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Publication Detail
Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E
  • Publication Type:
    Journal article
  • Authors:
    Lalaurie CJ, Splevins A, Barata TS, Bunting KA, Higazi DR, Zloh M, Spiteri VA, Perkins SJ, Dalby PA
  • Publisher:
    Elsevier BV
  • Publication date:
  • Journal:
    J Struct Biol
  • Volume:
  • Issue:
  • Article number:
  • Medium:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Botulinum Neurotoxin, Molecular Dynamics, Small-Angle X-Ray Scattering
  • Notes:
    © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Botulinum Neurotoxins (BoNT) are the most potent toxins currently known. However, they also have therapeutic applications for an increasing number of motor related conditions due to their specificity, and low diffusion into the system. Although the start- and end- points for the BoNT mechanism of action are well-studied, a critical step remains poorly understood. It is theorised that BoNTs undergo a pH-triggered conformational shift, activating the neurotoxin by priming it to form a transmembrane (TM) channel. To test this hypothesis, we combined molecular dynamic (MD) simulations and small-angle x-ray scattering (SAXS), revealing a new conformation of BoNT/E. This conformation was exclusively observed in simulations below pH 5.5, as determined by principal component analysis (PCA), and its theoretical SAXS profile matched an experimental SAXS profile obtained at pH 4. Additionally, a localised secondary structural change was observed in MD simulations below pH 5.5, in a region previously identified as instrumental for membrane insertion for BoNT/A. These changes were found at a critical pH value for BoNTs in vivo, and may be relevant for their therapeutic use.
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