Prestin (Slc26a5), a member of the Slc26 family of anion transporters, functions as a molecular motor critical to the electromotility of cochlear outer hair cells (OHCs). Embedded within the lateral plasma membrane, prestin exhibits voltage-dependent conformational transitions between expanded (ES) and compact (CS) states in response to changes in membrane potential. These transitions are coupled to alterations in membrane surface area, following the “area motor model,” which posits that the collective behavior of densely packed prestin molecules drives mechanical displacements of the OHC. While previous structural models of the ES conformation relied on ligand stabilization, we used multi-microsecond molecular dynamics simulations starting from the CS state in the presence of chloride to generate an ES model. This model resembles the inward-facing (IF) conformation of pendrin (Slc26a4), another member of the Slc26 family for which both IF and outward-facing (OF) structural states are known. Furthermore, molecular dynamics simulations reveal a previously uncharacterized compact conformation that structurally resembles the OF state of pendrin, along with an extracellular chloride-binding site analogous to that observed in pendrin. Complementary electrophysiological analyses demonstrate that pendrin exhibits non-linear capacitance akin prestin, suggesting voltage-dependent conformational transitions. Additionally, we solved the structure of gerbil prestin in the presence of thiocyanate (SCN-) using cryo-electron microscopy to 3.27 Å resolution. It confirms the presence of an extracellular anion binding site in prestin consistent with the one observed in pendrin. Collectively, these findings indicate that prestin and pendrin share fundamental structural features, including membrane area expansion and voltage sensitivity, which form the basis of the area motor model of OHC electromechanical transduction. Prestin's specialized function in this process may derive not from distinct structural attributes, but rather from its unique cellular environment, particularly its high-density membrane localization.
Zhang et al. (Sun,) studied this question.