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Asymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger

Author

Listed:
  • Qianying Liu

    (Fudan University)

  • Xiang Zhang

    (Fudan University)

  • Hui Huang

    (Fudan University)

  • Yuxin Chen

    (Fudan University
    Fudan University
    Fudan University)

  • Fang Wang

    (Fudan University
    Fudan University
    Fudan University)

  • Aihua Hao

    (Fudan University)

  • Wuqiang Zhan

    (Fudan University)

  • Qiyu Mao

    (Fudan University)

  • Yuxia Hu

    (Fudan University)

  • Lin Han

    (Fudan University)

  • Yifang Sun

    (Fudan University)

  • Meng Zhang

    (Fudan University)

  • Zhimin Liu

    (Fudan University)

  • Geng-Lin Li

    (Fudan University
    Fudan University
    Fudan University)

  • Weijia Zhang

    (Fudan University)

  • Yilai Shu

    (Fudan University
    Fudan University
    Fudan University
    Fudan University)

  • Lei Sun

    (Fudan University
    Shanghai Institute of Infectious Disease and Biosecurity
    Shanghai Key Laboratory of Medical Epigenetics)

  • Zhenguo Chen

    (Fudan University
    Shanghai Institute of Infectious Disease and Biosecurity
    Shanghai Key Laboratory of Medical Epigenetics)

Abstract

Pendrin (SLC26A4) is an anion exchanger expressed in the apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However its molecular structure has remained unknown, limiting our understanding of the structural basis of transport. Here, we determine the cryo-electron microscopy structures of mouse pendrin with symmetric and asymmetric homodimer conformations. The asymmetric homodimer consists of one inward-facing protomer and the other outward-facing protomer, representing coincident uptake and secretion- a unique state of pendrin as an electroneutral exchanger. The multiple conformations presented here provide an inverted alternate-access mechanism for anion exchange. The structural and functional data presented here disclose the properties of an anion exchange cleft and help understand the importance of disease-associated variants, which will shed light on the pendrin exchange mechanism.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38303-0
    DOI: 10.1038/s41467-023-38303-0
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    as
    1. 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.
    2. Carmen Butan & Qiang Song & Jun-Ping Bai & Winston J. T. Tan & Dhasakumar Navaratnam & Joseph Santos-Sacchi, 2022. "Single particle cryo-EM structure of the outer hair cell motor protein prestin," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Feiran Lu & Shuo Li & Yang Jiang & Jing Jiang & He Fan & Guifeng Lu & Dong Deng & Shangyu Dang & Xu Zhang & Jiawei Wang & Nieng Yan, 2011. "Structure and mechanism of the uracil transporter UraA," Nature, Nature, vol. 472(7342), pages 243-246, April.
    4. Navid Bavi & Michael David Clark & Gustavo F. Contreras & Rong Shen & Bharat G. Reddy & Wieslawa Milewski & Eduardo Perozo, 2021. "The conformational cycle of prestin underlies outer-hair cell electromotility," Nature, Nature, vol. 600(7889), pages 553-558, December.
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    Cited by:

    1. Makoto F. Kuwabara & Bassam G. Haddad & Dominik Lenz-Schwab & Julia Hartmann & Piersilvio Longo & Britt-Marie Huckschlag & Anneke Fuß & Annalisa Questino & Thomas K. Berger & Jan-Philipp Machtens & Do, 2023. "Elevator-like movements of prestin mediate outer hair cell electromotility," Nature Communications, Nature, vol. 14(1), pages 1-18, 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.

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