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

Sicai Zhang, Ronnie P.-A. Berntsson, William H. Tepp, Liang Tao, Eric A. Johnson, Pål Stenmark () and Min Dong ()
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Sicai Zhang: Boston Children’s Hospital, Harvard Medical School
Ronnie P.-A. Berntsson: Stockholm University
William H. Tepp: University of Wisconsin
Liang Tao: Boston Children’s Hospital, Harvard Medical School
Eric A. Johnson: University of Wisconsin
Pål Stenmark: Stockholm University
Min Dong: Boston Children’s Hospital, Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01534-z

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