isopeptidebinding

Isopeptide binding refers to the covalent linkage formed between amino acid residues via a side-chain–mediated amide bond, rather than the standard peptide bond along the protein backbone. An isopeptide bond is typically formed between the side-chain amino group of lysine and the carboxyl group of another residue, or between side-chain carboxyl groups of acidic residues (aspartate or glutamate) and amino groups. The most well-known example is the γ-glutamyl-ε-lysine isopeptide bond, which can arise in cross-linking reactions.

In biology, isopeptide bonds serve two broad roles. First, they enable cross-linking and stabilization of proteins and extracellular matrices; for example, transglutaminase enzymes catalyze the formation of ε-(γ-glutamyl)lysine cross-links that strengthen tissues such as skin and collagen-rich matrices, and Factor XIIIa creates such cross-links during blood coagulation. Second, isopeptide bonds are central to post-translational modification systems, most notably ubiquitination and SUMOylation, where the C-terminus of ubiquitin or other modifiers is joined to lysine residues on substrate proteins through isopeptide bonds. These modifications regulate protein stability, localization, and activity.

Formation and removal of isopeptide bonds are mediated by specialized enzymes. Transglutaminases catalyze bond formation; deubiquitinases and SUMO proteases (isopeptidases) cleave isopeptide bonds, reversing modifications or removing modifiers. Isopeptide binding can also influence structural properties by creating durable cross-links that affect protein dynamics.

In analyses, isopeptide linkages are distinguished from backbone peptide bonds in proteomics and structural studies, often requiring specific detection methods due to their covalent nature and biological significance.