EMD-3523
cryoEM Structure of Polycystin-2 in complex with cations and lipids
EMD-3523
Single-particle4.3 Å
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Map released: 18/01/2017
Last modified: 23/10/2024
Sample Organism:
Homo sapiens
Sample: Polycystin-2
Fitted models: 5mke (Avg. Q-score: 0.303)
Deposition Authors: Wilkes M, Madej MG
Sample: Polycystin-2
Fitted models: 5mke (Avg. Q-score: 0.303)
Deposition Authors: Wilkes M, Madej MG
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Molecular insights into lipid-assisted Ca(2+) regulation of the TRP channel Polycystin-2.
Wilkes M,
Madej MG
,
Kreuter L,
Rhinow D,
Heinz V,
De Sanctis S,
Ruppel S,
Richter RM
,
Joos F,
Grieben M,
Pike AC
,
Huiskonen JT
,
Carpenter EP
,
Kuhlbrandt W
,
Witzgall R,
Ziegler C
(2017) Nat Struct Mol Biol , 24 , 123 - 130
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(2017) Nat Struct Mol Biol , 24 , 123 - 130
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 PC2SI 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.
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 PC2SI 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.