Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4.

ABSTRACT: TMEM16A is a Ca²⁺-activated Cl^- channel that has crucial roles in various physiological and pathological processes. However, the structure of the open state of the channel and the mechanism of Ca²⁺-induced pore opening have remained elusive. Using extensive molecular dynamics simulations, protein structure prediction, and patch-clamp electrophysiology, we demonstrate that TMEM16A opens a hydrated Cl^--conductive pore via a pi-helical transition in transmembrane segment 4 (TM4). We also describe a coupling mechanism that links pi-helical transition and pore opening to the Ca²⁺-induced conformational changes in TMEM16A. Furthermore, we designed a pi-helix-stabilizing mutation (I551P) that facilitates TMEM16A activation, revealing atomisti

SUBMITTER: Kostritskii AY 

PROVIDER: S-EPMC12067253 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature