K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions

Marco Lolicato; Andrew M Natale; Fayal Abderemane-Ali; David Crottès; Sara Capponi; Ramona Duman; Armin Wagner; John M Rosenberg; Michael Grabe; Daniel L Minor Jr

doi:10.1126/sciadv.abc9174

K_2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions

Sci Adv. 2020 Oct 30;6(44):eabc9174. doi: 10.1126/sciadv.abc9174. Print 2020 Oct.

Authors

Marco Lolicato¹, Andrew M Natale¹, Fayal Abderemane-Ali¹, David Crottès², Sara Capponi¹, Ramona Duman³, Armin Wagner³, John M Rosenberg⁴, Michael Grabe^{5

6}, Daniel L Minor Jr^{5

7

8

9

10}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, CA 93858-2330, USA.
² Department of Physiology, University of California, San Francisco, CA 93858-2330, USA.
³ Science Division, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
⁴ Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
⁵ Cardiovascular Research Institute, University of California, San Francisco, CA 93858-2330, USA. michael.grabe@ucsf.edu daniel.minor@ucsf.edu.
⁶ Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 93858-2330, USA.
⁷ Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 93858-2330, USA.
⁸ California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA 93858-2330, USA.
⁹ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA, 93858-2330, USA.
¹⁰ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720 USA.

Abstract

K_2P potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K_2Ps is unknown. Here, combining K_2P2.1 (TREK-1) x-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and electrophysiology, we uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K_2P C-type gating. These asymmetric order-disorder transitions, enabled by the K_2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K_2P SF2-M4 loop and conserved "M3 glutamate network," and are suppressed by the K_2P C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K_2P channel modulator development.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

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