Abstract
Outer hair cell elecromotility, driven by prestin, is essential for mammalian cochlear amplification. Here, we report the cryo-EM structures of thermostabilized prestin (PresTS), complexed with chloride, sulfate, or salicylate at 3.52-3.63 Å resolutions. The central positively-charged cavity allows flexible binding of various anion species, which likely accounts for the known distinct modulations of nonlinear capacitance (NLC) by different anions. Comparisons of these PresTS structures with recent prestin structures suggest rigid-body movement between the core and gate domains, and provide mechanistic insights into prestin inhibition by salicylate. Mutations at the dimeric interface severely diminished NLC, suggesting that stabilization of the gate domain facilitates core domain movement, thereby contributing to the expression of NLC. These findings advance our understanding of the molecular mechanism underlying mammalian cochlear amplification.
Original language | English (US) |
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Article number | 6208 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2022 |
Funding
We thank the staff scientists at The University of Tokyo\u2019s cryo-EM facility, especially K. Kobayashi, H. Yanagisawa, A. Tsutsumi, M. Kikkawa, and R. Danev, and computational time at the Research Center for Computational Science, Okazaki, Japan. Cell imaging work was performed at the Northwestern University Center for Advanced Microscopy. Funded by: The MEXT Grant-in-Aid for Specially Promoted Research 16H06294 and JST CREST program 20344981 (to O.N.), JSPS KAKENHI grant 17H05000 and 20H03216 (to T.N.), AMED JP19am0101115 (support number 1111), NIH grant DC017482 (to K.H.), JSPS KAKENHI grant 19H03195 and 20H05441 (to S.H.). Northwestern University Center for Advanced Microscopy is supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General
- General Physics and Astronomy
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Thermostabilized human prestin in complex with chloride
Futamata, H. (Contributor), Fukuda, M. (Contributor), Umeda, R. (Contributor), Yamashita, K. (Contributor), Tomita, A. (Contributor), Takahashi, S. (Contributor), Shikakura, T. (Contributor), Hayashi, S. (Contributor), Kusakizako, T. (Contributor), Nishizawa, T. (Contributor), Homma, K. (Contributor) & Nureki, O. (Contributor), Protein Data Bank (PDB), Aug 31 2022
DOI: 10.2210/pdb7V73/pdb, https://www.wwpdb.org/pdb?id=pdb_00007v73
Dataset
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Thermostabilized human prestin in complex with salicylate
Futamata, H. (Contributor), Fukuda, M. (Contributor), Umeda, R. (Contributor), Yamashita, K. (Contributor), Tomita, A. (Contributor), Takahashi, S. (Contributor), Shikakura, T. (Contributor), Hayashi, S. (Contributor), Kusakizako, T. (Contributor), Nishizawa, T. (Contributor), Homma, K. (Contributor) & Nureki, O. (Contributor), Protein Data Bank (PDB), Aug 31 2022
DOI: 10.2210/pdb7V75/pdb, https://www.wwpdb.org/pdb?id=pdb_00007v75
Dataset
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Thermostabilized human prestin in complex with sulfate
Futamata, H. (Contributor), Fukuda, M. (Contributor), Umeda, R. (Contributor), Yamashita, K. (Contributor), Tomita, A. (Contributor), Takahashi, S. (Contributor), Shikakura, T. (Contributor), Hayashi, S. (Contributor), Kusakizako, T. (Contributor), Nishizawa, T. (Contributor), Homma, K. (Contributor) & Nureki, O. (Contributor), Protein Data Bank (PDB), Aug 31 2022
DOI: 10.2210/pdb7V74/pdb, https://www.wwpdb.org/pdb?id=pdb_00007v74
Dataset