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YEAR : 2019

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

AUTHORS : Flores A, Ramirez-Franco JJ, Desplantes R, Debreux K, Ferracci G, Wernert F, Blanchard MP, Maulet Y, Youssouf F, Sangiardi M, Iborra C, Popoff MR, Seagar M, Fantini J, Lévêque C, El Far O.

JOURNAL : PNAS
N° Pubmed : 31431523
Botulinum neurotoxin type B (BoNT/B) recognizes nerve terminals
by binding to 2 receptor components: a polysialoganglioside,
predominantly GT1b, and synaptotagmin 1/2. It is widely thought
that BoNT/B initially binds to GT1b then diffuses in the plane of
the membrane to interact with synaptotagmin. We have addressed
the hypothesis that a GT1b–synaptotagmin cis complex forms the
BoNT/B receptor.We identified a consensus glycosphingolipid-binding
motif in the extracellular juxtamembrane domain of synaptotagmins
1/2 and confirmed by Langmuir monolayer, surface plasmon resonance,
and circular dichroism that GT1b interacts with synaptotagmin
peptides containing this sequence, inducing α-helical structure. Molecular
modeling and tryptophan fluorescence spectroscopy were consistent
with the intertwining of GT1b and synaptotagmin, involving cis
interactions between the oligosaccharide and ceramide moieties
of GT1b and the juxtamembrane and transmembrane domains of
synaptotagmin, respectively. Furthermore, a point mutation on
synaptotagmin, located outside of the BoNT/B-binding segment,
inhibited GT1b binding and blocked GT1b-induced potentiation of
BoNT/B binding to synaptotagmin-expressing cells. Our findings are
consistent with amodel in which a preassembled GT1b–synaptotagmin
complex constitutes the high-affinity BoNT/B receptor.

Keys words : botulinum neurotoxin B receptor | synaptotagmin | gangliosides