title: Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel.
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.
authors.affiliation: 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.
authors.forename: Prafulla
authors.initials: P
authors.lastname: Aryal
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Viwan
authors.initials: V
authors.lastname: Jarerattanachat
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Clausen
authors.affiliation: Department of Physiology, University of Kiel, 24118 Kiel, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schewe
authors.affiliation: 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.
authors.forename: Conor
authors.initials: C
authors.lastname: McClenaghan
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Liam
authors.initials: L
authors.lastname: Argent
authors.affiliation: 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.
authors.forename: Linus J
authors.initials: LJ
authors.lastname: Conrad
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Yin Y
authors.initials: YY
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ashley C W
authors.initials: ACW
authors.lastname: Pike
authors.affiliation: OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Carpenter
authors.affiliation: Department of Physiology, University of Kiel, 24118 Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.affiliation: 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.
authors.forename: Mark S P
authors.initials: MSP
authors.lastname: Sansom
authors.affiliation: 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.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D006801:Humans; D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry; D040542:Mechanotransduction, Cellular; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry* / Q000378:metabolism
chemical_list: C503438:KCNK10 protein, human; D008051:Lipid Bilayers; D024683:Potassium Channels, Tandem Pore Domain
keywords: K(+) channel gating; K2P channel; KCNK10; KCNK2; KCNK4; Mechanosensitive; TREK-2