6WB8

Cryo-EM structure of PKD2 C331S disease variant

Summary for 6WB8

• Entry DOI: 10.2210/pdb6wb8/pdb
• EMDB information: 21586
• Descriptor: Polycystin-2, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: pkd2, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 348722.62

Authors

Cao, E.,Wang, J.,Decaen, P.G. (deposition date: 2020-03-26, release date: 2020-04-22, Last modification date: 2024-10-30)

Primary citation

Vien, T.N.,Wang, J.,Ng, L.C.T.,Cao, E.,DeCaen, P.G.
Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain.
Proc.Natl.Acad.Sci.USA, 117:10329-10338, 2020

PubMed Abstract: Genetic variants in 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 variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.

PubMed: 32332171
DOI: 10.1073/pnas.1920777117

Experimental method

ELECTRON MICROSCOPY (3.24 Å)