Figure 1

Allosteric regulation of tissue transglutaminase (TG2) activity and functions. TG2 is a relatively non-specific crosslinking enzyme, and its activity in and outside the cell is regulated by Ca²⁺, guanine nucleotides, and the redox potential. Binding of Ca²⁺ (dissociation constant of approximately 60 μM) is essential for TG2 to acquire a catalytically active 'open' or 'extended' conformation. In contrast, binding of GTP/GDP (dissociation constant of approximately 1.6 μM) renders TG2 in a catalytically inactive 'closed' or 'compact' conformation. Under physiological conditions, high levels of GTP, low redox potential, and low free Ca²⁺ level keep TG2 in its catalytically inactive compact state. However, a calcium ion influx due to extreme stress or cell damage can induce the catalytically active or 'extended' conformation. In comparison with the intracellular environment, the extracellular matrix has a considerably lower GTP level and relatively high Ca²⁺ level. Therefore, the newly secreted TG2 can be expected to be in a catalytically active state. However, a large fraction of the extracellular TG2 in most organs is in an inactive form because of disulfide bonding. Thioredoxin 1 has been suggested to be a physiological activator of oxidized TG2. In the compact or catalytically inactive state, TG2 can act as a scaffold protein and result in the activation of various signaling pathways. In its extended and catalytically active state, TG2 catalyzes highly stable protein crosslinking, resulting in apoptotic death if inside the cell or stabilization of the matrix if outside the cell. ECM, extracellular matrix.