Department of Chemistry, Georgia State University, Atlanta, GA, USA.
Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
Adv Exp Med Biol. 2022;1371:11-32. doi: 10.1007/5584_2021_618.
Eukaryotic transcription factors are versatile mediators of specificity in gene regulation. This versatility is achieved through mutual specification by context-specific DNA binding on the one hand, and identity-specific protein-protein partnerships on the other. This interactivity, known as combinatorial control, enables a repertoire of complex transcriptional outputs that are qualitatively disjoint, or non-continuum, with respect to binding affinity. This feature contrasts starkly with prokaryotic gene regulators, whose activities in general vary quantitatively in step with binding affinity. Biophysical studies on prokaryotic model systems and more recent investigations on transcription factors highlight an important role for folded state dynamics and molecular hydration in protein/DNA recognition. Analysis of molecular models of combinatorial control and recent literature in low-affinity gene regulation suggest that transcription factors harbor unique conformational dynamics that are inaccessible or unused by prokaryotic DNA-binding proteins. Thus, understanding the intrinsic dynamics involved in DNA binding and co-regulator recruitment appears to be a key to understanding how transcription factors mediate non-continuum outcomes in eukaryotic gene expression, and how such capability might have evolved from ancient, structurally conserved counterparts.
真核转录因子是基因调控特异性的多功能介质。这种多功能性是通过一方面特定于上下文的 DNA 结合，另一方面特定于身份的蛋白质-蛋白质相互作用来实现的。这种相互作用，称为组合控制，能够产生一系列复杂的转录输出，这些输出在结合亲和力方面是定性不同的，或者说是不连续的。这一特征与原核基因调控因子形成鲜明对比，原核基因调控因子的活性通常与结合亲和力呈定量变化。对原核模型系统的生物物理研究和最近对转录因子的研究强调了折叠态动力学和分子水合作用在蛋白质/DNA 识别中的重要作用。组合控制的分子模型分析和最近关于低亲和力基因调控的文献表明，转录因子具有独特的构象动力学，原核 DNA 结合蛋白无法获得或无法使用这些动力学。因此，理解 DNA 结合和共调节剂募集中涉及的固有动力学似乎是理解转录因子如何在真核基因表达中介导非连续结果的关键，以及这种能力如何从古老的、结构保守的对应物中进化而来。
