Structural Hot Spots Determine Functional Diversity of the Candida glabrata Epithelial Adhesin Family

For host colonization, the human fungal pathogen Candida glabrata is known to utilize a large family of highly related surface-exposed cell wall proteins, the lectin-like epithelial adhesins (Epas). To reveal the structure-function relationships within the entire Epa family, we have performed a large scale functional analysis of the adhesion (A) domains of 17 Epa paralogs in combination with three-dimensional structural studies of selected members with cognate ligands. Our study shows that most EpaA domains exert lectin-like functions and together recognize a wide variety of glycans with terminal galactosides for conferring epithelial cell adhesion. We further identify several conserved and variable structural features within the diverse Epa ligand binding pockets, which affect affinity and specificity. These features rationalize why mere phylogenetic relationships within the Epa family are weak indicators for functional classification and explain how Epa-like adhesins have evolved in C. glabrata and related fungal species. Background: The pathogenic yeast Candida glabrata harbors more than 20 epithelial adhesins (Epas). Results: Epas are lectins with binding pockets that contain conserved and variable structural features determining ligand binding affinity and specificity. Conclusion: The functionally diverse Epa family evolved in C. glabrata for efficient host infection. Significance: Epa-mediated host-ligand binding is a therapeutic target to combat C. glabrata infections.