ter truncated TG2 form has reduced transamidating activity upon expression in NIH3T3 fibroblasts but sensitizes these cells to apoptosis. Inside the cell, the transamidating activity of TG2 might be sensitized to even lower concentrations of Ca2 by a number of mechanisms, such as expression of alternatively spliced isoforms, limited proteolysis from the molecule, and some nonetheless poorly characterized molecular interactions of TG2 with lipids and proteins in different cellular compartments. Extracellularly, transamidating activity of TG2 is suppressed by NO mediated nitrosylation and regulated by reversible redox dependent formation with the inhibitory intramolecular disulfide bond. Around the cell surface and in the ECM, the direct binding of TG2 to heparan sulfate proteoglycans such as syndecan 4 was shown to improve transamidating activity of the enzyme.
It remains to be tested no matter whether and how other principal cell surface ECM binding partners of TG2, like integrins and fibronectin, or biomechanical forces, impact the TG2 mediated protein cross linking activity outside the cell. Even more normally, an interaction of TG2 with some effector protein may well shift and stabilize the enzyme in to the open conformation, thereby extra resources decreasing or perhaps eliminating the have to have for Ca2 activation. The existence of such nonetheless unidentified TG2 binding partners was postulated inside the case of cell responses to retinoids and EGF, the stimuli that both trigger relocation of cytoplasmic TG2 towards the inner leaflet from the plasma membrane and evoke a drastic upregulation of its transamidating activity. The interaction of TG2 with membrane lipids may be an additional critical aspect in assisting the TG2 enzyme to overcome the Ca2 activation barrier for transamidation. Notably, a sphingophospholipid sphingosine phosphorylcholine markedly improved the transamidation activity of TG2.
The biological significance of this observation remains unclear resulting from the exceptionally scarce volume of this lipid in biological membranes. Nonetheless, an eye-catching hypothesis suggests that endomembrane sequestered intracellular TG2 could undergo a conformational alter upon membrane lipid binding, which permits transamidation to proceed resulting from locally enhanced concentrations of Ca2 ions. Numerous alternatively spliced TG2 variants inhibitor NVP-BHG712 were shown to become coexpressed together with the major canonical isoform, which consists of 687 amino acids in humans. In erythroleukemia cells, Fraij and Gonzales detected the shortest currently known alternatively spliced isoform which consists of only 349 amino acids, 286 of which correspond for the N terminal TG2 sequence. This group also described an alternatively spliced TG2 type, which consists of 548 amino acids, 538 of that are identical towards the canonical TG2 isoform. Later, Antonyak and coauthors identified that this lat
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