Shifts in the Selectivity Filter Dynamics Cause Modal Gating in K + Channels

Nat Commun. 2019 Jan 10;10(1):123. doi: 10.1038/s41467-018-07973-6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Hydrogen Bonding
  • Ion Channel Gating / genetics
  • Ion Channel Gating / physiology*
  • Molecular Dynamics Simulation
  • Mutation
  • Potassium / metabolism*
  • Potassium Channels / chemistry
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Protein Conformation
  • Sequence Homology, Amino Acid

Substances

  • Bacterial Proteins
  • Potassium Channels
  • Potassium