Bai Jun-Ping, Zhang Chenou, Bahader Iman, Strenzke Nicola, Renigunta Vijay, Oliver Dominik, Navaratnam Dhasakumar, Beckstein Oliver, Santos-Sacchi Joseph
Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Center for Biological Physics and Department of Physics, Arizona State University, Tempe, AZ 85287-1504, USA.
Structure. 2025 Aug 7;33(8):1417-1424.e3. doi: 10.1016/j.str.2025.04.019. Epub 2025 May 21.
Prestin (SLC26A5) promotes mechanical feedback via outer hair cells (OHC) within the organ of Corti, governed by voltage-dependent kinetics of its charge movements; namely, nonlinear-capacitance (NLC). We study NLC frequency response in mouse OHC membrane patches. The characteristic frequency cut-off (F) is 27 kHz. Single point mutations within prestin's chloride binding pocket (S396E and S398E) lack usual anion influence. In agreement, we show absence of anion binding in these mutants through molecular dynamics (MD) simulations. NLC F in S396E knock-in mice is unaltered, indicating that high frequency activity is not governed by chloride but likely by viscoelastic loads. Also, the allosteric action of chloride does not underlie piezoelectric-like behavior in prestin, since tension sensitivity of S396E NLC is comparable to WT. Because structures of all studied species appear indistinguishable, with analogous chloride binding pockets, prestin performance likely evolved by modifying, not its protein-anion interaction, but instead mechanical loads on the protein.
Prestin（SLC26A5）通过柯蒂氏器内的外毛细胞（OHC）促进机械反馈，其电荷运动受电压依赖性动力学支配；即非线性电容（NLC）。我们研究了小鼠OHC膜片上的NLC频率响应。特征频率截止值（F）为27 kHz。Prestin氯离子结合口袋内的单点突变（S396E和S398E）缺乏常见的阴离子影响。与此一致，我们通过分子动力学（MD）模拟表明这些突变体中不存在阴离子结合。S396E基因敲入小鼠的NLC F未改变，表明高频活性不受氯离子控制，而可能受粘弹性负荷控制。此外，氯离子的变构作用并非Prestin中类似压电行为的基础，因为S396E NLC的张力敏感性与野生型相当。由于所有研究物种的结构看起来无法区分，具有类似的氯离子结合口袋，Prestin的性能可能是通过改变蛋白质上的机械负荷而非蛋白质-阴离子相互作用而进化的。
