Tissue Transglutaminase - Regulation

Regulation

Crosslinking activity by tTG requires the binding of Ca2+ ions. Multiple Ca2+ can bind to a single tTG molecule. In contrast, the binding of one molecule of GTP or GDP inhibits the crosslinking activity of the enzyme. Therefore, intracellular tTG is mostly inactive due to the relatively high concentration of GTP/GDP and the low levels of calcium inside the cell. Although extracellular tTG is expected to be active due to the low concentration of guanine nucleotides and the high levels of calcium in the extracellular space, evidence has shown that extracellular tTG is mostly inactive. Recent studies suggest that extracellular tTG is kept inactive by the formation of a disulfide bond between two vicinal Cys residues. Therefore, oxidation/reduction of the disulfide bond serves as a third allosteric regulatory mechanism (along with GTP/GDP and Ca2+) for the activation of tTG. Thioredoxin has been shown to activate extracellular tTG by reducing the disulfide bond. Recent studies have suggested that interferon-γ may serve as an activator of extracellular tTG in the small intestine; these studies have a direct implication to the pathogenesis of celiac disease. Activation of tTG has been shown to be accompanied by large conformational changes, switching from a compact (inactive) to an extended (active) conformation. (see Figure 2)