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Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

Author

Listed:
  • Zheng Liu

    (University of California, Irvine)

  • Pyung-Gang Lee

    (Boston Children’s Hospital
    Harvard Medical School)

  • Nadja Krez

    (Hannover Medical School)

  • Kwok-ho Lam

    (University of California, Irvine)

  • Hao Liu

    (Boston Children’s Hospital
    Harvard Medical School)

  • Adina Przykopanski

    (Hannover Medical School)

  • Peng Chen

    (University of California, Irvine)

  • Guorui Yao

    (University of California, Irvine)

  • Sicai Zhang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Jacqueline M. Tremblay

    (Tufts Cummings School of Veterinary Medicine)

  • Kay Perry

    (Cornell University, Argonne National Laboratory)

  • Charles B. Shoemaker

    (Tufts Cummings School of Veterinary Medicine)

  • Andreas Rummel

    (Hannover Medical School)

  • Min Dong

    (Boston Children’s Hospital
    Harvard Medical School)

  • Rongsheng Jin

    (University of California, Irvine)

Abstract

Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (HCE) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between HCE and SV2 provide the crucial location and specificity information for HCE to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, HCE exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications.

Suggested Citation

  • Zheng Liu & Pyung-Gang Lee & Nadja Krez & Kwok-ho Lam & Hao Liu & Adina Przykopanski & Peng Chen & Guorui Yao & Sicai Zhang & Jacqueline M. Tremblay & Kay Perry & Charles B. Shoemaker & Andreas Rummel, 2023. "Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37860-8
    DOI: 10.1038/s41467-023-37860-8
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    References listed on IDEAS

    as
    1. Qing Chai & Joseph W. Arndt & Min Dong & William H. Tepp & Eric A. Johnson & Edwin R. Chapman & Raymond C. Stevens, 2006. "Structural basis of cell surface receptor recognition by botulinum neurotoxin B," Nature, Nature, vol. 444(7122), pages 1096-1100, December.
    2. Liang Tao & Lisheng Peng & Ronnie P.-A. Berntsson & Sai Man Liu & SunHyun Park & Feifan Yu & Christopher Boone & Shilpa Palan & Matthew Beard & Pierre-Etienne Chabrier & Pål Stenmark & Johannes Krupp , 2017. "Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    3. Roger M. Benoit & Daniel Frey & Manuel Hilbert & Josta T. Kevenaar & Mara M. Wieser & Christian U. Stirnimann & David McMillan & Tom Ceska & Florence Lebon & Rolf Jaussi & Michel O. Steinmetz & Gebhar, 2014. "Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A," Nature, Nature, vol. 505(7481), pages 108-111, January.
    4. Rongsheng Jin & Andreas Rummel & Thomas Binz & Axel T. Brunger, 2006. "Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity," Nature, Nature, vol. 444(7122), pages 1092-1095, December.
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