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Nat Struct Mol Biol. 2017 Feb;24(2):123-130. doi: 10.1038/nsmb.3357. Epub 2017 Jan 16.

Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2.

Author information

  • 1Max Planck Institute of Biophysics, Department of Structural Biology, Frankfurt, Germany.
  • 2Biophysics II, Faculty of Biology and Preclinical Medicine, Regensburg, Germany.
  • 3Structural Genomics Consortium, University of Oxford, Oxford, UK.
  • 4Oxford Particle Imaging Centre, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 5Department of Anatomy, Faculty of Biology and Preclinical Medicine, Regensburg, Germany.

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.

PMID:
28092368
DOI:
10.1038/nsmb.3357
[PubMed - in process]
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