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

DOI: 10.1126/sciadv.abc9174 DOI Help

Authors: Marco Lolicato (University of California, San Francisco) , Andrew M. Natale (University of California, San Francisco) , Fayal Abderemane-Ali (University of California, San Francisco) , David Crottès (University of California, San Francisco) , Sara Capponi (University of California, San Francisco) , Ramona Duman (Diamond Light Source) , Armin Wagner (Diamond Light Source) , John M. Rosenberg (University of Pittsburgh) , Michael Grabe (University of California, San Francisco) , Daniel L. Minor (University of California, San Francisco; Lawrence Berkeley National Laboratory)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: October 2020

Open Access Open Access

Abstract: K2P 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 K2Ps is unknown. Here, combining K2P2.1 (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 K2P C-type gating. These asymmetric order-disorder transitions, enabled by the K2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K2P SF2-M4 loop and conserved “M3 glutamate network,” and are suppressed by the K2P 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 K2P channel modulator development.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I23-Long wavelength MX

Added On: 03/11/2020 08:27


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Long Wavelength Crystallography