Ion currents through Kir potassium channels are gated by anionic lipids

Ruitao Jin,Jani R Bolla,Oliver B Clarke,Peter M Colman,Carol V Robinson,Jacqueline M Gulbis,Brian J Smith,Sitong He,Agalya Periasamy,Paul Johnson,Ahmad Wardak,Di Wu,Peter Czabotar,Derek Laver,Katrina A Black

doi:10.1038/s41467-022-28148-4

Abstract

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.

Highlights

Ion currents through potassium channels are gated
To delve deeper into the factors underlying the effect of the Leu[124] collar on permeation, we investigated the energetic barrier encountered by potassium ions at the Leu[124] collar relative to Tyr[132] using all-atom enhanced sampling molecular dynamics (MD) simulations across the Leu[124] collar from the upper vestibule toward the cytosol (Fig. 1e, Supplementary Fig. 4, Supplementary Table 2)
We previously demonstrated that Kir channels conduct K+ through a very narrow pore[4], re-opening the question of how ion permeation is controlled in these channels

Summary

Introduction

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. 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. We have utilised the prokaryotic Kir channel KirBac3.1 to determine whether the acyl tails of bound lipids, protruding into the conduction pathway through fenestrations just below the selectivity filter, might represent key gating elements. We show that acyl tails of tightly bound lipids occupying conserved fenestrations into the pore engage individual side chains of the collar, drawing them away from the central conduction pathway and allowing ions to pass

Methods

Results

Conclusion