Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, UK.
Biomolecules. 2021 Jun 8;11(6):856. doi: 10.3390/biom11060856.
The human transcription factor FOXO3 (a member of the 'forkhead' family of transcription factors) controls a variety of cellular functions that make it a highly relevant target for intervention in anti-cancer and anti-aging therapies. FOXO3 is a mostly intrinsically disordered protein (IDP). Absence of knowledge of its structural properties outside the DNA-binding domain constitutes a considerable obstacle to a better understanding of structure/function relationships. Here, I present extensive molecular dynamics (MD) simulation data based on implicit solvation models of the entire FOXO3/DNA complex, and accelerated MD simulations under explicit solvent conditions of a central region of particular structural interest (FOXO3). A new graphical tool for studying and visualizing the structural diversity of IDPs, the Local Compaction Plot (LCP), is introduced. The simulations confirm the highly disordered nature of FOXO3 and distinguish various degrees of folding propensity. Unexpectedly, two 'linker' regions immediately adjacent to the DNA-binding domain are present in a highly extended conformation. This extended conformation is not due to their amino acid composition, but rather is caused by electrostatic repulsion of the domains connected by the linkers. FOXO3 is thus an IDP present in an unusually extended conformation to facilitate interaction with molecular interaction partners.
人类转录因子 FOXO3（叉头框转录因子家族的一员）控制着多种细胞功能，使其成为抗癌和抗衰老疗法干预的高度相关靶点。FOXO3 是一种主要的固有无序蛋白（IDP）。除 DNA 结合域外，其结构特性的知识缺失是对结构/功能关系更好理解的一个相当大的障碍。在这里，我提出了基于整个 FOXO3/DNA 复合物的隐式溶剂模型的广泛分子动力学（MD）模拟数据，以及在特定结构感兴趣的中央区域（FOXO3）的显式溶剂条件下的加速 MD 模拟。介绍了一种用于研究和可视化 IDP 结构多样性的新图形工具，即局部紧凑图（LCP）。模拟证实了 FOXO3 的高度无序性质，并区分了不同程度的折叠倾向。出乎意料的是，紧邻 DNA 结合域的两个“连接子”区域呈高度伸展构象。这种伸展构象不是由于它们的氨基酸组成，而是由连接子连接的结构域之间的静电排斥引起的。因此，FOXO3 是一种以异常伸展构象存在的 IDP，以促进与分子相互作用伙伴的相互作用。
