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The structural insight into the functional modulation of human anion exchanger 3

Author

Listed:
  • Liyan Jian

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Qing Zhang

    (Shanghai Jiao Tong University School of Medicine
    Memorial Sloan Kettering Cancer Center)

  • Deqiang Yao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Qian Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Moxin Chen

    (Shanghai Jiao Tong University
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Ying Xia

    (Shanghai Jiao Tong University School of Medicine)

  • Shaobai Li

    (Shanghai Jiao Tong University School of Medicine)

  • Yafeng Shen

    (Shanghai Jiao Tong University School of Medicine)

  • Mi Cao

    (Shanghai Jiao Tong University School of Medicine)

  • An Qin

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Lin Li

    (Shanghai Jiao Tong University
    Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology)

  • Yu Cao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

Abstract

Anion exchanger 3 (AE3) is pivotal in regulating intracellular pH across excitable tissues, yet its structural intricacies and functional dynamics remain underexplored compared to other anion exchangers. This study unveils the structural insights into human AE3, including the cryo-electron microscopy structures for AE3 transmembrane domains (TMD) and a chimera combining AE3 N-terminal domain (NTD) with AE2 TMD (hAE3NTD2TMD). Our analyzes reveal a substrate binding site, an NTD-TMD interlock mechanism, and a preference for an outward-facing conformation. Unlike AE2, which has more robust acid-loading capabilities, AE3’s structure, including a less stable inward-facing conformation due to missing key NTD-TMD interactions, contributes to its moderated pH-modulating activity and increased sensitivity to the inhibitor DIDS. These structural differences underline AE3’s distinct functional roles in specific tissues and underscore the complex interplay between structural dynamics and functional specificity within the anion exchanger family, enhancing our understanding of the physiological and pathological roles of the anion exchanger family.

Suggested Citation

  • Liyan Jian & Qing Zhang & Deqiang Yao & Qian Wang & Moxin Chen & Ying Xia & Shaobai Li & Yafeng Shen & Mi Cao & An Qin & Lin Li & Yu Cao, 2024. "The structural insight into the functional modulation of human anion exchanger 3," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50572-x
    DOI: 10.1038/s41467-024-50572-x
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    References listed on IDEAS

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    1. Qing Zhang & Liyan Jian & Deqiang Yao & Bing Rao & Ying Xia & Kexin Hu & Shaobai Li & Yafeng Shen & Mi Cao & An Qin & Jie Zhao & Yu Cao, 2023. "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. 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.
    3. Weiqi Zhang & Dian Ding & Yishuo Lu & Hongyi Chen & Peijun Jiang & Peng Zuo & Guangxi Wang & Juan Luo & Yue Yin & Jianyuan Luo & Yuxin Yin, 2024. "Structural and functional insights into the lipid regulation of human anion exchanger 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Kasper Thorsen & Vibeke S. Dam & Kasper Kjaer-Sorensen & Lisbeth N. Pedersen & V. Arvydas Skeberdis & Jonas Jurevičius & Rimantas Treinys & Ida M. B. S. Petersen & Morten S. Nielsen & Claus Oxvig & J., 2017. "Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    5. Kevin W. Huynh & Jiansen Jiang & Natalia Abuladze & Kirill Tsirulnikov & Liyo Kao & Xuesi Shao & Debra Newman & Rustam Azimov & Alexander Pushkin & Z. Hong Zhou & Ira Kurtz, 2018. "CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    6. Weiguang Wang & Kirill Tsirulnikov & Hristina R. Zhekova & Gülru Kayık & Hanif Muhammad Khan & Rustam Azimov & Natalia Abuladze & Liyo Kao & Debbie Newman & Sergei Yu. Noskov & Z. Hong Zhou & Alexande, 2021. "Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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