Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B
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....
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 36; pp. 18098 - 18108 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
03.09.2019
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| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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
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
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 a model in which a preassembled GT1b-synaptotagmin complex constitutes the high-affinity BoNT/B receptor. 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 a model in which a preassembled GT1b–synaptotagmin complex constitutes the high-affinity BoNT/B receptor. 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. Significance Botulism is induced by Clostridium botulinum neurotoxins (BoNTs). At neuromuscular junctions, BoNT/B binds to dual receptors: a plasma membrane resident polysialoganglioside and synaptotagmin, a synaptic vesicle protein transiently inserted in neuronal membranes upon exocytosis. It is widely thought that BoNT binds initially to gangliosides and that this binary complex then diffuses to interact with synaptotagmin. Here, we show that the true BoNT/B receptor is the preassembled GT1b–SYT complex and that the α-helical structure of the BoNT/B binding domain of synaptotagmin found in previous structural studies is induced by the ganglioside before it ever meets the toxin. BoNT/B thus exploits a preexisting protein–glycolipid complex of yet unknown physiological function. 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 a model in which a preassembled GT1b–synaptotagmin complex constitutes the high-affinity BoNT/B receptor. Botulism is induced by Clostridium botulinum neurotoxins (BoNTs). At neuromuscular junctions, BoNT/B binds to dual receptors: a plasma membrane resident polysialoganglioside and synaptotagmin, a synaptic vesicle protein transiently inserted in neuronal membranes upon exocytosis. It is widely thought that BoNT binds initially to gangliosides and that this binary complex then diffuses to interact with synaptotagmin. Here, we show that the true BoNT/B receptor is the preassembled GT1b–SYT complex and that the α-helical structure of the BoNT/B binding domain of synaptotagmin found in previous structural studies is induced by the ganglioside before it ever meets the toxin. BoNT/B thus exploits a preexisting protein–glycolipid complex of yet unknown physiological function. 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 a model in which a preassembled GT1b–synaptotagmin complex constitutes the high-affinity BoNT/B receptor. |
| Author | Popoff, Michel Robert Ramirez-Franco, Jorge Lévêque, Christian Maulet, Yves Debreux, Kévin Fantini, Jacques Seagar, Michael Far, Oussama El Youssouf, Fahamoe Sangiardi, Marion Desplantes, Richard Ferracci, Géraldine Flores, Alessandra Iborra, Cécile Wernert, Florian Blanchard, Marie-Pierre |
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| Keywords | gangliosides synaptotagmin botulinum neurotoxin B receptor |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: M. Seagar, C.L., and O.E.F. designed research; A.F., J.R.-F., R.D., K.D., G.F., F.W., M.-P.B., Y.M., F.Y., M. Sangiardi, C.I., J.F., and C.L. performed research; M.R.P. contributed new reagents/analytic tools; M. Seagar, C.L., and O.E.F. analyzed data; and M. Seagar, J.F., C.L., and O.E.F. wrote the paper. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 1, 2019 (received for review May 15, 2019) 1A.F. and J.R.-F. contributed equally to this work. |
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| Snippet | Botulinum neurotoxin type B (BoNT/B) recognizes nerve terminals by binding to 2 receptor components: a polysialoganglioside, predominantly GT1b, and... Significance Botulism is induced by Clostridium botulinum neurotoxins (BoNTs). At neuromuscular junctions, BoNT/B binds to dual receptors: a plasma membrane... Botulism is induced by Clostridium botulinum neurotoxins (BoNTs). At neuromuscular junctions, BoNT/B binds to dual receptors: a plasma membrane resident... |
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| SubjectTerms | Affinity Animals Binding Binding Sites Biological Sciences Botulinum toxin Botulinum toxin type B Botulinum Toxins, Type A - chemistry Botulinum Toxins, Type A - metabolism Cellular Biology Ceramide Circular dichroism Dichroism Domains Fluorescence Fluorescence spectroscopy Gangliosides Gangliosides - chemistry Gangliosides - pharmacology Life Sciences Molecular modelling Molecular structure Monomolecular films Mutation Nerve endings Neurotoxins Oligosaccharides Peptides PNAS Plus Point mutation Potentiation Protein Conformation, alpha-Helical Protein Domains Rats Surface plasmon resonance Synaptotagmin Synaptotagmin I - chemistry Synaptotagmin I - genetics Synaptotagmin I - metabolism Synaptotagmin II - chemistry Synaptotagmin II - genetics Synaptotagmin II - metabolism Toxins Transmembrane domains Tryptophan |
| Title | Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B |
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