CEACAMs are cell surface proteins with immunoglobulin (Ig) folds that regulate cell communication, cell signalling and immunity. Several human bacterial pathogens express adhesins that bind CEACAMs for enhanced adhesion to epithelial surfaces. Here, we report an adhesin-CEACAM interaction with unique properties. We found β protein from the human neonatal Gram-positive bacterial pathogen Streptococcus agalactiae contains a domain with Ig superfamily (IgSF) fold that promotes binding to the

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... inal domain of human CEACAM1 and CEACAM5. A crystal structure of the complex showed that the IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. β-IgI3 homologs in other human Gram-positive bacteria including pathogens, are predicted to maintain the IgI3 fold. Further, we show that one homolog interacts with CEACAM1, suggestive that the IgI3 fold could provide a broad mechanism to target CEACAMs.