What they found
TL;DR (qwen3.6:35b): Simulations and cryo-EM data reveal that prestin undergoes a spontaneous conformational shift resembling the transport cycle of the anion exchanger pendrin, including the identification of a specific extracellular anion-binding site. This suggests that prestin’s motor function shares core structural mechanisms with SLC26 family transporters, despite differences in transition speed.
Prestin (SLC26A5), a membrane protein in cochlear outer hair cells, drives electromechanical transduction essential for mammalian hearing. Unlike other SLC26 anion transporters, prestin functions as a voltage-dependent molecular motor, transitioning between compact and expanded conformations. How this transition relates to the transporter cycle of SLC26 family members remains unclear. Here, multi-microsecond molecular dynamics simulations starting from the compact state reveal a rapid, spontaneous transition to an expanded state that resembles the inward-facing conformation of the anion exchanger pendrin (SLC26A4 from mouse). An accompanying transmembrane area expansion is localized to the inner membrane leaflet, likely leading to membrane bending. In line with this observation, reduced unitary sensor charge movement accompanies neutralization of charged residues localized near the inner leaflet. Simulations also uncover a previously uncharacterized compact conformation resembling outward-facing pendrin and predict an extracellular anion-binding site in prestin. In fact, in the presence of thiocyanate anions, we observe a previously unresolved binding site in a 3.27-Angstrom cryo-electron microscopy structure of prestin. Furthermore, like prestin, pendrin exhibits a non-linear capacitance, an indication of voltage-dependent conformational switching. Together, these findings suggest that prestin and pendrin share core structural and functional properties, notably parallels between expansion-contraction states and transporter function, though transition speeds may differ.
How this applies to our program
This paper provides a critical mechanistic framework for understanding how SLC26 proteins undergo voltage-dependent conformational changes, which is directly relevant to the STRC/DFNB16 program’s investigation of hair cell electromechanics. By establishing parallels between prestin and pendrin, it offers insights into the anion-binding dynamics that may also influence STRC function or stability in hearing loss contexts.
Key numbers
- 3.27-Angstrom resolution cryo-EM structure
- multi-microsecond molecular dynamics simulations
- 1 previously uncharacterized compact conformation identified
Links
- biorxiv_id: https://www.biorxiv.org/content/10.64898/2026.06.06.730624
- DOI: https://doi.org/10.64898/2026.06.06.730624
Connections
[source]auto-indexed 2026-06-09 by strc-lit-watch