Substrates, inhibitors, and probes of mammalian transglutaminase 2

Abstract

Transglutaminase 2 (TG2) is a ubiquitous but enigmatic mammalian protein to which a number of biological functions have been ascribed but not definitively proven. As a member of the transglutaminase family, TG2 can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. It is also known to harbor other enzymatic properties, including protein disulfide isomerase, GTP-dependent signal transduction, and ATP dependent protein kinase activity. Given its multifunctional chemistry, it is unsurprising that a long list of proteins from the mammalian proteome have been identified as substrates and/or binding partners; however, the biological relevance of none of these protein-protein interactions has been clarified as yet. Remarkably, the most definitive insights into the biology of TG2 stem from its pathophysiological role in gluten peptide deamidation in celiac disease. Meanwhile our understanding of TG2 chemistry has been leveraged to engineer a spectrum of inhibitors and other molecular probes of TG2 biology in vivo. This review summarizes our current knowledge of the enzymology and regulation of human TG2 with a focus on its physiological substrates as well as tool molecules whose engineering was inspired by their identities.

Keywords: Chemical biology; Post-translational modifications; Transglutaminase.

Figure 1.. TG2 catalyzed transamidation and deamidation reactions.

P represents a Gln-containing peptide or protein, and R represents a small molecule or protein containing a primary amine.

Figure 2.. Crystal structures of open and closed conformations of TG2.

TG2 is comprised of the N-terminal β-sandwich (blue), the α/β-catalytic domain (green), and two C-terminal β-barrels (red and yellow, respectively). (A) “Closed” GTP-bound conformation of TG2 (1KV3). (B) “Open” DP3–3 bound conformation of TG2 (2Q3Z). (C) Space-filling model of GTP interacting with R580 in the closed conformation. (D) Space-filling model of DP3–3 interacting with C277 in the open conformation. (E) Space-filling model of the PDI-reactive, redox-regulated cysteines C230, C370, and C371.

Figure 3.. Redox regulation of TG2.

TG2 cofactors TRX and ERp57 reversibly regulate TG2 in a redox-dependent manner, and act as “on” and “off” switches for the active enzyme (green). As TG2 is natively inactive (gray), TRX is able to reduce the vicinal disulfide bond between C370-C371 to activate TG2, and ERp57 can oxidize the disulfide between C230 and C370 to catalytically inactivate the enzyme.