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PreprintCited by 9Botulinum Toxin and Related Neurological DisordersNeuroscience and Neuropharmacology ResearchEnzyme Structure and Function

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Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams

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Schenck, Stephan, Laeremans, Toon, Steyaert, Jan, Brunner, Janine D.·2024·Nature Communications
DOI 10.1101/2024.05.07.592960PMC PMC12053756

Preprint — published as 10.1038/s41467-025-59545-0

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Abstract

The synaptic vesicle glycoprotein 2A (SV2A) is a bona fide synaptic vesicle (SV) constituent of controversial function with homology to the major facilitator superfamily (MFS) and essential in vertebrate neurotransmission. Despite its high medical relevance as the target of the anti-epileptic drug Levetiracetam (LEV) and as receptor for clostridial neurotoxins (CNTs), among them several botulinum neurotoxin (BoNT) serotypes and potentially tetanus neurotoxin (TeNT), we lack detailed insight about these molecular interactions. We purified native SV2A from brain and subjected it to a structural analysis to advance our understanding of drug-binding to this enigmatic protein and explore structurally uncharacterized toxin-SV2A interfaces. Our analysis uncovered that TeNT binds SV2 proteins strikingly different from BoNT/A and delivers visual evidence for the dual receptor hypothesis through structurally resolved, co-purified gangliosides in the complex. The structures provide compelling support for SV2A as the protein receptor for TeNT in central neurons, recapitulate the geometry of CNT binding to dipartite SV2-ganglioside receptors on neuronal surfaces in a membrane-like constellation and have implications for toxin-engineering through a previously unknown SV2A-toxin interface. Further, a LEV-bound structure of SV2A reveals the drug-interacting residues and delineates a putative substrate pocket in SV2A. Our work provides an explanation for the SV2-isoform-specificity of LEV and its derivatives and paves the way for improved design of anti-convulsant drugs in epilepsy treatment.

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Metadata

Authors
Schenck, S., Laeremans, T., Steyaert, J., & Brunner, J. D.
Affiliations
Vrije Universiteit Brussel (BE)
Corresponding author
Brunner, Janine D.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-05-07
Volume
16
Issue
1
Pages
4172-4172
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.05.07.592960
PMC
PMC12053756
OpenAlex
W4410088632
Cited by
9
References
1
Citations by year
2026: 5 · 2025: 4
FWCI
5.48
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion, cc-by-nc-nd)
Funders
Vlaams Instituut voor Biotechnologie
Topics
  • Health Sciences › Medicine › Clinical Neurology › Botulinum Toxin and Related Neurological Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
SV2A, tetanus neurotoxin, clostridial neurotoxins, levetiracetam, racetams, antiepileptic drugs, major facilitator superfamily, ganglioside receptors, botulinum neurotoxin A, drug binding sites
MeSH terms
Levetiracetam, Animals, Anticonvulsants, Binding Sites, Brain, Humans, Membrane Glycoproteins, Metalloendopeptidases, Models, Molecular, Nerve Tissue Proteins, Protein Binding, Tetanus Toxin, Cryoelectron Microscopy, Rats

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