title: A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel.
abstract: Recent X-ray crystal structures of the two-pore domain (K2P) family of potassium channels have revealed a unique structural architecture at the point where the cytoplasmic bundle-crossing gate is found in most other tetrameric K(+) channels. However, despite the apparently open nature of the inner pore in the TWIK-1 (K2P1/KCNK1) crystal structure, the reasons underlying its low levels of functional activity remain unclear. In this study, we use a combination of molecular dynamics simulations and functional validation to demonstrate that TWIK-1 possesses a hydrophobic barrier deep within the inner pore, and that stochastic dewetting of this hydrophobic constriction acts as a major barrier to ion conduction. These results not only provide an important insight into the mechanisms which control TWIK-1 channel activity, but also have important implications for our understanding of how ion permeation may be controlled in similar ion channels and pores.
authors.affiliation: 1] Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK [2] Department of Biochemistry, University of Oxford, Oxford OX1 3QX, UK [3] 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.
authors.forename: Firdaus
authors.initials: F
authors.lastname: Abd-Wahab
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bucci
authors.affiliation: 1] Department of Biochemistry, University of Oxford, Oxford OX1 3QX, UK [2] OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.affiliation: 1] Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK [2] OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D000818:Animals; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D014867:Water; D014981:Xenopus
chemical_list: C109137:KCNK1 protein, human; D008051:Lipid Bilayers; D024683:Potassium Channels, Tandem Pore Domain; D014867:Water