期刊
SCIENCE
卷 344, 期 6190, 页码 1405-1410出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1253823
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) [R01AI091823]
- NIH [8P51OD011103-51, 1R56AI097834-01, 1R01NS080833-01]
- Swiss Federal Office for Civil Protection BABS [353003325]
- National Institute of General Medical Sciences [P41 GM103403]
- U.S. DOE [DE-AC02-06CH11357]
How botulinum neurotoxins (BoNTs) cross the host intestinal epithelial barrier in foodborne botulism is poorly understood. Here, we present the crystal structure of a clostridial hemagglutinin (HA) complex of serotype BoNT/A bound to the cell adhesion protein E-cadherin at 2.4 angstroms. The HA complex recognizes E-cadherin with high specificity involving extensive intermolecular interactions and also binds to carbohydrates on the cell surface. Binding of the HA complex sequesters E-cadherin in the monomeric state, compromising the E-cadherin-mediated intercellular barrier and facilitating paracellular absorption of BoNT/A. We reconstituted the complete 14-subunit BoNT/A complex using recombinantly produced components and demonstrated that abolishing either E-cadherin- or carbohydrate-binding of the HA complex drastically reduces oral toxicity of BoNT/A complex in vivo. Together, these studies establish the molecular mechanism of how HAs contribute to the oral toxicity of BoNT/A.
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