Lipid-mediated organization of prestin in the outer hair cell membrane and its implications in sound amplification

Prestin is a high-density motor protein in the outer hair cells (OHCs), whose conformational response to acoustic signals alters the shape of the cell, thereby playing a major role in sound amplification by the cochlea. Despite recent structural determination in active and inhibited states, the details of prestin’s intimate interactions with the membrane, which are central to its function remained unresolved. Here, employing a large set (collectively, more than 0.5 ms) of coarse-grained molecule dynamics simulations, we characterize the nature of prestin’s lipid-protein interactions, demonstrating their impact on the organization of prestin at densities relevant to the OHCs and its effectiveness in reshaping OHCs. Beyond local enrichment/depletion of various lipid types, prestin causes drastic anisotropic membrane deformation, which in turn mediates a preferential membrane organization of prestin in which deformation patterns by neighboring prestin copies are aligned constructively. The reduced membrane rigidity accompanying this arrangement is hypothesized to maximize the mechanical impact of prestin on OHC reshaping during cochlear sound amplification. Prestin’s preferential arrangement is further verified by extended simulations demonstrating strong correlation between prestin neighbors in their orientations. These results demonstrate a strong case of protein-protein cooperative communication in membrane, purely mediated by their interactions with lipids.