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

Kwok-ho Lam, Zhuojun Guo, Nadja Krez, Tsutomu Matsui, Kay Perry, Jasmin Weisemann, Andreas Rummel, Mark E. Bowen and Rongsheng Jin ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07789-4

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