UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E

Lalaurie, Christophe J; Splevins, Andrew; Barata, Teresa S; Bunting, Karen A; Higazi, Daniel R; Zloh, Mire; Spiteri, Valentina A; ... Dalby, Paul A; + view all (2022) Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E. J Struct Biol , 214 (3) , Article 107876. 10.1016/j.jsb.2022.107876. Green open access

[thumbnail of Dalby_1-s2.0-S1047847722000466-main.pdf]
Preview
Text
Dalby_1-s2.0-S1047847722000466-main.pdf - Published Version

Download (6MB) | Preview

Abstract

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.

Type: Article
Title: Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jsb.2022.107876
Publisher version: https://doi.org/10.1016/j.jsb.2022.107876
Language: English
Additional information: © 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/)
Keywords: Botulinum Neurotoxin, Molecular Dynamics, Small-Angle X-Ray Scattering
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10151029
Downloads since deposit
36Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item