A single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes.
Human E-cadherin promotes entry of the bacterial pathogen Listeria monocytogenes into mammalian cells by interacting with internalin (InlA), a bacterial surface protein. Here we show that mouse E-cadherin, although very similar to human E-cadherin (85% identity), is not a receptor for internalin. By a series of domain-swapping and mutagenesis experiments, we identify Pro16 of E-cadherin as a residue critical for specificity: a Pro-->Glu substitution in human E-cadherin totally abrogates interaction, whereas a Glu-->Pro substitution in mouse E-cadherin results in a complete gain of function. A correlation between cell permissivity and the nature of residue 16 in E-cadherins from several species is established. The location of this key specificity residue in a region of E-cadherin not involved in cell-cell adhesion and the stringency of the interaction demonstrated here have important consequences not only for the understanding of internalin function but also for the choice of the animal model to be used to study human listeriosis: mouse, albeit previously widely used, and rat appear as inappropriate animal models to study all aspects of human listeriosis, as opposed to guinea-pig, which now stands as a small animal of choice for future in vivo studies.
Lecuit
M
M
Unité des Interactions Bactéries-Cellules, Institut Pasteur, 75724 Paris Cedex 15, France.
Dramsi
S
S
Gottardi
C
C
Fedor-Chaiken
M
M
Gumbiner
B
B
Cossart
P
P
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004705:Endocytosis; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008089:Listeria monocytogenes / Q000254:growth & development* / Q000472:pathogenicity*; D008088:Listeriosis / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
D001426:Bacterial Proteins; D015820:Cadherins; D011993:Recombinant Fusion Proteins; C069761:internalin protein, Bacteria; D011392:Proline