2.A.53.2.19
Prestin (Solute carrier family 26 member 5).  The motor protein responsible for the somatic electromotility of cochlear outer hair cells (OHC); essential for normal hearing sensitivity and frequency selectivity in mammals. Prestin transports a wide variety of monovalent and divalent anions. Many SulP transporters have C-terminal hydrophilic STAS domains that are essential for plasma membrane targeting and protein function. The crystal structure of this STAS domain has been solved at 1.57 Å resolution (Pasqualetto et al. 2010).  It senses voltage and binds anions for induction of conformational changes (He et al. 2013).  Prestin's 7+7 inverted repeat architecture suggests a central cavity as the substrate-binding site located midway within the anion permeation pathway. Anion binding to this site controls the electromotile activity of prestin (Gorbunov et al. 2014).  Zhai et al. 2020 studied the maturation of voltage-induced shifts in the Prestin operating point during trafficking. Calmodulin binds to the STAS domain with a calcium-dependent, one-lobe, binding mode (Costanzi et al. 2021). Prestin is the molecular actuator that drives OHC electromotility (eM). eM is mediated by an area motor mechanism, in which prestin proteins 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 add up, resulting in macroscopic cellular movement. At the single protein level, this model implies major voltage-driven conformational rearrangements. SLC26 transporters including prestin generally are dimers. Lenz and Oliver 2021 reviewed the structures and discussed insights into a potential molecular mechanism. Distinct conformations were observed when purifying and imaging prestin bound to either its physiological ligand, chloride, or to competitively inhibitory anions, sulfate or salicylate. 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. 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 the generation of membrane deformation and thus may underly electromotility. Possibly, these or similar structural rearrangements are driven by the membrane potential to mediate piezoelectric activity (Lenz and Oliver 2021). Prestin differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Butan et al. 2022 used cryo-EM to determine prestin's structure at 3.6 Å resolution. Prestin was captured in an inward-open state which may reflect prestin's contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The TM domains consist of 14 TMSs in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin's chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function (Butan et al. 2022). A structure-based mechanism for the membrane motor prestin has been presented (Ge et al. 2021). A novel role of the folding equilibrium of the anion-binding site in defining prestin's unique voltage-sensing mechanism and electromotility has been proposed (Lin et al. 2023).

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