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

PLoS Pathogens

Guorui Yao¹  Shenyan Gu¹  Kwangkook Lee¹  Rongsheng Jin¹  Luisa W. Cheng²  Lei Jin³  Thi Tuc Nghi Le⁴  Jasmin Strotmeier⁴  Anna Magdalena Kruel⁴  Andreas Rummel⁴  Kay Perry⁵ 

[1] Department of Physiology and Biophysics, University of California, Irvine, California, United States of America;Foodborne Contaminants Research Unit, Western Regional Research Center, United States Department of Agriculture, Agricultural Research Service, Albany, California, United States of America;Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America;Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany;NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois, United States of America

关键词: Crystal structure;    Carbohydrates;    Botulinum toxin;    Gastrointestinal tract;    Toxins;    Electron microscopy;    Epithelial cells;    Intoxication;   

DOI  :  10.1371/journal.ppat.1003690

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY