Shifts in the selectivity filter dynamics cause modal gating in K+ channels

Shehrazade Jekhmane, João Medeiros-Silva, Jing Li, Felix Kümmerer, Christoph Müller-Hermes, Marc Baldus, Benoît Roux and Markus Weingarth ()
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Shehrazade Jekhmane: Utrecht University
João Medeiros-Silva: Utrecht University
Jing Li: The University of Chicago
Felix Kümmerer: Utrecht University
Christoph Müller-Hermes: Utrecht University
Marc Baldus: Utrecht University
Benoît Roux: The University of Chicago
Markus Weingarth: Utrecht University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Spontaneous activity shifts at constant experimental conditions represent a widespread regulatory mechanism in ion channels. The molecular origins of these modal gating shifts are poorly understood. In the K+ channel KcsA, a multitude of fast activity shifts that emulate the native modal gating behaviour can be triggered by point-mutations in the hydrogen bonding network that controls the selectivity filter. Using solid-state NMR and molecular dynamics simulations in a variety of KcsA mutants, here we show that modal gating shifts in K+ channels are associated with important changes in the channel dynamics that strongly perturb the selectivity filter equilibrium conformation. Furthermore, our study reveals a drastically different motional and conformational selectivity filter landscape in a mutant that mimics voltage-gated K+ channels, which provides a foundation for an improved understanding of eukaryotic K+ channels. Altogether, our results provide a high-resolution perspective on some of the complex functional behaviour of K+ channels.

Date: 2019
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DOI: 10.1038/s41467-018-07973-6

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