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A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1

Author

Listed:
  • Kwok-ho Lam

    (University of California)

  • Zhuojun Guo

    (Stony Brook University)

  • Nadja Krez

    (Medizinische Hochschule Hannover)

  • Tsutomu Matsui

    (Stanford University)

  • Kay Perry

    (Cornell University)

  • Jasmin Weisemann

    (Medizinische Hochschule Hannover)

  • Andreas Rummel

    (Medizinische Hochschule Hannover)

  • Mark E. Bowen

    (Stony Brook University)

  • Rongsheng Jin

    (University of California)

Abstract

Botulinum neurotoxin (BoNT) delivers its protease domain across the vesicle membrane to enter the neuronal cytosol upon vesicle acidification. This process is mediated by its translocation domain (HN), but the molecular mechanism underlying membrane insertion of HN remains poorly understood. Here, we report two crystal structures of BoNT/A1 HN that reveal a novel molecular switch (termed BoNT-switch) in HN, where buried α-helices transform into surface-exposed hydrophobic β-hairpins triggered by acidic pH. Locking the BoNT-switch by disulfide trapping inhibited the association of HN with anionic liposomes, blocked channel formation by HN, and reduced the neurotoxicity of BoNT/A1 by up to ~180-fold. Single particle counting studies showed that an acidic environment tends to promote BoNT/A1 self-association on liposomes, which is partly regulated by the BoNT-switch. These findings suggest that the BoNT-switch flips out upon exposure to the acidic endosomal pH, which enables membrane insertion of HN that subsequently leads to LC delivery.

Suggested Citation

  • Kwok-ho Lam & Zhuojun Guo & Nadja Krez & Tsutomu Matsui & Kay Perry & Jasmin Weisemann & Andreas Rummel & Mark E. Bowen & Rongsheng Jin, 2018. "A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07789-4
    DOI: 10.1038/s41467-018-07789-4
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    Cited by:

    1. Oneda Leka & Yufan Wu & Giulia Zanetti & Sven Furler & Thomas Reinberg & Joana Marinho & Jonas V. Schaefer & Andreas Plückthun & Xiaodan Li & Marco Pirazzini & Richard A. Kammerer, 2023. "A DARPin promotes faster onset of botulinum neurotoxin A1 action," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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