title: Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, California, United States of America.
authors.forename: Kwangkook
authors.initials: K
authors.lastname: Lee
authors.forename: Shenyan
authors.initials: S
authors.lastname: Gu
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Thi Tuc Nghi
authors.initials: TT
authors.lastname: Le
authors.forename: Luisa W
authors.initials: LW
authors.lastname: Cheng
authors.forename: Jasmin
authors.initials: J
authors.lastname: Strotmeier
authors.forename: Anna Magdalena
authors.initials: AM
authors.lastname: Kruel
authors.forename: Guorui
authors.initials: G
authors.lastname: Yao
authors.forename: Kay
authors.initials: K
authors.lastname: Perry
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
authors.forename: Rongsheng
authors.initials: R
authors.lastname: Jin
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D001906:Botulism; D003014:Clostridium botulinum / Q000235:genetics / Q000378:metabolism; D005260:Female; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
chemical_list: D046912:Multiprotein Complexes; D001905:Botulinum Toxins