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

ABSTRACT: 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 acce

SUBMITTER: Turney TS 

PROVIDER: S-EPMC9184524 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature