Portal de Periódicos da CAPES

Structure of a Bimodular Botulinum Neurotoxin Complex Provides Insights into Its Oral Toxicity

2013; Public Library of Science; Volume: 9; Issue: 10 Linguagem: Inglês

10.1371/journal.ppat.1003690

1553-7374

Kwangkook Lee, Shenyan Gu, Lei Jin, Thi Tuc Nghi Le, Luisa W. Cheng, Jasmin Weisemann, Anna Magdalena Kruel, Guorui Yao, Kay Perry, Andreas Rummel, Rongsheng Jin,

Plant-based Medicinal Research

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.