化学诱导 AIMP2-DX2 和 Siah1 之间的相互作用以增强泛素化。
Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination.
发表日期：2024 Sep 03
作者：
Dae Gyu Kim, Minkyoung Kim, Ja-Il Goo, Jiwon Kong, Dipesh S Harmalkar, Qili Lu, Aneesh Sivaraman, Hossam Nada, Sreenivasulu Godesi, Hwayoung Lee, Mo Eun Song, Eunjoo Song, Kang-Hyun Han, Woojin Kim, Pilhan Kim, Won Jun Choi, Chang Hoon Lee, Sunkyung Lee, Yongseok Choi, Sunghoon Kim, Kyeong Lee
来源：
Cell Chemical Biology
摘要：
AIMP2-DX2（以下简称 DX2）是氨酰基-tRNA 合成酶相互作用多功能蛋白 2 (AIMP2) 的致癌变体，可介导与癌症相关的各种因子的致瘤相互作用。降低DX2水平可以有效抑制肿瘤发生。我们之前报道过 DX2 可以通过 Siah1 介导的泛素化降解。在这项研究中，我们鉴定了一种化合物 SDL01，它增强 DX2 和 Siah1 之间的相互作用，从而促进 DX2 的泛素依赖性降解。发现 SDL01 与 DX2 N 端柔性区和 GST 结构域周围的口袋结合，引起构象变化，从而稳定其与 Siah1 的相互作用。我们的研究结果表明，蛋白质-蛋白质相互作用 (PPI) 可以通过化学诱导的构象变化进行调节。版权所有 © 2024 Elsevier Ltd。保留所有权利。
AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.Copyright © 2024 Elsevier Ltd. All rights reserved.