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

Le résumé fourni par la source

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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.