Transglutaminases: Nature’s biological glues

Abstract

Transglutaminases (Tgases) are a widely distributed group of enzymes that catalyse the post-translational modification of proteins by the formation of isopeptide bonds. This occurs either through protein cross-linking via epsilon-(gamma-glutamyl)lysine bonds or through incorporation of primary amines at selected peptide-bound glutamine residues. The cross-linked products, often of high molecular mass, are highly resistant to mechanical challenge and proteolytic degradation, and their accumulation is found in a number of tissues and processes where such properties are important, including skin, hair, blood clotting and wound healing. However, deregulation of enzyme activity generally associated with major disruptions in cellular homoeostatic mechanisms has resulted in these enzymes contributing to a number of human diseases, including chronic neurodegeneration, neoplastic diseases, autoimmune diseases, diseases involving progressive tissue fibrosis and diseases related to the epidermis of the skin. In the present review we detail the structural and regulatory features important in mammalian Tgases, with particular focus on the ubiquitous type 2 tissue enzyme. Physiological roles and substrates are discussed with a view to increasing and understanding the pathogenesis of the diseases associated with transglutaminases. Moreover the ability of these enzymes to modify proteins and act as biological glues has not gone unnoticed by the commercial sector. As a consequence, we have included some of the present and future biotechnological applications of this increasingly important group of enzymes.

Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

“…Transglutaminases (Tgases, EC 2.3.2.13) are calcium-dependent enzymes which catalyze protein cross-linking through an acyl-transfer reaction (Griffin et al, 2002;Lorand and Graham, 2003). The Tgase family includes nine genes although the physiological role of the encoded proteins has been defined for only some (Griffin et al, 2002;Lorand and Graham, 2003, Dahl et al, 2004).…”

“…Cells expressing mutant TG2 showed reduced TG activity when compared to TG2-WT: 75.5±8.5* nmol/h/mg of protein for TG2-M330R, 81,9±10.2* nmol/h/mg of protein for TG2-N333S and 33.1±4.1** nmol/h/mg of protein for TG2-I331N (*=p<0,05, **=p<0.01) (Fig. 2B).Expression of transglutaminase genes 1, 2, 3, 4, 5 and 7 in normal human pancreatic islet TGM2 belongs to a large family (9 members) of TGM genes (Griffin et al, 2002;Lorand and Graham, 2003). In order to clarify which TGM gene(s) is expressed in the human endocrine pancreas, we studied expression of 6 human genes: TGM1 to TGM5 and TGM7, which encode for the corresponding transglutaminase family member (TG1-TG5 and TG7) by real-time PCR (RT-PCR).…”

“…TG2 has been involved in several cellular processes such as cell adhesion and cell death, but its physiological role is still a matter of debate (Griffin et al, 2002;Lorand and Graham, 2003). In order to shed light on the function of TG2 in mammals, TG2 knock-out mice (Tgm2 -/-) have been generated (Bernassola et al, 2002;Nanda et al, 2001).…”

“…Our results support the notion that TG2 mutations may play a role in early-onset type 2 diabetes. Firstly, M330, I331 and N333 residues are well conserved in mouse, rat , dog, and chicken TG2 proteins (with I331 and N333 also conserved in Xenopus laevis); secondly, the mutations are not found in a large number of normoglycaemic controls, and thirdly, TGM2 Gene Mutations and Type 2 Diabetes 5 they are located in close proximity to the transamidation catalytic site (catalytic triad: C277, H335 and D538) (Griffin, et al, 2002;Lorand and Graham, 2003). It is worth noting that residue N333 (as well as residue H335) is conserved throughout all the members of the TGase family (but not band 4.2) and that this mutation has -among the three-the most significant impact on the transamidating activity of TG2 in vitro.…”

Screening of substrate peptide sequences for tissue-type transglutaminase (TGase 2) using T7 phage cDNA library

“…In the enzymatic reaction, glutamine residue is also modified by attachment of primary amine (Griffin et al 2002;Lorand and Graham 2003). In the initiation of this catalytic reaction, formation of the intermediate between the enzyme and the limited glutamine residues is rate-limiting.…”