Abstract
Multi-functional transglutaminase 2 (TG2), which possesses protein cross-linking and GTP hydrolysis activities, is involved in various cellular processes, including apoptosis, angiogenesis, wound healing, and neuronal regeneration, and is associated with many human diseases, including inflammatory disease, celiac disease, neurodegenerative disease, diabetes, tissue fibrosis, and cancers. Although most biochemical and cellular studies have been conducted with the TG2 (G224) form, the TG2 (G224V) form has recently emerged as a putative natural variant of TG2. In this study, we characterized the putative natural form of TG2, TG2 (G224V), and through a new crystal structure of TG2 (G224V), we revealed how TG2 (G224V) gained stability and higher Ca2+-dependent activity than an artificial variant of TG2 (G224).
Highlights
Transglutaminase 2 (TG2) is a multi-functional protein that possesses various biological activities, including protein cross-linking activity [1], GTPase activity [2], protein disulfide isomerase activity [3], kinase activity [4], and scaffold activity [5]
Because previous biochemical and structural studies showed that TG2 could exist as a monomer or dimer in solution, the stoichiometry of the TG2 (G224V) form was analyzed with size-exclusion chromatography
Most biochemical and cellular studies have been conducted with the TG2 (G224) form, it has been suggested that the actual sequence at position 224 on TG2 may be valine, and not glycine
Summary
Transglutaminase 2 (TG2) is a multi-functional protein that possesses various biological activities, including protein cross-linking activity [1], GTPase activity [2], protein disulfide isomerase activity [3], kinase activity [4], and scaffold activity [5]. TG2 acts as a signal transfer molecule that transmits a receptor signal to an intracellular effector through GTP hydrolysis [15]. When it is secreted into the extracellular environment, TG2 functions as a cross-linking enzyme in the matrix [16]. This protein transamidase activity of TG2 is positively regulated by calcium and negatively regulated by GTP [17]
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