Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity.

Publication Type:

Journal Article

Source:

PLoS Pathog, Volume 9, Issue 10, p.e1003690 (2013)

Keywords:

Animals, Botulinum Toxins, Botulism, Clostridium botulinum, Female, Mice, Multiprotein Complexes, Protein Structure, Quaternary, Structure-Activity Relationship

Abstract:

<p>Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the structure of a ∼760 kDa 14-subunit large PTC of serotype A (L-PTC/A) and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry. </p>

PDB: 
4LO1, 4LO7, 7LO8
Detector: 
Q315
PILATUS
Beamline: 
24-ID-C
24-ID-E