ArticlePLoS pathogens2025
Phosphorylation of SNAP-25 at Ser187 is enhanced following its cleavage by Botulinum Neurotoxin Serotype A, promoting the dominant-negative effect of the resulting fragment.
Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
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13 authors.
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Abstract
Botulinum Neurotoxin Serotype A (BoNT/A), responsible for most human botulism cases, inhibits neurotransmitter release by cleaving the target protein SNAP-25. Previous literature demonstrated that BoNT/A mediated cleavage of a small subset of the SNAP-25 pool, resulting in SNAP-25 (1-197) fragments, is sufficient to block exocytosis. SNAP-25 (1-197) potentially competes against intact SNAP-25 for SNARE complexes and blocks neurotransmission through a dominant-negative mechanism. However, how a tiny fraction of cleaved SNAP-25 efficiently outcompetes a large pool of intact SNAP-25 remains unknown. Here, we examined the importance of SNAP-25 phosphorylation at Ser187 residue, located in the C-terminus SNARE domain, in the context of BoNT action. Our results demonstrated that Ser187-phosphorylated SNAP-25 can be efficiently cleaved in cells. Importantly, BoNT/A-cleaved SNAP-25 fragments in neuronal and non-neuronal cells are heavily phosphorylated at Ser187 and localized on the cell membrane. SNAP-25 (1-197) binds to syntaxin-1A, and the interaction is enhanced by Ser187 phosphorylation. We also found that SNAP-25 (1-197) survives longer than the BoNT/A enzymatic component itself in cells. Molecular modeling suggested that SNAP-25 (1-197), phosphorylated or not, forms stable SNARE complexes; however, Ser187 phosphorylation induces local changes in surface electrostatic potential and dynamics of the complex. This study characterizes the molecular mechanism underlying the dominant-negative effect of SNAP-25 (1-197) on neurotransmission. This research could have implications for the future development of BoNT/A inhibitors and the generation of new BoNT/A clinical formulations by regulating the abundance of Ser187 phosphorylation in cleaved SNAP-25 fragments.
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