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Cell. 2016 Oct 20;167(3):763-773.e11. doi: 10.1016/j.cell.2016.09.048.

The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs.

Author information

1
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
2
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Howard Hughes Medical Institute, Boston, 02115 MA, USA; Cardiology, Boston Children's Hospital, Boston, 02115 MA, USA; Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
3
Howard Hughes Medical Institute, Boston, 02115 MA, USA; Cardiology, Boston Children's Hospital, Boston, 02115 MA, USA; Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
4
Keck Advanced Microscopy Laboratory and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Howard Hughes Medical Institute, Boston, 02115 MA, USA; Cardiology, Boston Children's Hospital, Boston, 02115 MA, USA; Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dclapham@enders.tch.harvard.edu.
6
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA. Electronic address: erhu.cao@biochem.utah.edu.

Abstract

The Polycystic Kidney Disease 2 (Pkd2) gene is mutated in autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic disorders. Here, we present the cryo-EM structure of PKD2 in lipid bilayers at 3.0 Å resolution, which establishes PKD2 as a homotetrameric ion channel and provides insight into potential mechanisms for its activation. The PKD2 voltage-sensor domain retains two of four gating charges commonly found in those of voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter and near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction. The extracellular domain of PKD2, a hotspot for ADPKD pathogenic mutations, contributes to channel assembly and strategically interacts with the transmembrane core, likely serving as a physical substrate for extracellular stimuli to allosterically gate the channel. Finally, our structure establishes the molecular basis for the majority of pathogenic mutations in Pkd2-related ADPKD.

KEYWORDS:

ADPKD; PKD2; TRP channel; TRPP2; cryo-EM; ion channel; polycystic kidney disease; polycystin; single particle electron cryo-microscopy

PMID:
27768895
PMCID:
PMC6055481
DOI:
10.1016/j.cell.2016.09.048
[Indexed for MEDLINE]
Free PMC Article

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