Abstract
Tissue transglutaminase (tTG), also referred to as type 2 transglutaminase or Gαh, 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.
Highlights
In 1957, Heinrich Waelsch discovered that liver extracts from guinea pigs would incorporate radio-labeled primary amines, such as cadaverine or lysine, into lysate proteins in a calcium dependent manner [1]
The catalytically inactive form of Tissue transglutaminase (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
In pancreatic cancer cells treated with the calcium ionophore A23187, tTG was shown to adopt the crosslinking-active open-state and to facilitate release of the apoptosis-inducing factor from mitochondria, promoting cell death
Summary
In 1957, Heinrich Waelsch discovered that liver extracts from guinea pigs would incorporate radio-labeled primary amines, such. [35] This structure (Fig. 1B, right side) showed that the C-terminal β-barrels swiveled almost 180° from their start position, resulting in a nearly linear conformation for the protein, which allowed access of substrates to the crosslinking catalytic site This conformational change eliminates the nucleotide binding site. [39,40] extracellular Ca2+ is at a higher concentration than GDP or GTP, suggesting that extracellular tTG would adopt the open-state, and be crosslinking-competent This view is somewhat complicated by the mildly oxidative conditions in the extracellular space, . [41,42] Either disulfide bond reduces crosslinking catalytic activity, but oxidized tTG maintains a conformation similar to the open-state. At least in the case of cancer, tTG’s conformation and activity must be considered individually
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