Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors
Davies, Jonathan R ; Masuyer, Geoffrey and Stenmark, Pål LU
(2020)
In Toxins
12(9).
- Abstract
Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the... (More)
Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT/B2 has a slightly higher affinity for GD1a than BoNT/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity.
(Less)
- author
- Davies, Jonathan R
; Masuyer, Geoffrey
and Stenmark, Pål
LU
- organization
- publishing date
- 2020-09-17
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Toxins
- volume
- 12
- issue
- 9
- article number
- 603
- publisher
- MDPI AG
- external identifiers
-
- scopus:85091210625
- pmid:32957706
- ISSN
- 2072-6651
- DOI
- 10.3390/toxins12090603
- language
- English
- LU publication?
- yes
- id
- fb5c9629-c4e7-41b9-80b2-2664cf513611
- date added to LUP
- 2020-09-25 08:28:37
- date last changed
- 2024-06-12 21:37:27
@article{fb5c9629-c4e7-41b9-80b2-2664cf513611,
abstract = {{<p>Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT/B2 has a slightly higher affinity for GD1a than BoNT/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity.</p>}},
author = {{Davies, Jonathan R and Masuyer, Geoffrey and Stenmark, Pål}},
issn = {{2072-6651}},
language = {{eng}},
month = {{09}},
number = {{9}},
publisher = {{MDPI AG}},
series = {{Toxins}},
title = {{Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors}},
url = {{http://dx.doi.org/10.3390/toxins12090603}},
doi = {{10.3390/toxins12090603}},
volume = {{12}},
year = {{2020}},
}