TY  - JOUR
AU  - Kostritskii, Andrei Y.
AU  - Kostritskaia, Yulia
AU  - Dmitrieva, Natalia
AU  - Stauber, Tobias
AU  - Machtens, Jan-Philipp
TI  - Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 122
IS  - 18
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - FZJ-2025-02439
SP  - e2421900122
PY  - 2025
N1  - 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.
AB  - 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1073/pnas.2421900122
UR  - https://juser.fz-juelich.de/record/1041803
ER  -