Selective Ligand Recognition by a Diversity-Generating Retroelement Variable Protein

Open Access
Publisher Website
Google Scholar
Abstract
Diversity-generating retroelements (DGRs) recognize novel ligands through massive protein sequence variation, a property shared uniquely with the adaptive immune response. Little is known about how recognition is achieved by DGR variable proteins. Here, we present the structure of the Bordetella bacteriophage DGR variable protein major tropism determinant (Mtd) bound to the receptor pertactin, revealing remarkable adaptability in the static binding sites of Mtd. Despite large dissimilarities in ligand binding mode, principles underlying selective recognition were strikingly conserved between Mtd and immunoreceptors. Central to this was the differential amplification of binding strengths by avidity (i.e., multivalency), which not only relaxed the demand for optimal complementarity between Mtd and pertactin but also enhanced distinctions among binding events to provide selectivity. A quantitatively similar balance between complementarity and avidity was observed for Bordetella bacteriophage DGR as occurs in the immune system, suggesting that variable repertoires operate under a narrow set of conditions to recognize novel ligands. The immune system long has been considered unique in its capacity to recognize alien molecules. This anticipatory recognition depends on a repertoire of receptors—antibodies and T cell receptors—with binding sites capable of accommodating trillions of different amino acid sequence combinations. A similar capacity was discovered recently in diversity-generating retroelements (DGRs), which are encoded by prokaryotes and the bacteriophages that infect them. The receptor-binding protein Mtd of Bordetella bacteriophage is encoded by a DGR and accommodates trillions of sequences in its binding site. DGR-programmed variation of Mtd allows the phage to use alternative host receptors—an ability that is crucial for phage infection because the expression pattern of these host receptors changes according to the environmental status of the bacterium. We sought to understand how Mtd recognizes receptors by determining the structure of an Mtd variant bound to the host receptor pertactin. With this structural knowledge, we then compared the binding properties of different variants and their ability to support phage infection. Despite large differences in physical details between Mtd and immunoreceptors, general principles emerged through which variable repertoires achieve selective molecule recognition, providing a view of how the Mtd family can rapidly evolve novel specificities.