title: The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs.
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.
authors: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors: Peter S
authors: PS
authors: Shen
authors: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors: Xiaoyong
authors: X
authors: Yang
authors: 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.
authors: Paul G
authors: PG
authors: DeCaen
authors: 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.
authors: Xiaowen
authors: X
authors: Liu
authors: Keck Advanced Microscopy Laboratory and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: David
authors: D
authors: Bulkley
authors: 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.
authors: David E
authors: DE
authors: Clapham
authors: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA. Electronic address: erhu.cao@biochem.utah.edu.
authors: Erhu
authors: E
authors: Cao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D020285:Cryoelectron Microscopy; D057809:HEK293 Cells; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D020125:Mutation, Missense; D049329:Nanostructures / Q000737:chemistry; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000235:genetics
chemical_list: D008051:Lipid Bilayers; D050396:TRPP Cation Channels
keywords: ADPKD; PKD2; TRP channel; TRPP2; cryo-EM; ion channel; polycystic kidney disease; polycystin; single particle electron cryo-microscopy