Structural basis of lipid-dependent allosteric gating mechanisms for PC1-PC2 ion channel

The polycystin complex, consisting of one polycystin-1 (PC1) and three polycystin-2 (PC2), forms a cation channel localized to the primary cilium and is critically involved in autosomal dominant polycystic kidney disease (ADPKD). This study reveals an allosteric gating mechanism of the PC1-PC2 channel modulated by specific membrane lipids. In typical membrane environments, phosphatidylglycerol (PG) and phosphatidic acid (PA) bind to the channel central pore, maintaining it in a closed state. Dissociation of these lipids transitions the channel to a pre-open state. The cilia-enriched oxysterol 7β,27-dihydroxycholesterol (7β,27-DHC) stabilizes the channel in a more open but still non-conductive conformation through an allosteric mechanism. Lipid-mediated regulation is coupled to large conformational rearrangements of the TOP and voltage-sensor-like domains (VSDs) of the third PC2 subunit, which eventually leads to pore opening. This lipid-dependent modulation is also observed in a gain-of-function channel. These findings reveal a distinct gating mechanism for the asymmetric 1:3 PC1-PC2 complex. Autosomal dominant polycystic kidney disease involves dysfunction of the PC1–PC2 ion channel. Here the authors reveal lipid-dependent allosteric gating and define multiple structural states showing how specific membrane lipids control channel opening.