Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 2, Pages 123-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3357
Keywords
-
Funding
- Deutsche Forschungsgemeinschaft [SFB699, SFB807]
- SGC
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Merck Co.
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking (ULTRA-DD) [115766]
- Wellcome Trust [092809/Z/10/Z, 090532/Z/09/Z]
- Wellcome Trust JIF award [060208/Z/00/Z]
- WT [093305/Z/10/Z]
- European Research Council under the European Union Horizon 2020 Research and Innovation Programme [649053]
- Wellcome Trust [093305/Z/10/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available