Department of Biochemistry, Science Institute, School of Engineering and Natural Sciences, University of Iceland, Sturlugata 7, 102, Reykjavík, Iceland.
Chemistry. 2023 Apr 13;29(21):e202203369. doi: 10.1002/chem.202203369. Epub 2023 Mar 6.
Eukaryotic transcription factors (TFs) are the final integrators of a complex molecular feedback mechanism that interfaces with the genome, consolidating information for transcriptional regulation. TFs consist of both structured DNA-binding domains and long intrinsically disordered regions (IDRs) embedded with motifs linked to transcriptional control. It is now well established that the dynamic multifunctionality of IDRs is the basis for a wide spectrum of TF functions necessary to navigate and regulate the human genome. This review dissects the chemical features of TF IDRs that endow them with structural plasticity that is central to their functions in the nucleus. Sequence analysis of a set of over 1600 human TFs through AlphaFold was used to identify key features of their IDRs. Recent studies were then highlighted to illustrate IDR involvement in processes such as protein interactions, DNA binding and specificity, chromatin opening, and phase separation. To expand our understanding of TF functions, future directions are suggested for integrating experiments and simulations, from in vitro to living systems.
真核转录因子 (TFs) 是复杂分子反馈机制的最终整合者，与基因组相互作用，整合转录调控的信息。TFs 由结构 DNA 结合域和嵌入与转录控制相关的基序的长固有无序区域 (IDR) 组成。现在已经确立，IDR 的动态多功能性是 TF 功能的基础，这些功能对于导航和调节人类基因组是必要的。本综述剖析了赋予 TF IDR 结构可塑性的化学特征，这是它们在核内发挥功能的核心。通过 AlphaFold 对超过 1600 个人类 TFs 的序列分析用于识别其 IDR 的关键特征。然后重点介绍了最近的研究，以说明 IDR 如何参与蛋白质相互作用、DNA 结合和特异性、染色质开放和相分离等过程。为了扩大我们对 TF 功能的理解，建议从体外到活体系统，整合实验和模拟的未来方向。
