Molecular infection: the invasion complex between internalin ofListeria monocytogenesand human E-cadherin

Abstract

The bacterium Listeria monocytogenes is a food-borne human pathogen. It infects humans by inducing its own uptake into epithelial cells of the intestine although these are normally non-phagocytic. Recognition, adhesion and invasion of intestinal epithelial cells is mediated by a single listerial surface protein, Internalin (InlA), through specific interaction with the host cell receptor E-cadherin. We have solved the crystal structure of the functional domain of InlA both uncomplexed and in complex with the extracellular, N-terminal domain of human E-cadherin (hEC1). In the complex between InlA and hEC1, the superhelically twisted leucine rich repeat (LRR) domain of InlA surrounds and specifically recognizes hEC1. Site-directed mutagenesis, analytical ultracentrifugation and Biacore experiments indicate that binding affinity is remarkably weak yet highly specific: Pro16 of hEC1, a major determinant for human susceptibility to L. Monocytogenes infection is essential for intermolecular recognition. Ca was found to stabilize the complex. Structurally, this is corroborated by a Ca-binding site bridging the two proteins. This indicates that complex formation in the intestine is favoured by high Ca-concentrations whereas low, intracellular concentrations induce dissociation, freeing the bacterium and allowing it to move through the eukaryotic cell. Our studies thus provide detailed insights into the molecular deception L. monocytogenes employs to exploit the host E-cadherin signal cascade through the expression of a single surface protein.