Structure and two differential state of TG2 activity. (a, b) Two distinct protein structures of TG2 are depicted. Calcium-bound active structure of TG2 (open form; a) and its GDP-bound inactive structure in the absence of calcium (closed form; b). Through these calcium-dependent conformational changes, TG2 activity is reversibly changed. (c, d) The open structure of TG2 has the functions of transamidation and protein disulfide isomerase, whereas its closed form displays the functions of protein disulfide isomerase, GTPase, and protein kinase. (e) The detailed chemical reactions mediated by TG2, such as the cross-linking, deamination, amine incorporation, and GTPase activities, and the structural changes of target proteins are described.