TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation
- 1University of Edinburgh
Abstract
PKD2 (TRPP1) is a TRPP ion channel whose dysfunction causes autosomal dominant polycystic kidney disease (ADPKD). Understanding its conformational states and gating mechanism is important for elucidating its function and for structure-based drug discovery. Cryo-EM structures of WT-PKD2 contain a local {pi}-helical turn in the S6 pore-lining helix ({pi}-conformation). In contrast, a fully -helical S6 (-conformation) was observed in the gain-of-function mutant F604P-PKD2 and interpreted as the open state, leading to the proposed {pi}-to- activation mechanism. However, whether the -conformation can support function has never been directly established. Here, using molecular dynamics simulations, we investigate the functional properties of the -and {pi}-conformations of PKD2. The -conformation remains dewetted unless the lower gate is widened beyond the conformational range observed in mammalian TRP channels. By contrast, the {pi}-conformation supports pore hydration and ion conduction following a small opening of the L677 gate, with simulated conductance comparable to experimental measurements. The closely related PKD2L1 (TRPP2) channel shows a similar dependence on conformation, with a hydrated {pi}-conformation and a dewetted -conformation. Together, these findings challenge the assignment of the -conformation as the conductive state and support a model in which the {pi}-conformation represents the functionally relevant state of TRPP channels. This model suggests that activation may involve an -to-{pi} transition rather than the previously proposed {pi}-to- transition, providing a new framework for understanding TRPP channel gating. This work sheds light on the molecular basis of polycystin channel dysfunction and could facilitate the development of PKD2-targeted therapeutic strategies for ADPKD.
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BibTeX
@misc{zhang2026trpp,
title = {{TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation}},
author = {C. Zhang and W. Kopec and J. Michel},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.764271},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation
AU - C. Zhang
AU - W. Kopec
AU - J. Michel
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.764271
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1
AB - PKD2 (TRPP1) is a TRPP ion channel whose dysfunction causes autosomal dominant polycystic kidney disease (ADPKD). Understanding its conformational states and gating mechanism is important for elucidating its function and for structure-based drug discovery. Cryo-EM structures of WT-PKD2 contain a local {pi}-helical turn in the S6 pore-lining helix ({pi}-conformation). In contrast, a fully -helical S6 (-conformation) was observed in the gain-of-function mutant F604P-PKD2 and interpreted as the open state, leading to the proposed {pi}-to- activation mechanism. However, whether the -conformation can support function has never been directly established. Here, using molecular dynamics simulations, we investigate the functional properties of the -and {pi}-conformations of PKD2. The -conformation remains dewetted unless the lower gate is widened beyond the conformational range observed in mammalian TRP channels. By contrast, the {pi}-conformation supports pore hydration and ion conduction following a small opening of the L677 gate, with simulated conductance comparable to experimental measurements. The closely related PKD2L1 (TRPP2) channel shows a similar dependence on conformation, with a hydrated {pi}-conformation and a dewetted -conformation. Together, these findings challenge the assignment of the -conformation as the conductive state and support a model in which the {pi}-conformation represents the functionally relevant state of TRPP channels. This model suggests that activation may involve an -to-{pi} transition rather than the previously proposed {pi}-to- transition, providing a new framework for understanding TRPP channel gating. This work sheds light on the molecular basis of polycystin channel dysfunction and could facilitate the development of PKD2-targeted therapeutic strategies for ADPKD.
ER -