Opening up about Tissue Transglutaminase: When Conformation Matters More than Enzymatic Activity

Tissue transglutaminase (tTG), also referred to as type 2 transglutaminase or Gα(h), can bind and hydrolyze GTP, as well as function as a protein crosslinking enzyme. tTG is widely expressed and can be detected both inside cells and in the extracellular space. In contrast to many enzymes, the active and inactive conformations of tTG are markedly different. The catalytically inactive form of tTG adopts a compact “closed-state” conformation, while the catalytically active form of the protein adopts an elongated “open-state” conformation. tTG has long been appreciated as an important player in numerous diseases, including celiac disease, neuronal degenerative diseases, and cancer, and its roles in these diseases often depend as much upon its conformation as its catalytic activity. While its ability to promote these diseases has been traditionally thought to be dependent on its protein crosslinking activity, more recent findings suggest that the conformational state tTG adopts is also important for mediating its effects. In particular, we and others have shown that the closed-state of tTG is important for promoting cell growth and survival, while maintaining tTG in the open-state is cytotoxic. In this review, we examine the two unique conformations of tTG and how they contribute to distinct biological processes. We will also describe how this information can be used to generate novel therapies to treat diseases, with a special focus on cancer.