Cryo-EM structures of thermostabilized prestin provide mechanistic insights underlying outer hair cell electromotility

Haon Futamata, Masahiro Fukuda, Rie Umeda, Keitaro Yamashita, Atsuhiro Tomita, Satoe Takahashi, Takafumi Shikakura, Shigehiko Hayashi, Tsukasa Kusakizako, Tomohiro Nishizawa*, Kazuaki Homma*, Osamu Nureki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 languageEnglish (US)
Article number6208
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - 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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