Year: 2026
Type: preprint
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 π-helical turn in the S6 pore-lining helix (π-conformation). In contrast, a fully α-helical S6 (α-conformation) was observed in the gain-of-function mutant F604P-PKD2 and interpreted as the open state, leading to the proposed π-to-α activation mechanism. However, whether the α-conformation can support function has never been directly established. Here, using molecular dynamics simulations, we investigate the functional properties of the α-and π-conformations of PKD2. The α-conformation remains dewetted unless the lower gate is widened beyond the conformational range observed in mammalian TRP channels. By contrast, the π-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 π-conformation and a dewetted α-conformation. Together, these findings challenge the assignment of the α-conformation as the conductive state and support a model in which the π-conformation represents the functionally relevant state of TRPP channels. This model suggests that activation may involve an α-to-π transition rather than the previously proposed π-to-α 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.
Authors: Chenfeng Zhang, Wojciech Kopec, Julien Michel
Institutions: University of Edinburgh, Queen Mary University of London
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225333605