Abstract
The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Here, we use cryo-electron microscopy to determine prestin’s structure at 3.6 Å resolution. Prestin is structurally similar to the anion transporter Slc26a9. It is 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 transmembrane domains consist of 14 transmembrane segments organized 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.
Highlights
The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc[26] family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification
We used singleparticle cryo-electron microscopy to obtain the structure of detergent-solubilized prestin from gerbil (Meriones unguiculatus) (Fig. 1, [https://www.rcsb.org/structure/7SUN])
The cryo-EM images obtained from plunge-frozen specimens of solubilized prestin (Supplementary Fig. 3A) revealed clear density for the transmembrane helices (TM), the cytoplasmic domains, and the micelle belt around the protein (Supplementary Fig. 3B)
Summary
The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc[26] family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. The underlying basis of prestin’s electromechanical capabilities resides in its unique piezoelectric-like property that drives OHC electromotility[7–11] For members of this diverse family, known structures are dimers with each protomer showing a common 7 + 7 inverted-repeat topology containing a core and gate domain; these proteins function variably as coupled transporters and uncoupled transporters/ion channels with a range of substrates[1,12,13]. Within the Slc[26] family, prestin and pendrin (Slc26a4) are unique in showing voltage sensitivity with signature nonlinear capacitance (NLC) or equivalently, displacement currents/gating charge movements[14–16]; while pendrin lacks intrinsic electromechanical behavior[17], prestin is a minimal transporter[18–20]. Mutations within prestin’s structurally confirmed anionbinding site show that the extrinsic voltage-sensor hypothesis[22] is likely incorrect[26], with the wider implication that a transporterlike mechanism driving electromotility is unlikely
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