Structural characterisation of the catalytic domain of botulinum neurotoxin X - high activity and unique substrate specificity
Masuyer, Geoffrey ; Zhang, Sicai ; Barkho, Sulyman ; Shen, Yi ; Henriksson, Linda ; Košenina, Sara ; Dong, Min and Stenmark, Pål LU
(2018)
In Scientific Reports
8(1).
- Abstract
Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6. Here we report the 1.35 Å X-ray crystal structure of the light chain of BoNT/X (LC/X). LC/X shares the core fold common to all other BoNTs, demonstrating that LC/X is a bona... (More)
Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6. Here we report the 1.35 Å X-ray crystal structure of the light chain of BoNT/X (LC/X). LC/X shares the core fold common to all other BoNTs, demonstrating that LC/X is a bona fide member of BoNT-LCs. We found that access to the catalytic pocket of LC/X is more restricted, and the regions lining the catalytic pocket are not conserved compared to other BoNTs. Kinetic studies revealed that LC/X cleaves VAMP1 with a ten times higher efficiency than BoNT/B and the tetanus neurotoxin. The structural information provides a molecular basis to understand the convergence/divergence between BoNT/X and other BoNTs, to develop effective LC inhibitors, and to engineer new scientific tools and therapeutic toxins targeting distinct SNARE proteins in cells.
(Less)
- author
- Masuyer, Geoffrey
; Zhang, Sicai
; Barkho, Sulyman
; Shen, Yi
; Henriksson, Linda
; Košenina, Sara
; Dong, Min
and Stenmark, Pål
LU
- publishing date
- 2018-03-14
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 8
- issue
- 1
- article number
- 4518
- pages
- 10 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85044219531
- pmid:29540745
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-018-22842-4
- language
- English
- LU publication?
- no
- id
- 3b91640e-b09c-4cd5-aae4-fcb9d2fc15a7
- date added to LUP
- 2019-04-30 07:48:40
- date last changed
- 2024-04-16 03:24:42
@article{3b91640e-b09c-4cd5-aae4-fcb9d2fc15a7,
abstract = {{<p>Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6. Here we report the 1.35 Å X-ray crystal structure of the light chain of BoNT/X (LC/X). LC/X shares the core fold common to all other BoNTs, demonstrating that LC/X is a bona fide member of BoNT-LCs. We found that access to the catalytic pocket of LC/X is more restricted, and the regions lining the catalytic pocket are not conserved compared to other BoNTs. Kinetic studies revealed that LC/X cleaves VAMP1 with a ten times higher efficiency than BoNT/B and the tetanus neurotoxin. The structural information provides a molecular basis to understand the convergence/divergence between BoNT/X and other BoNTs, to develop effective LC inhibitors, and to engineer new scientific tools and therapeutic toxins targeting distinct SNARE proteins in cells.</p>}},
author = {{Masuyer, Geoffrey and Zhang, Sicai and Barkho, Sulyman and Shen, Yi and Henriksson, Linda and Košenina, Sara and Dong, Min and Stenmark, Pål}},
issn = {{2045-2322}},
language = {{eng}},
month = {{03}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{Structural characterisation of the catalytic domain of botulinum neurotoxin X - high activity and unique substrate specificity}},
url = {{http://dx.doi.org/10.1038/s41598-018-22842-4}},
doi = {{10.1038/s41598-018-22842-4}},
volume = {{8}},
year = {{2018}},
}