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 () and Osamu Nureki ()
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Haon Futamata: The University of Tokyo, Bunkyo-ku
Masahiro Fukuda: The University of Tokyo, Bunkyo-ku
Rie Umeda: The University of Tokyo, Bunkyo-ku
Keitaro Yamashita: The University of Tokyo, Bunkyo-ku
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
Kazuaki Homma: Northwestern University
Osamu Nureki: The University of Tokyo, Bunkyo-ku

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34017-x

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