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

نویسندگان

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

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.

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عنوان ژورنال:

دوره 9  شماره 

صفحات  -

تاریخ انتشار 2013