Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/12/9/603 |
| _version_ | 1797553354865377280 |
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| author | Jonathan R. Davies Geoffrey Masuyer Pål Stenmark |
| author_facet | Jonathan R. Davies Geoffrey Masuyer Pål Stenmark |
| author_sort | Jonathan R. Davies |
| collection | DOAJ |
| description | 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 <i>Clostridium botulinum</i> 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. |
| first_indexed | 2024-03-10T16:14:10Z |
| format | Article |
| id | doaj.art-04c31c537e1341debe65b341d2fd1bdd |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T16:14:10Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-04c31c537e1341debe65b341d2fd1bdd2023-11-20T14:07:53ZengMDPI AGToxins2072-66512020-09-0112960310.3390/toxins12090603Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its ReceptorsJonathan R. Davies0Geoffrey Masuyer1Pål Stenmark2Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, SwedenDepartment of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, SwedenDepartment of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, SwedenBotulinum 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 <i>Clostridium botulinum</i> 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.https://www.mdpi.com/2072-6651/12/9/603<i>Clostridium botulinum</i>botulismbotulinum neurotoxinBoNT/Bsynaptotagminganglioside |
| spellingShingle | Jonathan R. Davies Geoffrey Masuyer Pål Stenmark Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors Toxins <i>Clostridium botulinum</i> botulism botulinum neurotoxin BoNT/B synaptotagmin ganglioside |
| title | Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors |
| title_full | Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors |
| title_fullStr | Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors |
| title_full_unstemmed | Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors |
| title_short | Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors |
| title_sort | structural and biochemical characterization of botulinum neurotoxin subtype b2 binding to its receptors |
| topic | <i>Clostridium botulinum</i> botulism botulinum neurotoxin BoNT/B synaptotagmin ganglioside |
| url | https://www.mdpi.com/2072-6651/12/9/603 |
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