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@ARTICLE{Kostritskii:1041803,
      author       = {Kostritskii, Andrei Y. and Kostritskaia, Yulia and
                      Dmitrieva, Natalia and Stauber, Tobias and Machtens,
                      Jan-Philipp},
      title        = {{C}alcium-activated chloride channel {TMEM}16{A} opens via
                      pi-helical transition in transmembrane segment 4},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {122},
      number       = {18},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {FZJ-2025-02439},
      pages        = {e2421900122},
      year         = {2025},
      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.},
      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.},
      cin          = {IBI-1},
      ddc          = {500},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524) / DFG project G:(GEPRIS)291198853 - FOR 2518:
                      Funktionale Dynamik von Ionenkanälen und Transportern -
                      DynIon - (291198853)},
      pid          = {G:(DE-HGF)POF4-5244 / G:(GEPRIS)291198853},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1073/pnas.2421900122},
      url          = {https://juser.fz-juelich.de/record/1041803},
}