Bilayer

Mechanotransduction

Cell biology

Biology

Lipid bilayer

Receptor

Mechanosensitive channels

Biochemistry

Membrane

Potassium channel

Crystallography

Gating

Chemistry

Transmembrane domain

Biophysics

Transmembrane protein

Ion channel

Structure

Highlights•Mechanogating of TREK-2 involves movement from the down to up conformation•Simulations sample a wide range of mechanosensitive K2P channel structures•Changes in the pressure profile and state-dependent lipid interactions play a key role•Lipid block of the inner pore does not mediate stretch activationSummaryThe mechanosensitive two-pore domain (K2P) K+ channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the "down" to "up" conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer.Graphical abstract

Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel