@article{0e7bd106a5454adb99d8c369bb43e8f7,
title = "Molecular mechanism of prestin electromotive signal amplification",
abstract = "Hearing involves two fundamental processes: mechano-electrical transduction and signal amplification. Despite decades of studies, the molecular bases for both remain elusive. Here, we show how prestin, the electromotive molecule of outer hair cells (OHCs) that senses both voltage and membrane tension, mediates signal amplification by coupling conformational changes to alterations in membrane surface area. Cryoelectron microscopy (cryo-EM) structures of human prestin bound with chloride or salicylate at a common “anion site” adopt contracted or expanded states, respectively. Prestin is ensconced within a perimeter of well-ordered lipids, through which it induces dramatic deformation in the membrane and couples protein conformational changes to the bulk membrane. Together with computational studies, we illustrate how the anion site is allosterically coupled to changes in the transmembrane domain cross-sectional area and the surrounding membrane. These studies provide insight into OHC electromotility by providing a structure-based mechanism of the membrane motor prestin.",
keywords = "cochlear amplification, cryo-EM, electromotility, hearing, intrinsic voltage sensor, mechanotransduction, membrane protein, outer hair cells, prestin, protein lipid interaction",
author = "Jingpeng Ge and Johannes Elferich and Sepehr Dehghani-Ghahnaviyeh and Zhiyu Zhao and Marc Meadows and {von Gersdorff}, Henrique and Emad Tajkhorshid and Eric Gouaux",
note = "Funding Information: We would like to thank the staff at Pacific Northwest Cryo-EM Center (PNCC), OHSU MMC, and Janelia Research Campus for the assistance in cryo-EM data collection and the staff at UW for the assistance in cryo-EM preliminary screening. We thank L. Vaskalis for assistance with figures, H. Owen and R. Hallford for help with manuscript preparation, J. Santos-Sacchi for help with jClamp, and Gouaux lab members for discussions. The computational component of the project was supported by the National Institutes of Health (NIH) under award numbers P41-GM104601 (to E.T.) and R01-GM123455 (to E.T.). We also acknowledge computing resources provided by Blue Waters at National Center for Supercomputing Applications (NCSA), Extreme Science and Engineering Discovery Environment (XSEDE) (grant MCA06N060 to E.T.), and by Microsoft Azure. This work is also supported by NIH grants RO1 DC004274 and DC012938 to H.v.G. from National Institute on Deafness and Other Communication Disorders. E.G. holds the Jennifer and Bernard Lacroute Endowed Chair in Neuroscience and is an investigator of the Howard Hughes Medical Institute. J.G. and E.G. designed the project. J.G. performed biochemistry, cryo-EM data collection and processing, and model building; J.G. and J.E. performed the prestin NLC measurement with the dual-sine method; M.M. and H.v.G. performed the prestin NLC measurement with the “sine+DC” method; S.D.-G. Z.Z. and E.T. performed and analyzed MD simulations; and J.G. and J.E. wrote the draft of the manuscript. All authors contributed to editing and manuscript preparation. The authors declare no competing interests. Funding Information: We would like to thank the staff at Pacific Northwest Cryo-EM Center (PNCC), OHSU MMC, and Janelia Research Campus for the assistance in cryo-EM data collection and the staff at UW for the assistance in cryo-EM preliminary screening. We thank L. Vaskalis for assistance with figures, H. Owen and R. Hallford for help with manuscript preparation, J. Santos-Sacchi for help with jClamp, and Gouaux lab members for discussions. The computational component of the project was supported by the National Institutes of Health (NIH) under award numbers P41-GM104601 (to E.T.) and R01-GM123455 (to E.T.). We also acknowledge computing resources provided by Blue Waters at National Center for Supercomputing Applications (NCSA), Extreme Science and Engineering Discovery Environment (XSEDE) (grant MCA06N060 to E.T.), and by Microsoft Azure. This work is also supported by NIH grants RO1 DC004274 and DC012938 to H.v.G. from National Institute on Deafness and Other Communication Disorders. E.G. holds the Jennifer and Bernard Lacroute Endowed Chair in Neuroscience and is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = sep,
day = "2",
doi = "10.1016/j.cell.2021.07.034",
language = "English (US)",
volume = "184",
pages = "4669--4679.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "18",
}