Abstract
Piezo proteins are bona fide mammalian mechanotransduction channels for various cell types including endothelial cells. The mouse Piezo1 of 2547 residues forms a three-bladed, propeller-like homo-trimer comprising a central pore-module and three propeller-structures that might serve as mechanotransduction-modules. However, the mechanogating and regulation of Piezo channels remain unclear. Here we identify the sarcoplasmic /endoplasmic-reticulum Ca2+ ATPase (SERCA), including the widely expressed SERCA2, as Piezo interacting proteins. SERCA2 strategically suppresses Piezo1 via acting on a 14-residue-constituted intracellular linker connecting the pore-module and mechanotransduction-module. Mutating the linker impairs mechanogating and SERCA2-mediated modulation of Piezo1. Furthermore, the synthetic linker-peptide disrupts the modulatory effects of SERCA2, demonstrating the key role of the linker in mechanogating and regulation. Importantly, the SERCA2-mediated regulation affects Piezo1-dependent migration of endothelial cells. Collectively, we identify SERCA-mediated regulation of Piezos and the functional significance of the linker, providing important insights into the mechanogating and regulation mechanisms of Piezo channels.
Highlights
Piezo proteins are bona fide mammalian mechanotransduction channels for various cell types including endothelial cells
Focusing on characterizing the interaction and regulation between Piezo[1] and sarcoplasmic/endoplasmic-reticulum Ca2+ ATPase (SERCA2), we have identified that a 14-residue-constituted intracellular linker region between the pore-module and the mechanotransduction-module is critically required for mechanogating and SERCA2-mediated suppression of Piezo[1]
We first carried out glutathione-S-transferase (GST) pull-down from Human embryonic kidney 293 T (HEK293T) cells transfected with constructs encoding either the GST control or the Piezo1-GST fusion protein
Summary
Piezo proteins are bona fide mammalian mechanotransduction channels for various cell types including endothelial cells. Focusing on characterizing the interaction and regulation between Piezo[1] and SERCA2, we have identified that a 14-residue-constituted intracellular linker region between the pore-module and the mechanotransduction-module is critically required for mechanogating and SERCA2-mediated suppression of Piezo[1]. These findings suggest that the linker region might play a key role in coupling the mechanotransductionmodule to the pore-module, in analogous to the role of the S4-S5 linker of the voltage-gated K+ channels or the transient receptor potential (TRP) channels[29,30]. Data shown as mean ± s.e.m. **p < 0.01, ***p < 0.001
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
