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Nat Commun. 2017 Nov 21;8(1):1637. doi: 10.1038/s41467-017-01534-z.

Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC.

Author information

1
Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
2
Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.
3
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91, Stockholm, Sweden.
4
Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
5
Department of Bacteriology, University of Wisconsin, Madison, WI, 53706, USA.
6
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91, Stockholm, Sweden. Stenmark@dbb.su.se.
7
Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. min.dong@childrens.harvard.edu.
8
Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. min.dong@childrens.harvard.edu.

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, 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.

PMID:
29158482
PMCID:
PMC5696347
DOI:
10.1038/s41467-017-01534-z
[Indexed for MEDLINE]
Free PMC Article

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