Superglue from bacteria: unbreakable bridges for protein nanotechnology

• Strong links between proteins are important in many areas of biotechnology.
• SpyTag is a peptide forming a spontaneous isopeptide bond to the protein SpyCatcher.
• Each component can be fused genetically and reacts under diverse conditions.
• Uses include resisting force, targeting nanoparticles, and enhancing enzyme stability.

Biotechnology is often limited by weak interactions. We suggest that an ideal interaction between proteins would be covalent, specific, require addition of only a peptide tag to the protein of interest, and form under a wide range of conditions. Here we summarize peptide tags that are able to form spontaneous amide bonds, based on harnessing reactions of adhesion proteins from the bacterium Streptococcus pyogenes. These include the irreversible peptide–protein interaction of SpyTag with SpyCatcher, as well as irreversible peptide–peptide interactions via SpyLigase. We describe existing applications, including polymerization to enhance cancer cell capture, assembly of living biomaterial, access to diverse protein shapes, and improved enzyme resilience. We also indicate future opportunities for resisting biological force and extending the scope of protein nanotechnology.