Structure and mechanogating mechanism of the Piezo1 channel

Abstract

The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Overall, Piezo1 possesses a unique 38-transmembrane-helix topology and designated mechanotransduction components, which enable a lever-like mechanogating mechanism.

Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

“…MSCs are mechanosensitive, and mechanical forces can induce ATP release, but the mechanisms for mechanical induction of ATP release from MSCs remain poorly understood . The Ca 2+ ‐permeable Piezo1 channel is a newly discovered mechanosensing mechanism in many types of cells . Furthermore, recent studies have reported that mechanical or chemical activation of the Piezo1 channel induces ATP release from endothelial cells, urothelial cells, and red blood cells .…”

Racemic crystal structures of peptide toxins, GsMTx4 prepared by protein total synthesis

“…Recently, the high‐resolution cryo‐EM structure of mouse Piezo1 has been determined . However, the dynamic process of mechanical control and regulation of the Piezo channel remains unclear.…”

Structural Biology: Piezo Senses Tension through Curvature

“…A channel with only one or two symmetrical blades is expected to respond to tension changes primarily along one axis, while three blades is the minimum for omnidirectional sensitivity. The three blades suggest rotation: does rotation of the blades produce a counter-rotation of the center that opens the pore, as suggested in Zhao et al [7]? The long blades hint at a large mechanical amplification so that a small change in membrane tension might be felt over a large membrane area.…”

“…Earlier structural and functional studies have elucidated two gating mechanisms: mechanical forces acting either via the cytoskeleton [2,3] or through tension in the membrane [4]. Structural studies using cryoEM of mouse Piezo1 (mPiezo1) [5–7], a member of a newly discovered family of channels [8], lead to the suggestion of a third gating mechanism: channel opening in response to change in the local curvature of the membrane [5]. …”

“…The new structures reveal a wealth of additional features [5–7]. Each propeller blade contains at least six helical units, each formed from four transmembrane helices (Figure 1A,B), and likely three more in the unresolved structure of the Piezo1 amino terminus, giving a total of 36 transmembrane helices per blade.…”