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Identification and characterization of a novel botulinum neurotoxin

Zhang, Sicai ; Masuyer, Geoffrey ; Zhang, Jie ; Shen, Yi ; Lundin, Daniel ; Henriksson, Linda ; Miyashita, Shin-Ichiro ; Martínez-Carranza, Markel ; Dong, Min and Stenmark, Pål LU orcid (2017) In Nature Communications 8. p.1-10
Abstract

Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a... (More)

Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile. Its discovery posts a challenge to develop effective countermeasures, provides a novel tool for studying intracellular membrane trafficking, and presents a new potential therapeutic toxin for modulating secretions in cells.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Amino Acid Motifs, Amino Acid Sequence, Animals, Botulinum Toxins/chemistry, Botulism/genetics, Clostridium botulinum/enzymology, Humans, Mice, Models, Molecular, Neurotoxins/chemistry, R-SNARE Proteins/chemistry, Sequence Alignment, Vesicle-Associated Membrane Protein 2/chemistry
in
Nature Communications
volume
8
article number
14130
pages
1 - 10
publisher
Nature Publishing Group
external identifiers
  • scopus:85026563366
  • pmid:28770820
ISSN
2041-1723
DOI
10.1038/ncomms14130
language
English
LU publication?
no
id
26cdc900-785c-486a-a0e2-352731ee7c6c
date added to LUP
2019-04-30 07:54:38
date last changed
2024-03-19 05:41:20
@article{26cdc900-785c-486a-a0e2-352731ee7c6c,
  abstract     = {{<p>Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile. Its discovery posts a challenge to develop effective countermeasures, provides a novel tool for studying intracellular membrane trafficking, and presents a new potential therapeutic toxin for modulating secretions in cells.</p>}},
  author       = {{Zhang, Sicai and Masuyer, Geoffrey and Zhang, Jie and Shen, Yi and Lundin, Daniel and Henriksson, Linda and Miyashita, Shin-Ichiro and Martínez-Carranza, Markel and Dong, Min and Stenmark, Pål}},
  issn         = {{2041-1723}},
  keywords     = {{Amino Acid Motifs; Amino Acid Sequence; Animals; Botulinum Toxins/chemistry; Botulism/genetics; Clostridium botulinum/enzymology; Humans; Mice; Models, Molecular; Neurotoxins/chemistry; R-SNARE Proteins/chemistry; Sequence Alignment; Vesicle-Associated Membrane Protein 2/chemistry}},
  language     = {{eng}},
  month        = {{08}},
  pages        = {{1--10}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Identification and characterization of a novel botulinum neurotoxin}},
  url          = {{http://dx.doi.org/10.1038/ncomms14130}},
  doi          = {{10.1038/ncomms14130}},
  volume       = {{8}},
  year         = {{2017}},
}