@article{TEXTUAL,
      recid = {10106},
      author = {Lin, Xiaoxuan and Haller, Patrick R. and Bavi, Navid and  Faruk, Nabil and Perozo, Eduardo and Sosnick, Tobin R.},
      title = {Folding of prestin’s anion-binding site and the mechanism  of outer hair cell electromotility},
      journal = {eLife},
      address = {2023-12-06},
      number = {TEXTUAL},
      abstract = {Prestin responds to transmembrane voltage fluctuations by  changing its cross-sectional area, a process underlying the  electromotility of outer hair cells and cochlear  amplification. Prestin belongs to the SLC26 family of anion  transporters yet is the only member capable of displaying  electromotility. Prestin’s voltage-dependent conformational  changes are driven by the putative displacement of residue  R399 and a set of sparse charged residues within the  transmembrane domain, following the binding of a  Cl<sup>−</sup> anion at a conserved binding site formed by  the amino termini of the TM3 and TM10 helices. However, a  major conundrum arises as to how an anion that binds in  proximity to a positive charge (R399), can promote the  voltage sensitivity of prestin. Using hydrogen–deuterium  exchange mass spectrometry, we find that prestin displays  an unstable anion-binding site, where folding of the amino  termini of TM3 and TM10 is coupled to Cl<sup>−</sup>  binding. This event shortens the TM3–TM10 electrostatic  gap, thereby connecting the two helices, resulting in  reduced cross-sectional area. These folding events upon  anion binding are absent in SLC26A9, a non-electromotile  transporter closely related to prestin. Dynamics of prestin  embedded in a lipid bilayer closely match that in detergent  micelle, except for a destabilized lipid-facing helix TM6  that is critical to prestin’s mechanical expansion. We  observe helix fraying at prestin’s anion-binding site but  cooperative unfolding of multiple lipid-facing helices,  features that may promote prestin’s fast electromechanical  rearrangements. These results highlight a novel role of the  folding equilibrium of the anion-binding site, and help  define prestin’s unique voltage-sensing mechanism and  electromotility.},
      url = {http://knowledge.uchicago.edu/record/10106},
}