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...

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Autores principales:	Guorui Yao, Kwok-ho Lam, Jasmin Weisemann, Lisheng Peng, Nadja Krez, Kay Perry, Charles B. Shoemaker, Min Dong, Andreas Rummel, Rongsheng Jin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/28d488b3904246b2b17c6304fa26a9f6
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spelling	oai:doaj.org-article:28d488b3904246b2b17c6304fa26a9f62021-12-02T15:05:53ZA camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding10.1038/s41598-017-07457-52045-2322https://doaj.org/article/28d488b3904246b2b17c6304fa26a9f62017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07457-5https://doaj.org/toc/2045-2322Abstract 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.Guorui YaoKwok-ho LamJasmin WeisemannLisheng PengNadja KrezKay PerryCharles B. ShoemakerMin DongAndreas RummelRongsheng JinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guorui Yao Kwok-ho Lam Jasmin Weisemann Lisheng Peng Nadja Krez Kay Perry Charles B. Shoemaker Min Dong Andreas Rummel Rongsheng Jin A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
description	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 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.
format	article
author	Guorui Yao Kwok-ho Lam Jasmin Weisemann Lisheng Peng Nadja Krez Kay Perry Charles B. Shoemaker Min Dong Andreas Rummel Rongsheng Jin
author_facet	Guorui Yao Kwok-ho Lam Jasmin Weisemann Lisheng Peng Nadja Krez Kay Perry Charles B. Shoemaker Min Dong Andreas Rummel Rongsheng Jin
author_sort	Guorui Yao
title	A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
title_short	A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
title_full	A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
title_fullStr	A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
title_full_unstemmed	A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding
title_sort	camelid single-domain antibody neutralizes botulinum neurotoxin a by blocking host receptor binding
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/28d488b3904246b2b17c6304fa26a9f6
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A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding

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