title: Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).
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.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Mariana
authors.initials: M
authors.lastname: Grieben
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Ashley C W
authors.identifier: 0000-0001-9661-2607
authors.initials: AC
authors.lastname: Pike
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Chitra A
authors.initials: CA
authors.lastname: Shintre
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Venturi
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: El-Ajouz
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Tessitore
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Leela
authors.initials: L
authors.lastname: Shrestha
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Shubhashish
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Pravin
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Rod
authors.initials: R
authors.lastname: Chalk
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Burgess-Brown
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sitsapesan
authors.affiliation: Oxford Particle Imaging Centre, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Juha T
authors.identifier: 0000-0002-0348-7323
authors.initials: JT
authors.lastname: Huiskonen
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Elisabeth P
authors.identifier: 0000-0001-9138-2937
authors.initials: EP
authors.lastname: Carpenter
mesh_terms: D000818:Animals; D020285:Cryoelectron Microscopy; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D061987:Sf9 Cells; D018411:Spodoptera; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000235:genetics
chemical_list: D050396:TRPP Cation Channels