Wilkes, Martin and Madej, M. Gregor and Kreuter, Lydia and Rhinow, Daniel and Heinz, Veronika and De Sanctis, Silvia and Ruppel, Sabine and Richter, Rebecca M. and Joos, Friederike and Grieben, Marina and Pike, Ashley C. W. and Huiskonen, Juha T. and Carpenter, Elisabeth P. and Kuhlbrandt, Werner and Witzgall, Ralph and Ziegler, Christine (2017) Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 24 (2). 123-+. ISSN 1545-9993, 1545-9985
Full text not available from this repository. (Request a copy)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, 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EM STRUCTURE DETERMINATION; HIGH-LEVEL EXPRESSION; BEAM-INDUCED MOTION; KIDNEY-DISEASE; CRYO-EM; ELECTRON CRYOMICROSCOPY; CATION CHANNEL; N-GLYCOSYLATION; PKD2; MECHANISMS; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Christine Ziegler Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 25 Feb 2019 11:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/480 |
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