Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Chemical Biology Pub Date : 2024-09-10 DOI:10.1016/j.chembiol.2024.08.004

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

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Abstract

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.

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化学诱导 AIMP2-DX2 和 Siah1 之间的相互作用以增强泛素化

AIMP2-DX2（以下简称 DX2）是氨基酰-tRNA 合成酶相互作用多功能蛋白 2（AIMP2）的致癌变体，它能介导致癌因子与多种癌症相关因子的相互作用。降低 DX2 的水平可有效抑制肿瘤发生。我们以前曾报道 DX2 可通过 Siah1 介导的泛素化降解。在这项研究中，我们发现了一种化合物 SDL01，它能增强 DX2 与 Siah1 之间的相互作用，从而促进 DX2 的泛素依赖性降解。研究发现，SDL01 能与围绕 DX2 N 端柔性区和 GST 结构域的口袋结合，导致构象变化，从而稳定了 DX2 与 Siah1 的相互作用。我们的研究结果表明，蛋白质与蛋白质之间的相互作用（PPIs）可以通过化学诱导的构象变化来调节。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.