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Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus.

Research paper by Nayeon N Kim, Joon Hee JH Kang, Won-Kyu WK Lee, Seul-Gi SG Kim, Jae-Seon JS Lee, Seon-Hyeong SH Lee, Jong Bae JB Park, Kyung-Hee KH Kim, Young-Dae YD Gong, Kwang Yeon KY Hwang, Soo-Youl SY Kim

Indexed on: 15 Aug '18Published on: 15 Aug '18Published in: Amino acids



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.