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CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1

Author

Listed:
  • Kevin W. Huynh

    (University of California
    University of California)

  • Jiansen Jiang

    (University of California
    University of California)

  • Natalia Abuladze

    (University of California)

  • Kirill Tsirulnikov

    (University of California)

  • Liyo Kao

    (University of California)

  • Xuesi Shao

    (University of California)

  • Debra Newman

    (University of California)

  • Rustam Azimov

    (University of California)

  • Alexander Pushkin

    (University of California)

  • Z. Hong Zhou

    (University of California
    University of California)

  • Ira Kurtz

    (University of California
    University of California)

Abstract

Na+-coupled acid–base transporters play essential roles in human biology. Their dysfunction has been linked to cancer, heart, and brain disease. High-resolution structures of mammalian Na+-coupled acid–base transporters are not available. The sodium-bicarbonate cotransporter NBCe1 functions in multiple organs and its mutations cause blindness, abnormal growth and blood chemistry, migraines, and impaired cognitive function. Here, we have determined the structure of the membrane domain dimer of human NBCe1 at 3.9 Å resolution by cryo electron microscopy. Our atomic model and functional mutagenesis revealed the ion accessibility pathway and the ion coordination site, the latter containing residues involved in human disease-causing mutations. We identified a small number of residues within the ion coordination site whose modification transformed NBCe1 into an anion exchanger. Our data suggest that symporters and exchangers utilize comparable transport machinery and that subtle differences in their substrate-binding regions have very significant effects on their transport mode.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03271-3
    DOI: 10.1038/s41467-018-03271-3
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    Cited by:

    1. Takaaki A. Kobayashi & Hiroto Shimada & Fumiya K. Sano & Yuzuru Itoh & Sawako Enoki & Yasushi Okada & Tsukasa Kusakizako & Osamu Nureki, 2024. "Dimeric transport mechanism of human vitamin C transporter SVCT1," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. Yan Jiang & Jiansen Jiang, 2024. "The Bor1 elevator transport cycle is subject to autoinhibition and activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. David B. Sauer & Jennifer J. Marden & Joseph C. Sudar & Jinmei Song & Christopher Mulligan & Da-Neng Wang, 2022. "Structural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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