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Title: A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding

Abstract

Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on H CA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions withmore » its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.« less

Authors:
; ; ; ; ; ; ORCiD logo; ; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIAIDOTHER
OSTI Identifier:
1379429
Resource Type:
Journal Article
Resource Relation:
Journal Name: Scientific Reports; Journal Volume: 7; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Yao, Guorui, Lam, Kwok-ho, Weisemann, Jasmin, Peng, Lisheng, Krez, Nadja, Perry, Kay, Shoemaker, Charles B., Dong, Min, Rummel, Andreas, and Jin, Rongsheng. A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding. United States: N. p., 2017. Web. doi:10.1038/s41598-017-07457-5.
Yao, Guorui, Lam, Kwok-ho, Weisemann, Jasmin, Peng, Lisheng, Krez, Nadja, Perry, Kay, Shoemaker, Charles B., Dong, Min, Rummel, Andreas, & Jin, Rongsheng. A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding. United States. doi:10.1038/s41598-017-07457-5.
Yao, Guorui, Lam, Kwok-ho, Weisemann, Jasmin, Peng, Lisheng, Krez, Nadja, Perry, Kay, Shoemaker, Charles B., Dong, Min, Rummel, Andreas, and Jin, Rongsheng. Mon . "A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding". United States. doi:10.1038/s41598-017-07457-5.
@article{osti_1379429,
title = {A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding},
author = {Yao, Guorui and Lam, Kwok-ho and Weisemann, Jasmin and Peng, Lisheng and Krez, Nadja and Perry, Kay and Shoemaker, Charles B. and Dong, Min and Rummel, Andreas and Jin, Rongsheng},
abstractNote = {Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on HCA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions with its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.},
doi = {10.1038/s41598-017-07457-5},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {Mon Aug 07 00:00:00 EDT 2017},
month = {Mon Aug 07 00:00:00 EDT 2017}
}