Ion currents through potassium channels are gated. Constriction of the ion conduction pathway at the inner helix bundle, the textbook gate of Kir potassium channels, has been shown to be an ineffective permeation control, creating a rift in our understanding of how these channels are gated. Here we present evidence that anionic lipids act as interactive response elements sufficient to gate potassium conduction. We demonstrate the limiting barrier to K+ permeation lies within the ion conduction pathway and show that this gate is operated by the fatty acyl tails of lipids that infiltrate the conduction pathway via fenestrations in the walls of the pore. Acyl tails occupying a surface groove extending from the cytosolic interface to the conduction pathway provide a potential means of relaying cellular signals, mediated by anionic lipid head groups bound at the canonical lipid binding site, to the internal gate.
Funding
We thank Mike Lawrence, Xiaowen Xiao and Ziyi Meng for advice and assistance. Diffraction data were collected on the MX2 beamline at the Australian Synchrotron, Victoria, Australia. Crystallisation trials were carried out by Janet Newman at the C3 Parkville Facility. This work was funded by Australian Research Training Scholarships (R.J. and S.H.); Medical Research Council Grant MR/V028839/1 (C.V.R. and J.R.B.); Wellcome Trust Grant No. 104633/Z/14/Z (C.V.R. and D.W.) and for the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission; J.R.B. holds a Royal Society University Research Fellowship; NHMRC Senior Principal Research Fellowship 1116934 (P.M.C.); Australian National Computational Infrastructure, provided through Intersect Australia Ltd. with support from the Australian Government through LIEF grant LE170100032, and the HPC-GPGPU Facility that was established with the assistance of LIEF Grant LE170100200 (B.J.S., S.H. and R.J.); NSW Health infrastructure grant through the Hunter Medical Research Institute (D.L. and P.J.); Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.