Molecular insights into lipid-assisted Ca²⁺ regulation of the TRP channel Polycystin-2

Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca²⁺ signaling pathways. Malfunctioning Ca²⁺ regulation in PC2 causes autosomal-dominant polycystic kidney disease. Here we report two cryo-EM structures of distinct channel states of full-length human PC2 in complex with lipids and cations. The structures reveal conformational differences in the selectivity filter and in the large exoplasmic domain (TOP domain), which displays differing N-glycosylation. The more open structure has one cation bound below the selectivity filter (single-ion mode, PC2_SI), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2_MI). Ca²⁺ binding at the entrance of the selectivity filter suggests Ca²⁺ blockage in PC2_MI, and we observed density for the Ca²⁺-sensing C-terminal EF hand in the unblocked PC2_SI state. The states show altered interactions of lipids with the pore loop and TOP domain, thus reflecting the functional diversity of PC2 at different locations, owing to different membrane compositions.