Synthetic Biology: A New Tool for the Trade

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 pairsisopeptag-N/pilin-N, isopeptag/pilin-C, and SpyTag/SpyCatcherthat 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.