Abstract
Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1–139 a.a)–p53 complex to the autophagosome, through TGase 2 (472–687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81–116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53–TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81–116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.
Highlights
Transglutaminase 2 (TGase 2) catalyzes intra- and intermolecular Nε-(γ-glutamyl)-lysine crosslinks (E.C. 2.3.2.13) between the γ-carboxamide groups of peptide-bound glutamine residues, which act as acyl donors, and the γ-amino groups of protein- and peptide-bound lysine residues, which act as acceptors (Folk 1983)
TGase 2 inhibitory effect of GK921 has been reported followed by development of GK13 quinoxaline derivative based on in vitro inhibition assay of recombinant human TGase 2 activity (IC50: 8.93 μM) as well as in vitro competition assay of p53 binding to TGase 2 (Ku et al 2014)
Most TGase 2 inhibitor developers aim at the active site or the GTP binding site of TGase 2 based on X-ray crystal structures (Liu et al 2002; Han et al 2010; Pinkas et al 2007)
Summary
Transglutaminase 2 (TGase 2) catalyzes intra- and intermolecular Nε-(γ-glutamyl)-lysine crosslinks (E.C. 2.3.2.13) between the γ-carboxamide groups of peptide-bound glutamine residues, which act as acyl donors, and the γ-amino groups of protein- and peptide-bound lysine residues, which act as acceptors (Folk 1983). TGase 2 has been identified as a therapeutic target (Kang et al 2016; Ku et al 2013, 2014) as well as a significant clinicopathologic marker in human clear cell renal cell carcinoma (RCC) (Park et al 2015). RCC shows highly increased expression of TGase 2 regardless of mutations, while low expression has been detected in the normal kidney epithelial cell. We found that TGase 2 knockdown or TGase 2 inhibition stabilized p53 in RCC, which induced p53-mediated apoptosis because there is less than 4% mutation of p53 in RCC (Kang et al 2016). A recent report showed that TGase 2 is a key molecular switch of necrosis-induced mesenchymal trans-differentiation by regulating master transcription factors such as C/EBPβ, TAZ,
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