Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex

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Science  20 Jun 2014:
Vol. 344, Issue 6190, pp. 1405-1410
DOI: 10.1126/science.1253823

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Breaking through the epithelial barrier

Botulinum neurotoxin (BoNT) poisons its host when it crosses the intestinal epithelial barrier. To help it cross this barrier, the toxin forms a large complex with three bacterial proteins called hemagglutinins (HAs). To find out what happens when this complex binds to a cell-adhesion protein called E-cadherin, Lee et al. crystallized the bound complex and protein. Toxin binding disrupted the way E-cadherin maintains the epithelial barrier. When the researchers prevented the toxin complex from binding to E-cadherin, mice were protected from the toxin's deadly effects.

Science, this issue p. 1405


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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