Title : Molecular insights into lipid-assisted
Ca2 + regulation of the
TRP channel Polycystin-2
Abstract :
- 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, PC2SI), whereas multiple cations are bound along the translocation pathway in the second structure ( multi-ion mode, PC2MI)
- Ca2 + binding at the entrance of the selectivity filter suggests Ca2 + blockage in PC2MI, 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 com positions