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

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Botulinum neurotoxins (BoNT) are highly potent toxins with increasing therapeutic applications.
• Their specificity and low systemic diffusion make them valuable for motor-related conditions.
• The precise mechanism of BoNT activation, particularly the pH-triggered conformational shift, remains poorly understood.

Purpose of the Study:

• To investigate the pH-dependent conformational changes of Botulinum Neurotoxin Serotype E (BoNT/E).
• To elucidate the role of pH in BoNT activation and transmembrane channel formation.
• To correlate structural changes with in vivo conditions and therapeutic potential.

Main Methods:

• Utilized molecular dynamics (MD) simulations to model BoNT behavior.
• Employed small-angle X-ray scattering (SAXS) to analyze structural changes.
• Applied principal component analysis (PCA) to identify conformational states.

Main Results:

• A novel conformation of BoNT/E was identified exclusively below pH 5.5 in MD simulations.
• The theoretical SAXS profile of this new conformation matched experimental data at pH 4.
• Localized secondary structural changes, relevant for membrane insertion, were observed below pH 5.5.

Conclusions:

• BoNTs undergo significant pH-dependent conformational changes critical for their activity.
• The newly identified BoNT/E conformation and structural alterations provide insights into neurotoxin activation.
• These findings may have implications for optimizing BoNT-based therapies.