Structural analysis of botulinum neurotoxins type B and E by Cryo-EM

Sara Košenina; Markel Martínez-Carranza; Jonathan R. Davies; Geoffrey Masuyer; Pål Stenmark

doi:10.3390/toxins14010014

Structural analysis of botulinum neurotoxins type B and E by Cryo-EM

Sara Košenina
, Markel Martínez-Carranza
, Jonathan R. Davies
, Geoffrey Masuyer
, Pål Stenmark

Stockholm University
Lund University

Research output: Contribution to journal › Article › peer-review

15 Citations (SciVal)

Abstract

Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.

Original language	English
Article number	14
Journal	Toxins
Volume	14
Issue number	1
DOIs	https://doi.org/10.3390/toxins14010014
Publication status	Published - 23 Dec 2021

Bibliographical note

Funding Information:
Funding: This work was supported by grants from the Novo Nordisk Foundation (NNF20OC0064789), the Swedish Research Council (2018-03406) and the Swedish Cancer Society (20 1287 PjF) to P.S. G.M. was supported by a Research Fellowship from Applied Molecular Transport Inc. (San Francisco, CA, USA) at the University of Bath (UK). The data was collected at the Cryo-EM Swedish National Facility funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Umeå University.

Funding

Funding: This work was supported by grants from the Novo Nordisk Foundation (NNF20OC0064789), the Swedish Research Council (2018-03406) and the Swedish Cancer Society (20 1287 PjF) to P.S. G.M. was supported by a Research Fellowship from Applied Molecular Transport Inc. (San Francisco, CA, USA) at the University of Bath (UK). The data was collected at the Cryo-EM Swedish National Facility funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Umeå University. This work was supported by grants from the Novo Nordisk Foundation (NNF20OC0064789), the Swedish Research Council (2018-03406) and the Swedish Cancer Society (20 1287 PjF) to P.S. G.M. was supported by a Research Fellowship from Applied Molecular Transport Inc. (San Francisco, CA, USA) at the University of Bath (UK). The data was collected at the Cryo-EM Swedish National Facility funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Ume? University.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

BoNT/B
BoNT/E
Botulinum neurotoxin
Botulism
Clostridium botulinum
Cryo-EM

ASJC Scopus subject areas

Toxicology
Health, Toxicology and Mutagenesis

Access to Document

10.3390/toxins14010014Licence: CC BY

Cite this

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title = "Structural analysis of botulinum neurotoxins type B and E by Cryo-EM",

abstract = "Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 {\AA} for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.",

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note = "Funding Information: Funding: This work was supported by grants from the Novo Nordisk Foundation (NNF20OC0064789), the Swedish Research Council (2018-03406) and the Swedish Cancer Society (20 1287 PjF) to P.S. G.M. was supported by a Research Fellowship from Applied Molecular Transport Inc. (San Francisco, CA, USA) at the University of Bath (UK). The data was collected at the Cryo-EM Swedish National Facility funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Ume{\aa} University. ",

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N2 - Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.

AB - Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.

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KW - Botulism

KW - Clostridium botulinum

KW - Cryo-EM

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Structural analysis of botulinum neurotoxins type B and E by Cryo-EM

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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