Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC
Zhang, Sicai ; Berntsson, Ronnie P-A ; Tepp, William H ; Tao, Liang ; Johnson, Eric A ; Stenmark, Pål LU
and Dong, Min
(2017)
In Nature Communications
8(1).
p.1637-1637
- Abstract
Botulinum neurotoxins (BoNTs), the most potent toxins known, are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here, we report that BoNT/DC, a presumed mosaic toxin between BoNT/D and BoNT/C1, binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid, but not other moieties in gangliosides. Using liposome flotation assays, we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes,... (More)
Botulinum neurotoxins (BoNTs), the most potent toxins known, are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here, we report that BoNT/DC, a presumed mosaic toxin between BoNT/D and BoNT/C1, binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid, but not other moieties in gangliosides. Using liposome flotation assays, we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes, and the co-occurring sialic acid binding and loop-membrane interactions mediate the recognition of gangliosides in membranes by BoNT/DC. These findings reveal a unique mechanism for cell membrane recognition and demonstrate that BoNT/DC can use a broad range of sialic acid-containing moieties as co-receptors.
(Less)
- author
- Zhang, Sicai
; Berntsson, Ronnie P-A
; Tepp, William H
; Tao, Liang
; Johnson, Eric A
; Stenmark, Pål
LU
and Dong, Min
- publishing date
- 2017-11-21
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Binding Sites, Botulinum Toxins/chemistry, Botulism/metabolism, Cell Membrane/chemistry, Crystallography, X-Ray, Female, Gangliosides/chemistry, Humans, Male, Mice, N-Acetylneuraminic Acid/chemistry
- in
- Nature Communications
- volume
- 8
- issue
- 1
- pages
- 1637 - 1637
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:29158482
- scopus:85034639606
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-017-01534-z
- language
- English
- LU publication?
- no
- id
- 18879a41-8e14-4265-bec2-0ed6cdc95d9a
- date added to LUP
- 2019-04-30 07:52:21
- date last changed
- 2024-02-14 22:52:08
@article{18879a41-8e14-4265-bec2-0ed6cdc95d9a,
abstract = {{<p>Botulinum neurotoxins (BoNTs), the most potent toxins known, are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here, we report that BoNT/DC, a presumed mosaic toxin between BoNT/D and BoNT/C1, binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid, but not other moieties in gangliosides. Using liposome flotation assays, we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes, and the co-occurring sialic acid binding and loop-membrane interactions mediate the recognition of gangliosides in membranes by BoNT/DC. These findings reveal a unique mechanism for cell membrane recognition and demonstrate that BoNT/DC can use a broad range of sialic acid-containing moieties as co-receptors.</p>}},
author = {{Zhang, Sicai and Berntsson, Ronnie P-A and Tepp, William H and Tao, Liang and Johnson, Eric A and Stenmark, Pål and Dong, Min}},
issn = {{2041-1723}},
keywords = {{Animals; Binding Sites; Botulinum Toxins/chemistry; Botulism/metabolism; Cell Membrane/chemistry; Crystallography, X-Ray; Female; Gangliosides/chemistry; Humans; Male; Mice; N-Acetylneuraminic Acid/chemistry}},
language = {{eng}},
month = {{11}},
number = {{1}},
pages = {{1637--1637}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC}},
url = {{http://dx.doi.org/10.1038/s41467-017-01534-z}},
doi = {{10.1038/s41467-017-01534-z}},
volume = {{8}},
year = {{2017}},
}