Identification and characterization of a novel botulinum neurotoxin

Sicai Zhang, Geoffrey Masuyer, Jie Zhang, Yi Shen, Daniel Lundin, Linda Henriksson, Shin-Ichiro Miyashita, Markel Martínez-Carranza, Min Dong () and Pål Stenmark ()
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Sicai Zhang: Boston Children’s Hospital, Harvard Medical School
Geoffrey Masuyer: Stockholm University
Jie Zhang: Boston Children’s Hospital, Harvard Medical School
Yi Shen: Boston Children’s Hospital, Harvard Medical School
Daniel Lundin: Stockholm University
Linda Henriksson: Stockholm University
Shin-Ichiro Miyashita: Boston Children’s Hospital, Harvard Medical School
Markel Martínez-Carranza: Stockholm University
Min Dong: Boston Children’s Hospital, Harvard Medical School
Pål Stenmark: Stockholm University

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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 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.

Date: 2017
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DOI: 10.1038/ncomms14130

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