%0 Journal Article
%A Kostritskii, Andrei Y.
%A Kostritskaia, Yulia
%A Dmitrieva, Natalia
%A Stauber, Tobias
%A Machtens, Jan-Philipp
%T Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4
%J Proceedings of the National Academy of Sciences of the United States of America
%V 122
%N 18
%@ 0027-8424
%C Washington, DC
%I National Acad. of Sciences
%M FZJ-2025-02439
%P e2421900122
%D 2025
%Z We thank Anna Klemmer and Fan Wang for excellent technical assistance and Dr. Claudia Alleva for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation)—426950122 (MA 7525/1-2, as part of the Research Unit FOR 2518, DynIon, project P4; and MA 7525/2-2, as part of the Research Unit FOR 5046, project P2). We gratefully acknowledge the computing time granted through JARA on the supercomputer JURECA at Forschungszentrum Jülich under Grant No. ano1.
%X 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 atomistic details of the ion-conduction mechanism. Finally, AlphaFold2 structure predictions revealed the importance of the pi helix in TM4 to structure-function relations in TMEM16 and the related OSCA/TMEM63 family, further highlighting the relevance of dynamic pi helices for gating in various ion channels.
%F PUB:(DE-HGF)16
%9 Journal Article
%R 10.1073/pnas.2421900122
%U https://juser.fz-juelich.de/record/1041803