Potassium dependent structural changes in the selectivity filter of HERG potassium channels
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<sup>+</sup> 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.
Authors
- Carus H. Y. Lau (ORCID: https://orcid.org/0000-0002-4363-181X)
- Alastair G. Stewart (ORCID: https://orcid.org/0000-0002-2070-6030)
- Karen Corbett (ORCID: https://orcid.org/0000-0002-7430-9188)
- Billy J. Williams‐Noonan (ORCID: https://orcid.org/0000-0002-6900-3862)
- Jamie I. Vandenberg (ORCID: https://orcid.org/0000-0002-3859-3716)
- Mark J. Hunter
- James C. Bouwer (ORCID: https://orcid.org/0000-0003-2384-070X)
- Toby W. Allen (ORCID: https://orcid.org/0000-0002-3521-7950)
- E. A. Flood (ORCID: https://orcid.org/0000-0002-1981-9636)
- Chai‐Ann Ng (ORCID: https://orcid.org/0000-0002-3120-5450)
- Eduardo Perozo (ORCID: https://orcid.org/0000-0001-7132-2793)
Institutions
- Victor Chang Cardiac Research Institute (AU)
- University of Wollongong (AU)
- UNSW Sydney (AU)
- University of Chicago (US)
- MIT University (MK)
- St Vincent's Clinic (AU)
- RMIT University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s41467-024-51208-w
- Citations
- 21
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 4.91
Funders
- Victor Chang Cardiac Research Institute
- Medical Advances Without Animals Trust
- University of New South Wales
- New South Wales Government
- National Institutes of Health
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Office of Extramural Research, National Institutes of Health