Hauptseite > Publikationsdatenbank > Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4 > print

001     1041803
005     20260123203310.0
024 7 _ |a 10.1073/pnas.2421900122
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024 7 _ |a 10.34734/FZJ-2025-02439
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037 _ _ |a FZJ-2025-02439
082 _ _ |a 500
100 1 _ |a Kostritskii, Andrei Y.
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245 _ _ |a Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4
260 _ _ |a Washington, DC
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|b National Acad. of Sciences
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500 _ _ |a 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.
520 _ _ |a 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.
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536 _ _ |a DFG project G:(GEPRIS)291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853)
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700 1 _ |a Kostritskaia, Yulia
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700 1 _ |a Dmitrieva, Natalia
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700 1 _ |a Stauber, Tobias
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700 1 _ |a Machtens, Jan-Philipp
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773 _ _ |a 10.1073/pnas.2421900122
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|t Proceedings of the National Academy of Sciences of the United States of America
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|y 2025
|x 0027-8424
856 4 _ |u https://juser.fz-juelich.de/record/1041803/files/PNAS_Kostritskii_Dmitrieva_Machtens_03_2025.pdf
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