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

• Published in: Amino acids Vol. 50; no. 11; pp. 1583 - 1594
• Main Authors: Kim, Nayeon, Kang, Joon Hee, Lee, Won-Kyu, Kim, Seul-Gi, Lee, Jae-Seon, Lee, Seon-Hyeong, Park, Jong Bae, Kim, Kyung-Hee, Gong, Young-Dae, Hwang, Kwang Yeon, Kim, Soo-Youl
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01.11.2018; Springer Nature B.V
• Subjects: Allosteric properties; Analytical Chemistry; Autophagy; Binding sites; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; Cell death; Complex formation; Conformation; Deactivation; Kidney cancer; Life Sciences; Neurobiology; Original Article; p53 Protein; Polymerization; Proteomics; Pyrazine; Renal cell carcinoma; Transglutaminase 2; Allosteric binding site; Transglutaminase 2; p53; GK921
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-018-2635-2

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.