Protein folding modulates the adhesion strategy of Gram positive pathogens
Gram positive bacteria colonize mucosal tissues against large mechanical perturbations, such as coughing, which generate large shear forces that exceed the ability of non-covalent bonds to remain attached. To overcome these challenges, the pathogen Streptococcus pyogenes utilizes the protein Cpa, a pilus tip-end adhesin equipped with a Cys-Gln thioester bond. The reactivity of this bond towards host surface ligands enables covalent anchoring of the bacterium, allowing it to resist large mechanical shocks; however, colonization also requires cell migration and spreading over surfaces. The molecular mechanisms underlying these seemingly incompatible requirements remain unknown. Here, we demonstrate a magnetic tweezers force spectroscopy assay that resolves the dynamics of Cpa thioester bond under force. While folded at forces < 6 pN, Cpa thioester bond reacts reversibly with amine ligands, of common occurrence in inflammation sites; however, mechanical unfolding and exposure to forces higher than 35 pN blocks thioester reactivity entirely. We propose that this folding-coupled thioester reactivity switch allows the adhesin to hop and sample host surface ligands at low force (nomadic mobility phase), and yet gets covalently anchored in place while under mechanical stress (locked phase). We dub such bonds \"smart covalent bonds\", adding a novel class to the known repertoire of non-covalent adhesion strategies that include slip bonds, and catch bonds.