2. Academic Validation
  3. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)

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

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.

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