Structural Basis for pH-gating of the K+ channel TWIK1 at the selectivity filter

TWIK1 is a pH-gated K + channel highly expressed in brain and heart that contributes to cardiac rhythm and insulin release. Here, Turney et al. use cryo-EM and electrophysiology to show how TWIK1 gates closed in response to lowered pH through conformational changes centered at the selectivity filter. TWIK1 (K2P1.1, KCNK1) is a widely expressed pH-gated two-pore domain K+ channel (K2P) that contributes to cardiac rhythm generation and insulin release from pancreatic beta cells. TWIK1 displays unique properties among K2Ps including low basal activity and inhibition by extracellular protons through incompletely understood mechanisms. Here, we present cryo-EM structures of TWIK1 in lipid nanodiscs at high and low pH that reveal a previously undescribed gating mechanism at the K+ selectivity filter. At high pH, TWIK1 adopts an open conformation. At low pH, protonation of an extracellular histidine results in a cascade of conformational changes that close the channel by sealing the top of the selectivity filter, displacing the helical cap to block extracellular ion access pathways, and opening gaps for lipid block of the intracellular cavity. These data provide a mechanistic understanding for extracellular pH-gating of TWIK1 and illustrate how diverse mechanisms have evolved to gate the selectivity filter of K+ channels.

Automated summary

Researchers use cryo-EM and electrophysiology to discover the gating mechanism of the TWIK1 channel in response to lowered pH. They find that conformational changes at the selectivity filter lead to the closure of the channel. This study provides mechanistic insights into the pH-gating of TWIK1 and sheds light on the diversity of gating mechanisms in K+ channels.