Hydrophobic gating in BK channels

Zhiguang Jia,Mahdieh Yazdani,Jianmin Cui,Guohui Zhang,Jianhan Chen

doi:10.1038/s41467-018-05970-3

Zhiguang Jia, Mahdieh Yazdani + Show 3 more

Open Access

https://doi.org/10.1038/s41467-018-05970-3

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Journal: Nature Communications	Publication Date: Aug 24, 2018
Citations: 73	License type: open-access

Affiliation: University of Massachusetts Amherst

Abstract

The gating mechanism of transmembrane ion channels is crucial for understanding how these proteins control ion flow across membranes in various physiological processes. Big potassium (BK) channels are particularly interesting with large single-channel conductance and dual regulation by membrane voltage and intracellular Ca2+. Recent atomistic structures of BK channels failed to identify structural features that could physically block the ion flow in the closed state. Here, we show that gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation. Importantly, the dry pore remains physically open and is readily accessible to quaternary ammonium channel blockers. The hydrophobic gating mechanism is also consistent with scanning mutagenesis studies showing that modulation of pore hydrophobicity is correlated with activation properties.

Highlights

Ion channels facilitate the flow of ions through cell membranes via opening of their pores in response to various electrical and chemical signals[1]
We note that the gate observed in this work for the hBK channel belong to an expanding list of examples of ion channels with true hydrophobic gates[23,24,25,26], where the barrier to ion permeation arises directly from dewetting transitions instead of physical blockage generated by the subsequent structural collapse of the pore
It is plausible that the observed changes in the pore geometry and surface hydrophobicity in metal-free Cryo-EM structures prime the pore for dewetting transitions and represent initial steps toward deactivation of BK channels

Summary

Introduction

Ion channels facilitate the flow of ions through cell membranes via opening of their pores in response to various electrical and chemical signals[1]. Most ion channels with the pore adopting a similar membrane topology feature a cytosolic gate that is formed by the bundle crossing of four S6 helices[13, 14], which creates a physical barrier and blocks the ion permeation pathway in the closed state. Free-energy calculations further demonstrate that hydrophobic ions such as small QAs can readily access the deep-pore region with minimal or modest barriers in both dry (closed) and hydrated (open) states. Such a hydrophobic gating mechanism is consistent with findings of scanning mutagenesis studies showing that modulation of the polarity and hydrophobicity of pore-lining residues can be directly correlated with hBK channel activation probabilities[22]. We note that the gate observed in this work for the hBK channel belong to an expanding list of examples of ion channels with true hydrophobic gates[23,24,25,26], where the barrier to ion permeation arises directly from dewetting transitions instead of physical blockage generated by the subsequent structural collapse of the pore

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Conclusion