A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel

Nat Commun. 2014 Jul 8;5:4377. doi: 10.1038/ncomms5377.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Bilayers
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Potassium Channels, Tandem Pore Domain / chemistry*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Protein Conformation
  • Water
  • Xenopus

Substances

  • KCNK1 protein, human
  • Lipid Bilayers
  • Potassium Channels, Tandem Pore Domain
  • Water