Journal Article

FZJ-2025-02439

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4

Kostritskii, A. Y. (Corresponding author)FZJ* ; Kostritskaia, Y. ; Dmitrieva, N.FZJ* ; Stauber, T. ; Machtens, J.-P. (Corresponding author)FZJ*

2025
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2421900122  doi:10.34734/FZJ-2025-02439

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 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.

Note: 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.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)
2. DFG project G:(GEPRIS)291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853) (291198853)

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