Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse

Sci Adv. 2023 Dec 8;9(49):eadj5539. doi: 10.1126/sciadv.adj5539. Epub 2023 Dec 8.

Abstract

Eukaryotic voltage-gated K+ channels have been extensively studied, but the structural bases for some of their most salient functional features remain to be established. C-type inactivation, for example, is an auto-inhibitory mechanism that confers temporal resolution to their signal-firing activity. In a recent breakthrough, studies of a mutant of Shaker that is prone to inactivate indicated that this process entails a dilation of the selectivity filter, the narrowest part of the ion conduction pathway. Here, we report an atomic-resolution cryo-electron microscopy structure that demonstrates that the wild-type channel can also adopt this dilated state. All-atom simulations corroborate this conformation is congruent with the electrophysiological characteristics of the C-type inactivated state, namely, residual K+ conductance and altered ion specificity, and help rationalize why inactivation is accelerated or impeded by certain mutations. In summary, this study establishes the molecular basis for an important self-regulatory mechanism in eukaryotic K+ channels, laying a solid foundation for further studies.

MeSH terms

  • Cryoelectron Microscopy
  • Dilatation
  • Ion Channel Gating* / physiology
  • Potassium Channels, Voltage-Gated*

Substances

  • Potassium Channels, Voltage-Gated