Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)

  • Nat Struct Mol Biol. 2017 Feb;24(2):114-122. doi: 10.1038/nsmb.3343.
Mariana Grieben  1 ,  Ashley C W Pike  1 ,  Chitra A Shintre  1 ,  Elisa Venturi  2 ,  Sam El-Ajouz  2 ,  Annamaria Tessitore  1 ,  Leela Shrestha  1 ,  Shubhashish Mukhopadhyay  1 ,  Pravin Mahajan  1 ,  Rod Chalk  1 ,  Nicola A Burgess-Brown  1 ,  Rebecca Sitsapesan  2 ,  Juha T Huiskonen  3 ,  Elisabeth P Carpenter  1
Affiliations
  • 1. Structural Genomics Consortium, University of Oxford, Oxford, UK.
  • 2. Department of Pharmacology, University of Oxford, Oxford, UK.
  • 3. Oxford Particle Imaging Centre, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
PMID: 27991905 DOI: 10.1038/nsmb.3343
Abstract

Mutations in either polycystin-1 (PC1 or PKD1) or polycystin-2 (PC2, PKD2 or TRPP1) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms. Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-Å resolution. The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential (TRP) channel structure. The TOP domain is formed from two extensions to the voltage-sensor-like domain (VSLD); it covers the channel's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway. The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1, and is the site of a cluster of ADPKD-associated missense variants. Extensive contacts among the TOP-domain subunits, the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli.