Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

Li, Jinyuan Vero and Ng, Chai-Ann and Cheng, Delfine and Zhou, Zijing and Yao, Mingxi and Guo, Yang and Yu, Ze-Yan and Ramaswamy, Yogambha and Ju, Lining Arnold and Kuchel, Philip W. and Feneley, Michael P. and Fatkin, Diane and Cox, Charles D. (2021) Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations. Communications Biology, 4 (1). ISSN 2399-3642

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Mechanosensitive channels are integral membrane proteins that sense mechanical stimuli. Like most plasma membrane ion channel proteins they must pass through biosynthetic quality control in the endoplasmic reticulum that results in them reaching their destination at the plasma membrane. Here we show that N-linked glycosylation of two highly conserved asparagine residues in the 'cap' region of mechanosensitive Piezo1 channels are necessary for the mature protein to reach the plasma membrane. Both mutation of these asparagines (N2294Q/N2331Q) and treatment with an enzyme that hydrolyses N-linked oligosaccharides (PNGaseF) eliminates the fully glycosylated mature Piezo1 protein. The N-glycans in the cap are a pre-requisite for N-glycosylation in the 'propeller' regions, which are present in loops that are essential for mechanotransduction. Importantly, trafficking-defective Piezo1 variants linked to generalized lymphatic dysplasia and bicuspid aortic valve display reduced fully N-glycosylated Piezo1 protein. Thus the N-linked glycosylation status in vitro correlates with efficient membrane trafficking and will aid in determining the functional impact of Piezo1 variants of unknown significance.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 10 Dec 2021 04:00
Last Modified: 10 Dec 2021 04:00

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