Abstract
Mechanosensitive ion channels convert external mechanical stimuli into electrochemical signals for critical processes including touch sensation, balance, and cardiovascular regulation. The best understood mechanosensitive channel, MscL, opens a wide pore, which accounts for mechanosensitive gating due to in-plane area expansion. Eukaryotic Piezo channels have a narrow pore and therefore must capture mechanical forces to control gating in another way. We present a cryo-EM structure of mouse Piezo1 in a closed conformation at 3.7Å-resolution. The channel is a triskelion with arms consisting of repeated arrays of 4-TM structural units surrounding a pore. Its shape deforms the membrane locally into a dome. We present a hypothesis in which the membrane deformation changes upon channel opening. Quantitatively, membrane tension will alter gating energetics in proportion to the change in projected area under the dome. This mechanism can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore.
Highlights
Piezo ion channels, Piezo1 and Piezo2, are mechanosensitive channels (MS channels) that underlie force-detection in eukaryotic cells (Coste et al, 2010; Wu et al, 2017)
Using cryo-electron microscopy we determined a structure of mouse Piezo1 (mPiezo1) to an overall resolution of 3.7 A (Figure 2 and Figure 2—figure supplement 1)
A crystal structure (PDB ID: 4RAX) was docked into density corresponding to the C-terminal extracellular domain (CED) and the remaining model (26 TM helices per subunit) was built de novo (Figure 2—figure supplements 2 and 3) (Ge et al, 2015)
Summary
Piezo and Piezo, are mechanosensitive channels (MS channels) that underlie force-detection in eukaryotic cells (Coste et al, 2010; Wu et al, 2017). The number of cellular processes found mediated by Piezo channels is large and growing at a rapid rate (Eisenhoffer et al, 2012; McHugh et al, 2012; Pathak et al, 2014; Li et al, 2014; Cahalan et al, 2015; Alper, 2017). Their essential biophysical characteristics include responsiveness in gating to mechanical force (i.e. mechanosensitivity) and selectivity of the pore for cations (Gnanasambandam et al, 2015; Lewis and Grandl, 2015). Structural, biophysical and functional analyses show that MscL undergoes a large ( 20 nm2) in-plane area expansion when it opens
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