Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 6, D-14195 Berlin, Germany.
Max Planck Institute for Multidisciplinary Sciences, Bioanalytical Mass Spectrometry Group, Am Fassberg 11, D-37077 Goettingen, Germany.
Nucleic Acids Res. 2022 Oct 14;50(18):10665-10679. doi: 10.1093/nar/gkac797.
The RNA-binding protein tristetraprolin (TTP) is a potent activator of mRNA decay, specifically for transcripts bearing AU-rich elements (AREs) in their 3'-untranslated regions. TTP functions as a mediator for mRNA decay by interacting with the decay machinery and recruiting it to the target ARE-mRNA. In this study, we report a weak, but direct interaction between TTP and the human decapping enzyme DCP2, which impacts the stability of ARE transcripts. The TTP-DCP2 interaction is unusual as it involves intrinsically disordered regions (IDRs) of both binding partners. We show that the IDR of DCP2 has a propensity for oligomerization and liquid-liquid phase separation in vitro. Binding of TTP to DCP2 leads to its partitioning into phase-separated droplets formed by DCP2, suggesting that molecular crowding might facilitate the weak interaction between the two proteins and enable assembly of a decapping-competent mRNA-protein complex on TTP-bound transcripts in cells. Our studies underline the role of weak interactions in the cellular interaction network and their contribution towards cellular functionality.
RNA 结合蛋白 tristetraprolin（TTP）是一种有效的 mRNA 降解激活剂，特别是针对其 3'非翻译区含有富含 AU 元件（AREs）的转录本。TTP 通过与降解机制相互作用并将其招募到靶标 ARE-mRNA 上来作为 mRNA 降解的中介。在这项研究中，我们报告了 TTP 与人类脱帽酶 DCP2 之间的弱但直接的相互作用，该相互作用影响 ARE 转录本的稳定性。TTP-DCP2 相互作用不寻常，因为它涉及两个结合伴侣的固有无序区域（IDR）。我们表明，DCP2 的 IDR 具有体外寡聚化和液-液相分离的倾向。TTP 与 DCP2 的结合导致其分配到由 DCP2 形成的相分离液滴中，这表明分子拥挤可能促进这两种蛋白质之间的弱相互作用，并使在细胞中 TTP 结合的转录本上形成具有脱帽能力的 mRNA-蛋白质复合物。我们的研究强调了弱相互作用在细胞相互作用网络中的作用及其对细胞功能的贡献。
