Identification and characterization of a novel botulinum neurotoxin
(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.
(Less)
- author
- Zhang, Sicai ; Masuyer, Geoffrey ; Zhang, Jie ; Shen, Yi ; Lundin, Daniel ; Henriksson, Linda ; Miyashita, Shin-Ichiro ; Martínez-Carranza, Markel ; Dong, Min and Stenmark, Pål LU
- publishing date
- 2017-08-03
- 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
- 2024-09-18 17:49:22
@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}}, }