Structural Mechanism of Prestin-Membrane Mechanotransduction

The motor protein prestin is responsible for the electromotive behavior of outer hair cells (OHCs), which is essential for the sound amplification process in the cochlea ^1–3 . Previous studies have shown unequivocally that prestin exhibits piezoelectricity in the plasma membrane ¹⁴ . However, the mechanism by which prestin converts sound-elicited receptor potential changes into mechanical movement remains unclear. This electromechanical process entails thinning and thickening of the cell membrane, which reciprocally affects prestin’s motor function ^4,5 . To model membrane thinning during OHC elongation, we determined multiple high-resolution structures of dolphin prestin in lipid nanodiscs of varying thicknesses using single particle cryo-electron microscopy. Membrane thinning triggered a conformational transition in prestin from the compact “Sensor Up” state to the expanded “Sensor Down” state. Combined with four mutant structures, hydrogen-deuterium exchange mass spectromtery, and patch-clamp electrophysiology, we investigated the structural dynamics of prestin’s response to mechanical force stemming from the membrane. By contrasting dolphin prestin with novel structures of lizard SLC26A5 (an anion exchanger), we demonstrate how, driven by the force-from-lipids principle, prestin’s motor function is distinct from nonmammalian transporter SLC26A5. Our data suggests that the anion is an inseparable part of the electromotile dolphin prestin anion binding pocket (voltage sensor), which facilitates core-gate interactions in response to mechanical stress. These structural insights offer a high-resolution understanding of how prestin translates membrane tension into charge and motor movement during sound-evoked vibrations, revealing its piezoelectric reciprocal mechanosensing as an essential property in cochlear amplification.