研究动态
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无细胞分析揭示了 RG/RGG 基序在 DDX3X 相分离中的作用及其与癌症发病机制的潜在联系。

Cell-free analysis reveals the role of RG/RGG motifs in DDX3X phase separation and their potential link to cancer pathogenesis.

发表日期:2024 Aug 31
作者: Hongran Chen, Boyang Li, Xinyue Zhao, Caini Yang, Sa Zhou, Wenjian Ma
来源: Int J Biol Macromol

摘要:

DEAD-box RNA 解旋酶 DDX3X 是一种参与 RNA 代谢和应激反应的多功能蛋白。在本研究中,我们使用无细胞测定研究了 RG/RGG 基序在 DDX3X 液-液相分离 (LLPS) 动态过程中的作用,并通过生物信息学分析探讨了它们与癌症发展的潜在联系。我们的结果表明,RG/RGG 基序的数量、位置和组成显着影响 DDX3X 进行相分离和形成自聚集体的能力。突变分析表明,RG/RGG 基序之间的间距和每个基序内甘氨酸残基的数量是决定相分离程度的关键因素。此外,我们发现 DDX3X 在几种癌症类型中与应激颗粒蛋白 G3BP1 共表达,并且可以在无细胞系统中与 G3BP1 进行共相分离,这表明这些蛋白质在相分离结构中存在潜在的功能相互作用。 DDX3X 和 G3BP1 可能通过其 RG/RGG 结构域相互作用,随后在应激情况下发挥重要的细胞功能。总的来说,我们的研究结果为 RG/RGG 基序在调节 DDX3X 相分离中的作用及其对癌症发病机制的潜在贡献提供了新的见解。版权所有 © 2024。由 Elsevier B.V. 出版。
The DEAD-box RNA helicase DDX3X is a multifunctional protein involved in RNA metabolism and stress responses. In this study, we investigated the role of RG/RGG motifs in the dynamic process of liquid-liquid phase separation (LLPS) of DDX3X using cell-free assays and explored their potential link to cancer development through bioinformatic analysis. Our results demonstrate that the number, location, and composition of RG/RGG motifs significantly influence the ability of DDX3X to undergo phase separation and form self-aggregates. Mutational analysis revealed that the spacing between RG/RGG motifs and the number of glycine residues within each motif are critical factors in determining the extent of phase separation. Furthermore, we found that DDX3X is co-expressed with the stress granule protein G3BP1 in several cancer types and can undergo co-phase separation with G3BP1 in a cell-free system, suggesting a potential functional interaction between these proteins in phase-separated structures. DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently exert important cellular functions under stress situation. Collectively, our findings provide novel insights into the role of RG/RGG motifs in modulating DDX3X phase separation and their potential contribution to cancer pathogenesis.Copyright © 2024. Published by Elsevier B.V.