The conformational cycle of prestin underlies outer-hair cell electromotility

被引:45
作者
Bavi, Navid [1 ]
Clark, Michael David [1 ]
Contreras, Gustavo F. [1 ]
Shen, Rong [1 ]
Reddy, Bharat G. [1 ,3 ]
Milewski, Wieslawa [1 ]
Perozo, Eduardo [1 ,2 ]
机构
[1] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA
[2] Univ Chicago, Grossman Inst Neurosci Quantitat Biol & Human Beh, Chicago, IL 60637 USA
[3] Rectify Pharmaceut, Cambridge, MA USA
基金
美国国家卫生研究院;
关键词
MOLECULAR-DYNAMICS; MOTOR PROTEIN; MEMBRANE MOTOR; CRYO-EM; MECHANICAL RESPONSES; LATERAL MEMBRANE; VOLTAGE SENSOR; MOTILITY; MODEL; SENSITIVITY;
D O I
10.1038/s41586-021-04152-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The voltage-dependent motor protein prestin (also known as SLC26A5) is responsible for the electromotive behaviour of outer-hair cells and underlies the cochlear amplifier(1). Knockout or impairment of prestin causes severe hearing loss(2-5). Despite the key role of prestin 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 new conformation. Our data suggest that the bound anion together with its coordinating charged residues and helical dipole act as a dynamic voltage sensor. An analysis of all of the anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein-membrane interface, suggesting a previously undescribed mechanism of area expansion. Visualization of the electromotility cycle of prestin distinguishes the protein from the closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at a high resolution.
引用
收藏
页码:553 / +
页数:22
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