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Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger

Author

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  • Yangzhuoqun Wan

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Shuangshuang Guo

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Wenxuan Zhen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Lizhen Xu

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Xiaoying Chen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Fangyue Liu

    (Zhejiang University School of Medicine)

  • Yi Shen

    (Zhejiang University School of Medicine)

  • Shuangshuang Liu

    (Zhejiang University School of Medicine)

  • Lidan Hu

    (National Clinical Research Center for Child Health)

  • Xinyan Wang

    (DP Technology)

  • Fengcan Ye

    (DP Technology)

  • Qinrui Wang

    (DP Technology)

  • Han Wen

    (DP Technology
    Institute for Advanced Algorithms Research
    State Key Laboratory of Medical Proteomics
    AI for Science Institute)

  • Fan Yang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

Abstract

The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.

Suggested Citation

  • Yangzhuoqun Wan & Shuangshuang Guo & Wenxuan Zhen & Lizhen Xu & Xiaoying Chen & Fangyue Liu & Yi Shen & Shuangshuang Liu & Lidan Hu & Xinyan Wang & Fengcan Ye & Qinrui Wang & Han Wen & Fan Yang, 2024. "Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50975-w
    DOI: 10.1038/s41467-024-50975-w
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    References listed on IDEAS

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    1. Olaf Scheel & Anselm A. Zdebik & Stéphane Lourdel & Thomas J. Jentsch, 2005. "Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins," Nature, Nature, vol. 436(7049), pages 424-427, July.
    2. Alessio Accardi & Christopher Miller, 2004. "Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels," Nature, Nature, vol. 427(6977), pages 803-807, February.
    3. Raimund Dutzler & Ernest B. Campbell & Martine Cadene & Brian T. Chait & Roderick MacKinnon, 2002. "X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity," Nature, Nature, vol. 415(6869), pages 287-294, January.
    4. Christopher Miller, 2006. "ClC chloride channels viewed through a transporter lens," Nature, Nature, vol. 440(7083), pages 484-489, March.
    5. Janice L. Robertson & Ludmila Kolmakova-Partensky & Christopher Miller, 2010. "Design, function and structure of a monomeric ClC transporter," Nature, Nature, vol. 468(7325), pages 844-847, December.
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