Transglutaminases: crosslinking enzymes with pleiotropic functions

Key Points Transglutaminases (TGs) are Ca 2+ -dependent enzymes that post-translationally modify specific glutaminyl (Gln) side-chains in proteins by deamidation, transamidation or esterification. Notwithstanding active-centre similarities with the papain family of cysteine proteases, structural as well as kinetic features set TGs apart as a separate superfamily of enzymes that are widely distributed in nature. The human genome encodes eight TGs; at least one of these, TG2, is regulated by GTP/GDP and could function in signal transduction. Another protein, erythrocyte band 4.2, is a catalytically inactive member of the TG family and functions as a scaffolding protein. Independent of its catalytic activity, TG2 can also form tight multipartite complexes with fibronectin and integrins; a role that is important for cell spreading and migration and for extracellular matrix (wound healing) organization. TG-catalysed transamidation between glutamine and lysine residues can lead to the formation of covalent side-chain bridges between protein units; in this sense, TGs function as nature's catalysts to glue proteins together, and so to generate crosslinked supramolecular protein assemblies. Blood clotting, skin-barrier and bone formation are some well-known examples of the physiological role of TGs; crosslinking might also be important in the maturation of pathological insoluble protein aggregates, and in apoptosis. Genetic deficiencies of these enzymes are known to cause severe bleeding and skin disorders, and in several autoimmune diseases (including the gluten sensitivity diseases) a TG is the main — if not the sole — autoantigen. Blood coagulation, skin-barrier formation, hardening of the fertilization envelope, extracellular-matrix assembly and other important biological processes are dependent on the rapid generation of covalent crosslinks between proteins. These reactions — which are catalysed by transglutaminases — endow the resulting supramolecular structure with extra rigidity and resistance against proteolytic degradation. Some transglutaminases function as molecular switches in cytoskeletal scaffolding and modulate protein–protein interactions. Having knowledge of these enzymes is essential for understanding the aetiologies of diverse hereditary diseases of the blood and skin, and various autoimmune, inflammatory and degenerative conditions.