Structural and Functional Characterizations of the Mechanosensitive Piezo Channel

Abstract

Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels that play critical roles in various mechanotransduction processes. However, the overall structural architecture, ion permeation and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 A. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore. Importantly, by characterizing the structurally revealed featured domains, we provide functional evidence to support this hypothesis. Taken together, these findings significantly advance our understanding of the structure-function relationship of this novel class of mechanosensitive cation channels.