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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.

Original publication

DOI

10.1038/nsmb.3343

Type

Journal

Nat Struct Mol Biol

Publication Date

02/2017

Volume

24

Pages

114 - 122

Keywords

Animals, Cryoelectron Microscopy, Humans, Models, Molecular, Mutation, Missense, Polycystic Kidney, Autosomal Dominant, Protein Conformation, alpha-Helical, Protein Domains, Sf9 Cells, Spodoptera, TRPP Cation Channels