Abstract
Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.
Highlights
Piezo1 represents a prototype of eukaryotic mechanotransduction channels
Combining structural and functional characterizations, we have identified that the two extracellular loops of TM15-16 (L15-16) and TM19-20 (L19-20) in the distal blade and the two leucine residues L1342 and L1345 in the proximal end of the beam play critical roles in the mechanical activation of Piezo139 (Fig. 1)
To identify specific chemical activators of Piezo channels, we have used the fluorescent imaging plate reader (FLIPR) in a 96-well format to screen about 3000 compounds for those that can evoke Ca2+ increase in human embryonic kidney 293T (HEK293T) cells co-transfected with either Mouse Piezo1 (mPiezo1) or mPiezo2, and the genetically encoded Ca2 + reporter GCAMP6s43
Summary
Piezo represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ionconducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. Mechanosensitive (MS) ion channels are molecular force transducers that specialize in rapidly converting various mechanical stimuli into electrochemical signals for controlling key biological activities such as touch, vascular development, and blood pressure regulation. Mutations of Piezo genes resulting in altered channel functions have been linked to a number of genetic diseases involving mechanotransduction. Mutations of Piezo genes resulting in altered channel functions have been linked to a number of genetic diseases involving mechanotransduction25–31 These studies demonstrate the functional importance of Piezo channels and their potential as therapeutic targets. Piezo represents a prototype for understanding the mechanogating and ionpermeating mechanisms of mammalian MS cation channels, which will lead to a better understanding of their biological roles in health and disease. The cryo-electron microscopy structure of mPiezo reveals that it trimerizes to form a unique three-bladed, propeller-shaped architecture, comprising a central ionconducting pore module, three peripheral blades, and three 90
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