Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 2, Pages 114-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3343
Keywords
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Funding
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Merck Co.
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking [ULTRA-DD 115766]
- Wellcome Trust [092809/Z/10/Z, 090532/Z/09/Z]
- British Heart Foundation [RG/10/14/28576]
- Wellcome Trust JIF award [060208/Z/00/Z]
- WT equipment grant [093305/Z/10/Z]
- European Research Council under the European Union's Horizon 2020 Research and Innovation Programme [649053]
- NIGMS [P41-GM103311]
- British Heart Foundation [RG/10/14/28576] Funding Source: researchfish
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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-angstrom 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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