It is in the flanks: Conformational flexibility of transcription factor binding sites.
It is in the flanks: Conformational flexibility of transcription factor binding sites.
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它位于侧翼：转录因子结合位点的构象灵活性。
DOI：
10.1016/j.bpj.2022.09.020
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发表时间：
2022
影响因子：
3.4
通讯作者：
Rohs,Remo
中科院分区：
文献类型：
--
作者：
Chiu,Tsu-Pei;Li,Jinsen;Jiang,Yibei;Rohs,Remo
转录因子（TF）利用基因组中广泛的DNA结合位点来调节基因表达。尽管有很多研究（1，2），TF-DNA结合机制仍然没有完全理解，部分原因是没有简单的读出代码将TF引导到它们的基因组靶位点（3）。除了靶DNA的一级序列及其构象外，DNA的结构动力学在TF识别中也起着重要作用。四十多年前，Bansal和他的同事们是第一批从结构上解释双螺旋构象灵活性及其多态性的人。他们将柔性与双链DNA磷酸二酯骨架中扭转角的可变性联系起来（4）。DNA核心结合位点的蛋白质读出机制是多年来研究的焦点（5）。然而，不直接与TF接触的侧翼区域也可以在识别过程中发挥作用。侧翼区在影响TF结合特异性中的作用首先被鉴定为围绕基本螺旋-环-螺旋TF结合位点的E-box靶位点的基因组侧翼（6），尽管先前的研究定义了不存在构象柔性的DNA形状。嵌入侧翼区结构中的内在动力学可能影响TF-DNA结合亲和力。Bansal及其同事最近将DNA结构特征与不同真核TF的体外衍生结合亲和力相关联（7）。他们的研究表明，TF结合亲和力与DNA结构特征相关，这些特征受基因组中TF结合靶点周围侧翼区域的影响（7）。然而，完整的机制仍不清楚。在一项新的研究中，Ghoshdastidar和Bansal研究了构象柔性作为TF-DNA读出的额外机制的影响（8）。为了实现这一目标，他们使用分子动力学（MD）模拟作为原子探针来测量TF结合靶点中复杂的内部运动。作者发现，对于果蝇Hox异源二聚体Ultrabithorax（Ubx）及其辅因子Extradenticle（Exd）的DNA靶标，侧翼区域影响核心结合位点的构象灵活性。作者对与长度为20个碱基对（bp）的DNA片段复合的Exd-Hox异二聚体进行了MD模拟。在这20个bp中，中心的8个bp代表核心结合位点，每个侧翼的4个bp是可变的，并且GC二核苷酸加帽于寡核苷酸结合位点。
Transcription factors (TFs) utilize a wide range of DNA binding sites in the genome to regulate gene expression. Despite much research (1, 2), TF-DNA binding mechanisms are still not completely understood, in part because there is no simple readout code that directs TFs to their genomic target sites (3). Apart from the primary sequence of the target DNA and its conformational landscape, the structural dynamics of DNA could play an important role in TF recognition. More than four decades ago, Bansal and colleagues were among the first to structurally explain the conformational flexibility of the double helix and its polymorphisms. They related the flexibility to the variability of torsion angles in the phosphodiester backbone of double-stranded DNA (4). Protein readout mechanisms of the DNA core binding site were the focus of investigation over the years (5). However, flanking regions that are not directly contacted by TFs can also play a role in the recognition process. A role of flanking regions in affecting TF binding specificity was first identified for genomic flanks of E-box target sites surrounding basic helix-loop-helix TF binding sites (6), although that previous study defined DNA shape without the presence of conformational flexibility. Intrinsic dynamics embedded in the structure of flanking regions may influence TF-DNA binding affinity. Bansal and co-workers recently related DNA structural features to in vitro-derived binding affinity for different eukaryotic TFs (7). Their study revealed that TF binding affinity correlates with DNA structural features that are influenced by flanking regions surrounding TF-binding targets in the genome (7). Nevertheless, the complete mechanisms remained unclear.In a new study, Ghoshdastidar and Bansal investigated the effect of conformational flexibility as an additional mechanism in TF-DNA readout (8). To achieve this, they used molecular dynamics (MD) simulations as an atomistic probe to measure intricate internal motions in TF-binding targets. The authors found that, for DNA targets of the Drosophila melanogaster Hox heterodimer Ultrabithorax (Ubx) and its cofactor Extradenticle (Exd), the flanking regions influenced the conformational flexibility of the core binding sites. The authors ran MD simulations for Exd-Hox heterodimers in complex with DNA fragments of 20 base pairs (bp) in length. Of these 20 bp, the central 8 bp represented the core binding site, 4 bp in each flank were variable, and GC dinucleotides capped the oli-