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

DOI: 10.1016/j.jsb.2022.107876

Authors: Christophe J. Lalaurie (University College London) , Andrew Splevins (Evox Therapeutics Ltd; Ipsen Bioinnovation) , Teresa S. Barata (FairJourney Biologics; Ipsen Bioinnovation) , Karen A. Bunting (Ipsen Bioinnovation) , Daniel R. Higazi (Ipsen Biopharm Ltd) , Mire Zloh (University College London) , Valentina A. Spiteri (University College London) , Stephen J. Perkins (University College London) , Paul A. Dalby (University College London)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Structural Biology , VOL 12

State: Published (Approved)
Published: June 2022
Diamond Proposal Number(s): 30822

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.

Journal Keywords: Botulinum Neurotoxin; Molecular Dynamics; Small-Angle X-Ray Scattering

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 22/06/2022 09:26

Documents:
1-s2.0-S1047847722000466-main.pdf

Discipline Tags:

Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)