Molecular landscape of BoNT/B bound to a membrane-inserted synaptotagmin/ganglioside complex

authors

• Ramirez-Franco Jorge
• Azzaz Fodil
• Sangiardi Marion
• Ferracci Géraldine
• Youssouf Fahamoe
• Popoff Michel Robert
• Seagar Michael
• Lévêque Christian
• Fantini Jacques
• El Far Oussama

keywords

• Botulinum Neurotoxin type B
• Synaptotagmin
• Gangliosides
• Molecular modelling

document type

abstract

Botulinum neurotoxin serotype B (BoNT/B) uses two separate protein and polysialoglycolipid-binding pockets to interact with synaptotagmin 1/2 and gangliosides. However, an integrated model of BoNT/B bound to its neuronal receptors in a native membrane topology is still lacking. Using a panel of in silico and experimental approaches, we present here a new model for BoNT/B binding to neuronal membranes, in which the toxin binds to a preassembled synaptotagminganglioside GT1b complex and a free ganglioside allowing a lipid-binding loop of 2 BoNT/B to interact with the glycone part of the synaptotagmin-associated GT1b. Furthermore, our data provide molecular support for the decrease in BoNT/B sensitivity in Felidae that harbor the natural variant synaptotagmin2-N59Q. These results reveal multiple interactions of BoNT/B with gangliosides and support a novel paradigm in which a toxin recognizes a protein/ganglioside complex.

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