Force-sensing in Piezo ion channels.

Abstract

In 2010, Piezo proteins were discovered, which has led to stunning progress in the elucidation of the molecular basis for mechanosensation. Piezo channels are mechanosensitive ion channels that locally curve the membrane into a dome shape. Membrane elasticity theory predicts that the curved shape of the Piezo dome deforms the surrounding lipid membrane into a membrane footprint, which may amplify Piezo's sensitivity to applied forces and explain the observed modulation of Piezo gating through the cytoskeleton. We directly test the membrane elasticity theory of Piezo's membrane footprint through cryo-electron tomography of lipid bilayer vesicles deformed by Piezo channels, finding quantitative agreement between observed and predicted membrane shapes, with no free parameters. On this basis, it becomes possible to deduce elastic properties of membrane proteins solely from membrane shape measurements. We thus derive a force-distortion relationship for the Piezo dome, from which we infer the Piezo dome's intrinsic radius of curvature and bending stiffness in free-standing lipid membranes mimicking cell membranes, and predict Piezo's gating curve, with no free parameters. Our results suggest that Piezo's intrinsic curvature, membrane footprint, small stiffness, and large area are the key properties of Piezo that give rise to low-threshold, high-sensitivity mechanical gating.