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

Author

Listed:
  • Haon Futamata

    (The University of Tokyo, Bunkyo-ku)

  • Masahiro Fukuda

    (The University of Tokyo, Bunkyo-ku
    The University of Tokyo; Meguro-ku)

  • Rie Umeda

    (The University of Tokyo, Bunkyo-ku)

  • Keitaro Yamashita

    (The University of Tokyo, Bunkyo-ku
    MRC Laboratory of Molecular Biology)

  • Atsuhiro Tomita

    (The University of Tokyo, Bunkyo-ku)

  • Satoe Takahashi

    (Northwestern University)

  • Takafumi Shikakura

    (Kyoto University, Kitashirakawa, Oiwake-cho, Sakyo-ku)

  • Shigehiko Hayashi

    (Kyoto University, Kitashirakawa, Oiwake-cho, Sakyo-ku)

  • Tsukasa Kusakizako

    (The University of Tokyo, Bunkyo-ku)

  • Tomohiro Nishizawa

    (The University of Tokyo, Bunkyo-ku
    Yokohama City University)

  • Kazuaki Homma

    (Northwestern University
    Northwestern University)

  • Osamu Nureki

    (The University of Tokyo, Bunkyo-ku)

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.

Suggested Citation

  • Haon Futamata & Masahiro Fukuda & Rie Umeda & Keitaro Yamashita & Atsuhiro Tomita & Satoe Takahashi & Takafumi Shikakura & Shigehiko Hayashi & Tsukasa Kusakizako & Tomohiro Nishizawa & Kazuaki Homma &, 2022. "Cryo-EM structures of thermostabilized prestin provide mechanistic insights underlying outer hair cell electromotility," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34017-x
    DOI: 10.1038/s41467-022-34017-x
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    References listed on IDEAS

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    Cited by:

    1. Qianying Liu & Xiang Zhang & Hui Huang & Yuxin Chen & Fang Wang & Aihua Hao & Wuqiang Zhan & Qiyu Mao & Yuxia Hu & Lin Han & Yifang Sun & Meng Zhang & Zhimin Liu & Geng-Lin Li & Weijia Zhang & Yilai S, 2023. "Asymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Lie Wang & Anthony Hoang & Eva Gil-Iturbe & Arthur Laganowsky & Matthias Quick & Ming Zhou, 2024. "Mechanism of anion exchange and small-molecule inhibition of pendrin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Wenxin Hu & Alex Song & Hongjin Zheng, 2024. "Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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