiac Research Institute
    UNSW Sydney)

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.

Suggested Citation

  • 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 & Jamie I. Vandenbe, 2024. "Potassium dependent structural changes in the selectivity filter of HERG potassium channels," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51208-w
    DOI: 10.1038/s41467-024-51208-w
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    References listed on IDEAS

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    1. Shehrazade Jekhmane & João Medeiros-Silva & Jing Li & Felix Kümmerer & Christoph Müller-Hermes & Marc Baldus & Benoît Roux & Markus Weingarth, 2019. "Shifts in the selectivity filter dynamics cause modal gating in K+ channels," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Carlos A. Z. Bassetto & Flavio Costa & Carlo Guardiani & Francisco Bezanilla & Alberto Giacomello, 2023. "Noncanonical electromechanical coupling paths in cardiac hERG potassium channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Jared Ostmeyer & Sudha Chakrapani & Albert C. Pan & Eduardo Perozo & Benoît Roux, 2013. "Recovery from slow inactivation in K+ channels is controlled by water molecules," Nature, Nature, vol. 501(7465), pages 121-124, September.
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    5. Luis G. Cuello & Vishwanath Jogini & D. Marien Cortes & Eduardo Perozo, 2010. "Structural mechanism of C-type inactivation in K+ channels," Nature, Nature, vol. 466(7303), pages 203-208, July.
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