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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 (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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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
pages
1 - 10
publisher
Nature Publishing Group
external identifiers
  • scopus:85026563366
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
2019-10-08 03:50:04
@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>},
  articleno    = {14130},
  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},
  keyword      = {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},
  volume       = {8},
  year         = {2017},
}