Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol

Amanda Buyan, Charles D Cox*, Jonathan Barnoud, Jinyuan Li, Hannah S M Chan, Boris Martinac, Siewert J Marrink, Ben Corry*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Touch, hearing, and blood pressure regulation require mechanically gated ion channels that convert mechanical stimuli into electrical currents. One such channel is Piezo1, which plays a key role in the transduction of mechanical stimuli in humans and is implicated in diseases, such as xerocytosis and lymphatic dysplasia. There is building evidence that suggests Piezo1 can be regulated by the membrane environment, with the activity of the channel determined by the local concentration of lipids, such as cholesterol and phosphoinositides. To better understand the interaction of Piezo1 with its environment, we conduct simulations of the protein in a complex mammalian bilayer containing more than 60 different lipid types together with electrophysiology and mutagenesis experiments. We find that the protein alters its local membrane composition, enriching specific lipids and forming essential binding sites for phosphoinositides and cholesterol that are functionally relevant and often related to Piezo1-mediated pathologies. We also identify a number of key structural connections between the propeller and pore domains located close to lipid-binding sites.

Original languageEnglish
Article numberj.bpj.2020.07.043
Pages (from-to)1683-1697
Number of pages15
JournalBiophysical Journal
Volume119
Issue number8
Early online date2-Sep-2020
DOIs
Publication statusPublished - 20-Oct-2020

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