Polycystin-2
plasma membrane
Molecular insights into lipid-assisted Ca<sup>2+</sup> regulation of the TRP channel Polycystin-2.
Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca<sup>2+</sup> signaling pathways. Malfunctioning Ca<sup>2+</sup> 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<sub>SI</sub>), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2<sub>MI</sub>). Ca<sup>2+</sup> binding at the entrance of the selectivity filter suggests Ca<sup>2+</sup> blockage in PC2<sub>MI</sub>, and we observed density for the Ca<sup>2+</sup>-sensing C-terminal EF hand in the unblocked PC2<sub>SI</sub> 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.