The recent discovery of intramolecular isopeptide bonds formed between lysine and asparagine residues in certain bacterial cell-surface proteins represents a new component in nature's toolbox for stabilising proteins. Although isopeptide bonds are well known as intermolecular crosslinks in processes such as ubiquitylation, these intramolecular isopeptide bonds form autocatalytically during protein folding, as the reacting groups are brought together in a hydrophobic environment. First identified in the Ig-like pilin subunits of Gram-positive bacterial pili, these internal crosslinks provide stabilisation against chemical, thermal and mechanical stress and provide new opportunities for applications in biotechnology. The crucial role of structural biology and mass spectrometry in their discovery and characterisation raises the likelihood that further novel post-translational modifications resulting from intramolecular reactions in proteins await discovery.
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