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Structure and mechanism of the human NHE1-CHP1 complex

Author

Listed:
  • Yanli Dong

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiwei Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Alina Ilie

    (McGill University)

  • DuSik Kim

    (McGill University)

  • Annie Boucher

    (McGill University)

  • Bin Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xuejun C. Zhang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • John Orlowski

    (McGill University)

  • Yan Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.

Suggested Citation

  • Yanli Dong & Yiwei Gao & Alina Ilie & DuSik Kim & Annie Boucher & Bin Li & Xuejun C. Zhang & John Orlowski & Yan Zhao, 2021. "Structure and mechanism of the human NHE1-CHP1 complex," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23496-z
    DOI: 10.1038/s41467-021-23496-z
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    Cited by:

    1. Yishuo Lu & Peng Zuo & Hongyi Chen & Hui Shan & Weize Wang & Zonglin Dai & He Xu & Yayu Chen & Ling Liang & Dian Ding & Yan Jin & Yuxin Yin, 2023. "Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Yuhang Wang & Chengcai Pan & Qihao Chen & Qing Xie & Yiwei Gao & Lingli He & Yue Li & Yanli Dong & Xingyu Jiang & Yan Zhao, 2023. "Architecture and autoinhibitory mechanism of the plasma membrane Na+/H+ antiporter SOS1 in Arabidopsis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Ashutosh Gulati & Surabhi Kokane & Annemarie Perez-Boerema & Claudia Alleva & Pascal F. Meier & Rei Matsuoka & David Drew, 2024. "Structure and mechanism of the K+/H+ exchanger KefC," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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