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

Nayeon Kim, Joon Hee Kang, Won Kyu Lee, Seul Gi Kim, Jae Seon Lee, Seon Hyeong Lee, Jong Bae Park, Kyung Hee Kim, Young Dae Gong, Kwang Yeon Hwang, Soo Youl Kim

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1583-1594
    Number of pages12
    JournalAmino Acids
    Volume50
    Issue number11
    DOIs
    Publication statusPublished - 2018 Nov 1

    Bibliographical note

    Publisher Copyright:
    © 2018, The Author(s).

    Keywords

    • Allosteric binding site
    • GK921
    • Transglutaminase 2
    • p53

    ASJC Scopus subject areas

    • Biochemistry
    • Clinical Biochemistry
    • Organic Chemistry

    Fingerprint

    Dive into the research topics of 'Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus'. Together they form a unique fingerprint.

    Cite this