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Abstract
Mutations on genes encoding polycystin-1 (PC1) and PC2 cause autosomal-dominant polycystic kidney disease. How these 2 proteins work together to exert anticystogenesis remains elusive. PC1 resembles adhesion G-protein coupled receptors and undergoes autocleavage in the extracellular N-terminus to expose a hidden “stalk” region, which is hypothesized to act as a “tethered agonist.” Here, we show that WT PC1 and PC2 formed functional heteromeric channel complexes in Xenopus oocytes with different biophysical properties from PC2 homomeric channels. Deletion of PC1 N-terminus, which exposed the stalk, increased calcium permeability in PC1/PC2 heteromers that required the presence of stalk. Extracellular application of synthetic stalk peptide increased calcium permeation in stalkless PC1/PC2. Application of Wnt9B protein increased calcium permeability in PC1/PC2 but not in heteromers containing cleavage-resistant mutant PC1. Wnt9B interacted with N-terminal leucine-rich repeat (LRR) of PC1. Pretreatment with LRR blunted the increase in calcium permeability by Wnt9B. Thus, PC1 and PC2 form receptor-channel complexes that is activated by exposure of the stalk region following ligand binding to the PC1 N-terminus. The stalk peptide acts as a tethered agonist to activate PC1/PC2 by affecting ion selectivity of the complexes.
Authors
Runping Wang, Danish Idrees, Mohammad Amir, Biswajit Padhy, Jian Xie, Chou-Long Huang
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