Structure deformation and curvature sensing of PIEZO1 in lipid membranes

PIEZO channels respond to piconewton-scale forcesto mediate critical physiological and pathophysiological processes(1-5). Detergent-solubilized PIEZO channels form bowl-shaped trimers comprising a central ion-conducting pore with an extracellular cap and three curved and non-planar blades with intracellular beams(6-10), which may undergo force-induced deformation within lipid membranes(11). However, the structures and mechanisms underlying the gating dynamics of PIEZO channels in lipid membranes remain unresolved. Here we determine the curved and flattened structures of PIEZO1 reconstituted in liposome vesicles, directly visualizing the substantial deformability of the PIEZO1-lipid bilayer system and an in-plane areal expansion of approximately 300 nm(2) in the flattened structure. The curved structure of PIEZO1 resembles the structure determined from detergent micelles, but has numerous bound phospholipids. By contrast, the flattened structure exhibits membrane tension-induced flattening of the blade, bending of the beam and detaching and rotating of he cap, which could collectively lead to gating of the ion-conducting pathway. On the basis of the measured in-plane membrane area expansion and stiffness constant of PIEZO1 (ref.(11)), we calculate a half maximal activation tension of about 1.9 pN nm(-1) , matching experimentally measured values. Thus, our studies provide a fundamental understanding of how the notable deformability and structural rearrangement of PIEZO1 achieve exquisite mechanosensitivity and unique curvature-based gating in lipid membranes.

Automated summary

This study reveals the structures and mechanisms of PIEZO1 channels in lipid membranes through observations of reconstituted PIEZO1 channels in liposome vesicles. It is found that PIEZO1 channels undergo substantial deformation in lipid membranes and the gating of the ion-conducting pathway is achieved through membrane tension-induced structural rearrangement. These findings provide important insights into the mechanosensitivity and curvature-based gating mechanism of PIEZO1 channels.