Cell surface β-lactamase recruitment: A facile selection to identify protein-protein interactions

Protein-protein interactions (PPIs) are central to many cellular processes, and the identification of novel PPIs is a critical step in the discovery of protein therapeutics. Simple methods to identify naturally existing or laboratory evolved PPIs are therefore valuable research tools. We have developed a facile selection that links PPI-dependent β-lactamase recruitment on the surface of Escherichia coli with resistance to ampicillin. Bacteria displaying a protein that forms a complex with a specific protein-β-lactamase fusion are protected from ampicillin-dependent cell death. In contrast, bacteria that do not recruit β-lactamase to the cell surface are killed by ampicillin. Given its simplicity and tunability, we anticipate this selection will be a valuable addition to the palette of methods for illuminating and interrogating PPIs.