小柯机器人

美国芝加哥大学Eduardo Perozo研究组发现，Prestin的构象变化是外毛细胞电活动的基础。相关论文于2021年10月25日在线发表于国际学术期刊《自然》。

研究人员利用单粒子冷冻电镜确定了海豚Prestin在六个不同状态下的结构。结构和功能数据表明，Prestin采取了一套独特而复杂的状态，可通过结合的阴离子（Cl^-或SO₄^2-）进行调整。水杨酸盐是一种能引起可逆性听力损失的药物，它能竞争Prestin的阴离子结合位点，并通过将Prestin固定在一个新的构象中而抑制其功能。数据表明，结合的阴离子与其协调的带电残基和螺旋偶极作为一个动态电压传感器。

对所有依赖阴离子的构象分析揭示了电压传感器的结构重排是如何与蛋白质-膜界面的构象转换相联系的，这表明了一种新的区域扩展机制。Prestin电迁移周期的可视化将其与密切相关的SLC26阴离子转运蛋白区分开来，进而在高分辨率下突出了哺乳动物耳蜗放大器进化特化的基础。

据悉，电压依赖性运动蛋白Prestin（SLC26A5）负责外毛细胞的电动行为，是耳蜗放大器的基础。 Prestin的敲除或损伤导致严重的听力损失。尽管Prestin在听力中起着关键作用，但人们对哺乳动物的Prestin感知电压并将其转变成细胞规模的运动（电动性）的机制却知之甚少。

附：英文原文

Title: Prestin’s conformational cycle underlies outer hair cell electromotility

Author: Bavi, Navid, Clark, Michael David, Contreras, Gustavo F., Shen, Rong, Reddy, Bharat G., Milewski, Wieslawa, Perozo, Eduardo

Issue&Volume: 2021-10-25

Abstract: The voltage-dependent motor protein Prestin (SLC26A5) is responsible for the electromotive behavior of outer hair cells and underlies the cochlear amplifier1. Knock out or impairment of Prestin causes severe hearing loss2–5. Despite Prestin’s key role in hearing, the mechanism by which mammalian Prestin senses voltage and transduces it into cellular-scale movements (electromotility) is poorly understood. Here, we determined the structure of dolphin Prestin in six distinct states using single particle cryo-electron microscopy. Our structural and functional data suggest that Prestin adopts a unique and complex set of states, tunable by the identity of bound anions (Cl- or SO42-). Salicylate, a drug that can cause reversible hearing loss, competes for the anion-binding site of Prestin, and inhibits its function by immobilizing Prestin in a novel conformation. Our data suggests that the bound anion together with its coordinating charged residues and helical dipole act as a dynamic voltage sensor. Analysis of all anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein-membrane interface, suggesting a novel mechanism of area expansion. Visualization of Prestin’s electromotility cycle distinguishes Prestin from closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at high resolution.

DOI: 10.1038/s41586-021-04152-4

Source: https://www.nature.com/articles/s41586-021-04152-4

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