Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2

Abstract

Transglutaminase 2 (TG2) is a ubiquitously expressed member of an enzyme family catalyzing Ca(2+)-dependent transamidation of proteins. It is a multifunctional protein having several well-defined enzymatic (GTP binding and hydrolysis, protein disulfide isomerase, and protein kinase activities) and non-enzymatic (multiple interactions in protein scaffolds) functions. Unlike its enzymatic interactions, the significance of TG2's non-enzymatic regulation of its activities has recently gained importance. In this review, we summarize all the partners that directly interact with TG2 in a non-enzymatic manner and analyze how these interactions could modulate the crosslinking activity and cellular functions of TG2 in different cell compartments. We have found that TG2 mostly acts as a scaffold to bridge various proteins, leading to different functional outcomes. We have also studied how specific structural features, such as intrinsically disordered regions and embedded short linear motifs contribute to multifunctionality of TG2. Conformational diversity of intrinsically disordered regions enables them to interact with multiple partners, which can result in different biological outcomes. Indeed, ID regions in TG2 were identified in functionally relevant locations, indicating that they could facilitate conformational transitions towards the catalytically competent form. We reason that these structural features contribute to modulating the physiological and pathological functions of TG2 and could provide a new direction for detecting unique regulatory partners. Additionally, we have assembled all known anti-TG2 antibodies and have discussed their significance as a toolbox for identifying and confirming novel TG2 regulatory functions.

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…Interestingly, CD73 is expressed not only on MSC but also on tumor cells and Treg cells, suggesting that the adenosine found within TME can be derived from different sources, to further amplify the strong inhibitory effect derived from a single cell type [13,14,15]. Transglutaminase (TG)-II can be used to selectively identify MSC in immunohistochemistry and cytofluorimetry [16,17,18,19,20,21,22,23]; however, it is also expressed on tumor cells undergoing EMT. TG-II is involved in several processes that can regulate tumor cell proliferation and apoptosis [16,17,18,19,20,21].…”

“…Transglutaminase (TG)-II can be used to selectively identify MSC in immunohistochemistry and cytofluorimetry [16,17,18,19,20,21,22,23]; however, it is also expressed on tumor cells undergoing EMT. TG-II is involved in several processes that can regulate tumor cell proliferation and apoptosis [16,17,18,19,20,21]. MSC also express matrix metalloprotease (MMP) and some members of a disintegrin and metalloproteases (ADAM) family [24,25,26].…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…69 A whole collection of structural effects has been put together for transglutaminase 2. 70 Further examples are nonenzymatic functions of matrix metalloproteinase 12 and the g-secretase component presenilin 1. 71,72 BACE1 itself has been discussed as a non-enzymatic binding partner for a set of proteins, including BRI3, which is, like BACE1, processed by furin.…”

Transglutaminase 2 and Transglutaminase 2 Autoantibodies in Celiac Disease: a Review

“…The function TG2 evinces depends on its cellular location, prevailing conditions, and the substrates and interacting proteins available [21,22]. The principal and best-characterized function of TG2 is the Ca 2+ -dependent covalent and irreversible crosslinking of proteins with a glutamine residue to a primary amine, often another protein with a lysine residue, in a two-step reaction, resulting in the formation of an isopeptide bond between the target proteins ( Fig.…”