Abstract
The botulinum neurotoxins are potent molecules that are not only responsible for the lethal paralytic disease botulism, but have also been harnessed for therapeutic uses in the treatment of an increasing number of chronic neurological and neuromuscular disorders, in addition to cosmetic applications. The toxins act at the cholinergic nerve terminals thanks to an efficient and specific mechanism of cell recognition which is based on a dual receptor system that involves gangliosides and protein receptors. Binding to surface-anchored gangliosides is the first essential step in this process. Here, we determined the X-ray crystal structure of the binding domain of BoNT/E, a toxin of clinical interest, in complex with its GD1a oligosaccharide receptor. Beyond confirmation of the conserved ganglioside binding site, we identified key interacting residues that are unique to BoNT/E and a significant rearrangement of loop 1228–1237 upon carbohydrate binding. These observations were also supported by thermodynamic measurements of the binding reaction and assessment of ganglioside selectivity by immobilised-receptor binding assays. These results provide a structural basis to understand the specificity of BoNT/E for complex gangliosides.
Highlights
The botulinum neurotoxins (BoNT) are among the most toxic molecules known to man and are responsible for botulism, a rare but potentially fatal paralytic disease
These results provide the molecular details of BoNT/E’s specificity for complex gangliosides by identifying significant conformational changes upon receptor-binding, involving residues outside of the conserved ganglioside binding motif
The purified heavy chain (HC)/E protein consisted of residues 820 to 1252 of full-length BoNT/E with a dual N-terminal poly-His and HA tag
Summary
The botulinum neurotoxins (BoNT) are among the most toxic molecules known to man and are responsible for botulism, a rare but potentially fatal paralytic disease. They act at the neuromuscular junction by inhibiting the release of presynaptic acetylcholine [1]. We evaluated the carbohydrate selectivity of the toxin by analysing receptor-binding to a range of immobilised gangliosides. These results provide the molecular details of BoNT/E’s specificity for complex gangliosides by identifying significant conformational changes upon receptor-binding, involving residues outside of the conserved ganglioside binding motif. This study may help the design of botulinum neurotoxins with enhanced pharmacological properties
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