Synthetic Biology: A New Tool for the Trade

Abstract Protein–protein interactions are fundamental to many biological processes. Yet, the weak and transient noncovalent bonds that characterize most protein–protein interactions found in nature impose limits on many bioengineering experiments. Here, a new class of genetically encodable peptide–protein pairs—isopeptag‐N/pilin‐N, isopeptag/pilin‐C, and SpyTag/SpyCatcher—that interact through autocatalytic intermolecular isopeptide bond formation is described. Reactions between peptide–protein pairs are specific, robust, orthogonal, and able to proceed under most biologically relevant conditions both in vitro and in vivo. As fusion constructs, they provide a handle on molecules of interest, both organic and inorganic, that can be grasped with an iron grip. Such stable interactions provide robust post‐translational control over biological processes and open new opportunities in synthetic biology for engineering programmable and self‐assembling protein nanoarchitectures.