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

Prafulla Aryal; Viwan Jarerattanachat; Michael V Clausen; Marcus Schewe; Conor McClenaghan; Liam Argent; Linus J Conrad; Yin Y Dong; Ashley C W Pike; Elisabeth P Carpenter; Thomas Baukrowitz; Mark S P Sansom; Stephen J Tucker

doi:10.1016/j.str.2017.03.006

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

Structure. 2017 May 2;25(5):708-718.e2. doi: 10.1016/j.str.2017.03.006. Epub 2017 Apr 6.

Authors

Affiliations

¹ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
² Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
³ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
⁴ Department of Physiology, University of Kiel, 24118 Kiel, Germany.
⁵ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
⁶ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
⁷ Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
⁸ OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
⁹ Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK. Electronic address: mark.sansom@bioch.ox.ac.uk.
¹⁰ Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK. Electronic address: stephen.tucker@physics.ox.ac.uk.

Abstract

The 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.

Keywords: K(+) channel gating; K2P channel; KCNK10; KCNK2; KCNK4; Mechanosensitive; TREK-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Ion Channel Gating*
Lipid Bilayers / chemistry
Mechanotransduction, Cellular
Potassium Channels, Tandem Pore Domain / chemistry*
Potassium Channels, Tandem Pore Domain / metabolism

Substances

KCNK10 protein, human
Lipid Bilayers
Potassium Channels, Tandem Pore Domain

Abstract

Publication types

MeSH terms

Substances

Grants and funding