Progress in understanding the structural mechanism underlying prestin's electromotile activity.

Prestin (SLC26A5), a member of the SLC26 transporter family, is the molecular actuator that drives OHC electromotility (eM). A wealth of biophysical data indicates that eM is mediated by an area motor mechanism, in which prestin molecules act as elementary actuators by changing their area in the membrane in response to changes in membrane potential. The area changes of a large and densely packed population of prestin molecules sum up, resulting in macroscopic cellular movement. At the single protein level, this model implies major voltage-driven conformational rearrangements. However, the nature of these structural dynamics remained unknown. A main obstacle in elucidating the eM mechanism has been the lack of structural information about SLC26 transporters. The recent emergence of several high-resolution cryo-EM structures of prestin as well as other SLC26 transporter family members now provides a reliable picture of prestin's molecular architecture. Thus, SLC26 transporters including prestin generally are dimers, and each protomer is folded according to a 7+7 transmembrane domain inverted repeat (7TMIR) architecture. Here, we review these structural findings and discuss insights into a potential molecular mechanism. Most important, distinct conformations were observed when purifying and imaging prestin bound to either its physiological ligand, chloride, or to competitively inhibitory anions, sulfate or salicylate. Despite differences in detail, these structural snapshots indicate that the conformational landscape of prestin includes rearrangements between the two major domains of prestin's transmembrane region (TMD), core and scaffold ('gate') domains. Notably, distinct conformations differ in the area the TMD occupies in the membrane and in their impact on the immediate lipid environment. Both effects can contribute to generate membrane deformation and thus may underly electromotility. Further functional studies will be necessary to determine whether these or similar structural rearrangements are driven by membrane potential to mediate piezoelectric activity. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.