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September 1st, 2025
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Aix-Marseille University
biochemistry
bioRxiv

Membrane constraints reshape synaptotagmin recognition by botulinum neurotoxin B1

Azzaz, F.Open in Google Scholar•Far, O. E.Open in Google Scholar•Fantini, J.Open in Google Scholar

Synaptotagmins 1 and 2 (SYT1 and SYT2) are essential membrane proteins in neurotransmission, aiding in synaptic vesicle fusion. The juxtamembrane domains of both SYT1 and SYT2 are recognized by botulinum neurotoxin B1 (BoNT/B1), the agent of botulism. Current experimental models describe SYT1 and SYT2 interactions with BoNT/B1 but lack membrane insertion, which may bias the observed interactions. Objective: To explore the interactions of membrane-inserted SYT1 and SYT2 with BoNT/B1 and assess the impact of membrane constraints on these interactions. Methods: We used molecular dynamics simulations to study the conformational changes of membrane-inserted SYT1 and SYT2 when bound to BoNT/B1, focusing on the influence of membrane constraints. Results: Our simulations predict that membrane constraints reshape SYT1 and SYT2, enabling their juxtamembrane domains to interact with the BoNT/B1 lipid-binding loop, a unique interaction not seen in Xray models but in agreement with experimental data. SYT1's conformation is particularly affected, increasing solvent exposure at its BoNT/B1 binding site. The GT1b ganglioside stabilizes this complex by reducing solvent exposure, providing mechanistic insights into its role in BoNT/B1-SYT1 interaction, as experimental data support. Conclusion: Our study reveals overlooked molecular mechanisms in non-membrane models, highlighting dynamics essential to BoNT/B1-SYT interactions. These findings could guide the design of BoNT/B1-targeted antidotes or drugs able to enhance binding efficacy for therapeutic purposes.

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