Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 19, Pages 10329-10338Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1920777117
Keywords
ion channels; polycystic kidney disease; structural biology; TRP channels; ADPKD
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Funding
- NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program [U24 GM129539]
- Simons Foundation [SF349247]
- New York State
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [1R56DK119709-01, R00 DK106655, 1R01DK123463-01]
- NIH National Institute of Diabetes and Digestive and Kidney Diseases (NU GoKidney George M. O'Brien Kidney Research Core Center) [P30DK11485]
- PKD Foundation Research Grant
- Mayo Clinic's PKD Center Pilot and Feasibility Program grant
- Carl W. Gottschalk Research Scholar Grant from the American Nephrology Society
- NIH from the Department of Defense [R01 DK110575, W81XWH-17-1-0158]
- Pew Charitable Trusts
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Genetic variants in PKD2 which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding of the genetic basis of ADPKD, we do not know how most variants impact channel function. Polycystin-2 is found in organelle membranes, including the primary cilium-an antennae-like structure on the luminal side of the collecting duct. In this study, we focus on the structural and mechanistic regulation of polycystin-2 by its TOP domain-a site with unknown function that is commonly altered by missense variants. We use direct cilia electrophysiology, cryogenic electron microscopy, and superresolution imaging to determine that variants of the TOP domain finger 1 motif destabilizes the channel structure and impairs channel opening without altering cilia localization and channel assembly. Our findings support the channelopathy classification of PKD2 variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.
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