Nov 25, 2013

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

BioRxiv : the Preprint Server for Biology
Guopeng RenDaniel L Minor

Abstract

K2P channels regulate nervous, cardiovascular, and immune system functions1,2 through the action of their selectivity filter (C type) gate3-6. Although structural studies show K2P conformations that impact activity7-13, no selectivity filter conformational changes have been observed. Here, combining K2P2.1 (TREK 1) X ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and functional studies, we uncover the unprecedented, asymmetric, potassium dependent conformational changes underlying K2P C type gating. Low potassium concentrations evoke conformational changes in selectivity filter strand 1 (SF1), selectivity filter strand 2 (SF2), and the SF2 transmembrane helix 4 loop (SF2 M4 loop) that destroy the S1 and S2 ion binding sites and are suppressed by C-type gate activator ML335. Shortening the uniquely long SF2-M4 loop to match the canonical length found in other potassium channels or disrupting the conserved Glu234 hydrogen bond network supporting this loop blunts C type gate response to various physical and chemical stimuli. Glu234 network destabilization also compromises ion selectivity, but can be reversed by channel activation, indicating that the ion binding site ...Continue Reading

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