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001041803 1001_ $$0P:(DE-Juel1)171961$$aKostritskii, Andrei Y.$$b0$$eCorresponding author
001041803 245__ $$aCalcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4
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001041803 500__ $$aWe 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.
001041803 520__ $$aTMEM16A is a Ca2+-activated Cl- channel that has crucial roles in various physiological and pathological processes. However, the structure of the open state of the channel and the mechanism of Ca2+-induced pore opening have remained elusive. Using extensive molecular dynamics simulations, protein structure prediction, and patch-clamp electrophysiology, we demonstrate that TMEM16A opens a hydrated Cl--conductive pore via a pi-helical transition in transmembrane segment 4 (TM4). We also describe a coupling mechanism that links pi-helical transition and pore opening to the Ca2+-induced conformational changes in TMEM16A. Furthermore, we designed a pi-helix-stabilizing mutation (I551P) that facilitates TMEM16A activation, revealing atomistic details of the ion-conduction mechanism. Finally, AlphaFold2 structure predictions revealed the importance of the pi helix in TM4 to structure-function relations in TMEM16 and the related OSCA/TMEM63 family, further highlighting the relevance of dynamic pi helices for gating in various ion channels.
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001041803 7001_ $$0P:(DE-Juel1)171438$$aKostritskaia, Yulia$$b1
001041803 7001_ $$0P:(DE-Juel1)180309$$aDmitrieva, Natalia$$b2
001041803 7001_ $$0P:(DE-HGF)0$$aStauber, Tobias$$b3
001041803 7001_ $$0P:(DE-Juel1)156429$$aMachtens, Jan-Philipp$$b4$$eCorresponding author
001041803 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2421900122$$gVol. 122, no. 18, p. e2421900122$$n18$$pe2421900122$$tProceedings of the National Academy of Sciences of the United States of America$$v122$$x0027-8424$$y2025
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