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

Peter S. Shen, Xiaoyong Yang, Paul G. DeCaen, Xiaowen Liu, David Bulkley, David E. Clapham*, Erhu Cao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)763-773.e11
JournalCell
Volume167
Issue number3
DOIs
StatePublished - Oct 20 2016

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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