Mechanism of Ganglioside Receptor Recognition by Botulinum Neurotoxin Serotype E

Masuyer, Geoffrey; Davies, Jonathan; Stenmark, Pål

doi:10.3390/ijms22158315

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…This finding is also consistent with the structure of H C E–ganglioside complex that was published during the preparation of this manuscript (Fig. 1d ) 48 . Furthermore, we previously reported that mutating H C E-W1224 was sufficient to abolish its ganglioside binding 26 , 28 .…”

Section: Resultssupporting

confidence: 92%

“…We found that the structure of the G6-bound H C E is virtually identical to that in complex with GD1a (root mean square deviation, r.m.s.d. ~0.38 Å over 359 aligned Cα pairs) 48 . Therefore, we hypothesized that G6 could be used as a ganglioside surrogate to facilitate SV2A binding to H C E when G6 and SV2A are properly connected with a flexible peptide linker because such a fusion protein would allow synergistic binding of G6 and SV2A to H C E in a way resembling the dual receptor binding.…”

Section: Resultsmentioning

confidence: 99%

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Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

et al. 2023

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Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (HCE) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between HCE and SV2 provide the crucial location and specificity information for HCE to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, HCE exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

et al. 2023

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“…Serotypes A, B and E are the main BoNT associated with human botulism [5]. These neurotoxins specifically target presynaptic motoneurons via a dual-receptor binding mechanism, which involves membrane-anchored gangliosides [6][7][8] and a protein receptor [9]. BoNT/A, /D, /E and /F recognise the synaptic vesicle glycoprotein 2 (SV2), whereas BoNT/B, /G and /DC utilise one of the synaptotagmin isoforms [10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Botulinum Neurotoxins Type B and E by Cryo-EM

Košenina

Martínez‐Carranza

Davies

et al. 2021

Toxins

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Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.

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“…Remarkably, the stretch SXWY is the conserved ganglioside binding site (GBS) and has been identified first in tetanus neurotoxin as well as in BoNT/A, B, E, F, and G [39][40][41]. Interestingly, in E1 GBS, key interacting residues that are unique to BoNT/E have been identified along with a significant rearrangement of loop 1228-1237 upon carbohydrate binding [42]. In BoNT/B, the LBL is located between the GBS and the receptor binding site, and is significantly exposed to the solvent, in particular the sidechains of W 1248 and W 1249 [43].…”

Section: Flexibility Of the Lipid-binding And Ganglioside-binding Dom...mentioning

confidence: 99%

In silicoconformational features of botulinum toxins A1 and E1 according to the intraluminal acidification

Cottone

Chiodo

Maragliano

et al. 2022

Preprint

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Although the botulinum neurotoxins (BoNTs) are among the most toxic compounds found in nature, their molecular mechanism of action is far from being elucidated. A key event is the conformational transition due to the acidification of the interior of synaptic vesicles, and leading to the translocation of the BoNT catalytic domain into the neuronal cytosol. To investigate these conformational variations, homology modelling and atomistic simulations are combined to explore the internal dynamics of the subtypes BoNT/A1, the most-used in medical applications, and BoNT/E1, the most kinetically efficient. This first simulation study of di-chain BoNTs in closed and open states includes the effects of neutral and acidic pH. The conformational mobility is driven by domains displacements; the ganglioside binding site in the receptor binding domain, the translocation domain (HCNT) switch and the belt α helix visit multiple conformations depending on the primary sequence and on the pH. Fluctuations of the belt α helix are observed for closed conformations of the toxins and at acidic pH, and patches of more accessible residues appear in the same conditions in the core translocation domain HCNT. These findings suggest that during translocation, the larger mobility of belt could be transmitted to HCNT, leading to a favorable interaction of HCNT residues with the non-polar membrane environment.

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Mechanism of Ganglioside Receptor Recognition by Botulinum Neurotoxin Serotype E

Cited by 7 publications

References 45 publications

Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2

Structural Analysis of Botulinum Neurotoxins Type B and E by Cryo-EM

In silicoconformational features of botulinum toxins A1 and E1 according to the intraluminal acidification

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