Bilayer-Mediated Structural Transitions in the TREK-2 Mechanosensitive K2P Channel

Abstract

Mammalian mechanosensitive ion channels are molecular sensors that transduce mechanical stimulus into altered electrical activity of cells. They are involved in numerous physiological processes such as touch, hearing, and cell growth. Recently, crystal structures for several mechanosensitive Two-Pore Domain Potassium channels (K2P) in different conformations have been published. However, functional annotation of these structures remains challenging, especially as these proteins were crystallized in the presence of detergents. Using crystal structures and functional studies of state-dependent inhibitor, we have recently shown that “Down” state of the TREK-2 channel most likely represents a non-stretched closed channel, whereas a more expanded “Up” conformation likely represents that of a stretch-activated channel {1}. To test this hypothesis, we now combine computational and experimental studies to demonstrate that TREK-2 channels can sense forces directly from their surrounding lipids. Molecular dynamics simulation of TREK-2 “Down” channels embedded in phospholipid bilayers reveal that these channels undergo structural transitions when the surrounding bilayer is stretched. The stretched conformations are remarkably similar to several of the “Up” structures published for TREK-2 and TRAAK channels. We further investigated the dynamics of stretch dependent conformational change in the TREK-2 channel and find that coordinated movement of TM4 with respect to TM2 and TM3, which involves interaction between the channel and phospholipids, is also required for successful transition between conformations. These finding demonstrate that stretching the surrounding bilayer leads to compensatory changes in TREK-2 structures and that this underlies mechanosensitive K2P channels’ ability to directly sense forces from the membrane.1. Dong YY et al. K2P channel gating mechanism revealed by structures of TREK-2 and a complex with Prozac Science 2015 Mar 13;347(6227):1256-9.