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Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding

Gustafsson, Robert ; Zhang, Sicai ; Masuyer, Geoffrey ; Dong, Min and Stenmark, Pål LU orcid (2018) In Toxins 10(4).
Abstract

Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in... (More)

Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Binding Sites, Botulinum Toxins, Type A/chemistry, Crystallography, Membrane Glycoproteins/chemistry, Nerve Tissue Proteins/chemistry, Protein Binding, Protein Conformation
in
Toxins
volume
10
issue
4
pages
16 pages
publisher
MDPI AG
external identifiers
  • scopus:85045624381
  • pmid:29649119
ISSN
2072-6651
DOI
10.3390/toxins10040153
language
English
LU publication?
no
id
e0766179-df45-43a1-b6bc-8c6fc7b2ef0d
date added to LUP
2019-04-30 07:47:10
date last changed
2025-01-09 06:55:29
@article{e0766179-df45-43a1-b6bc-8c6fc7b2ef0d,
  abstract     = {{<p>Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic.</p>}},
  author       = {{Gustafsson, Robert and Zhang, Sicai and Masuyer, Geoffrey and Dong, Min and Stenmark, Pål}},
  issn         = {{2072-6651}},
  keywords     = {{Binding Sites; Botulinum Toxins, Type A/chemistry; Crystallography; Membrane Glycoproteins/chemistry; Nerve Tissue Proteins/chemistry; Protein Binding; Protein Conformation}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  publisher    = {{MDPI AG}},
  series       = {{Toxins}},
  title        = {{Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding}},
  url          = {{http://dx.doi.org/10.3390/toxins10040153}},
  doi          = {{10.3390/toxins10040153}},
  volume       = {{10}},
  year         = {{2018}},
}