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首页> 外文期刊>Journal of Molecular Biology >Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains.
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Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains.

机译：尾巴介导的HMGB1塌陷是动态的，是通过酸性尾巴与A和B结构域的差异结合而发生的。

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摘要

The architectural DNA-binding protein HMGB1 consists of two tandem HMG-box domains joined by a basic linker to a C-terminal acidic tail, which negatively regulates HMGB1-DNA interactions by binding intramolecularly to the DNA-binding faces of both basic HMG boxes. Here we demonstrate, using NMR chemical-shift mapping at different salt concentrations, that the tail has a higher affinity for the B box and that A box-tail interactions are preferentially disrupted. Previously, we proposed a model in which the boxes are brought together in a collapsed, tail-mediated assembly, which is in dynamic equilibrium with a more extended form. Small-angle X-ray scattering data are consistent with such a dynamic equilibrium between collapsed and extended structures and are best represented by an ensemble. The ensembles contain a significantly higher proportion of collapsed structures when the tail is present. (15)N NMR relaxation measurements show that full-length HMGB1 has a significantly lower rate of rotational diffusion than the tail-less protein, consistent with the loss of independent domain motions in an assembled complex. Mapping studies using the paramagnetic spin label MTSL [(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidin-3-yl)methyl methanethiosulfonate] placed at three locations in the tail confirm our previous findings that the tail binds to both boxes with some degree of specificity. The end of the tail lies further from the body of the protein and is therefore potentially free to interact with other proteins. MTSL labelling at a single site in the A domain (C44) causes detectable relaxation enhancements of B domain residues, suggesting the existence of a "sandwich"-like collapsed structure in which the tail enables the close approach of the basic domains. These intramolecular interactions are presumably important for the dynamic association of HMGB1 with chromatin and provide a mechanism by which protein-protein interactions or posttranslational modifications might regulate the function of the protein at particular sites, or at particular stages in the cell cycle.
机译：结构性DNA结合蛋白HMGB1由两个串联的HMG-box域组成，这些域通过基本接头与C末端酸性尾部相连，该末端通过分子内结合两个基本HMG盒的DNA结合面来负调控HMGB1-DNA相互作用。在这里，我们证明了使用不同盐浓度的NMR化学位移图谱，可以看出尾巴对B盒具有更高的亲和力，并且A盒尾相互作用优先受到破坏。以前，我们提出了一个模型，其中盒子以折叠的，尾部介导的组件组装在一起，该组件处于动态平衡状态且具有更扩展的形式。小角X射线散射数据与塌陷结构和扩展结构之间的这种动态平衡相一致，并且最好用整体表示。当存在尾巴时，合奏包含相当高比例的塌陷结构。 （15）N NMR弛豫测量表明，全长HMGB1的旋转扩散速率明显低于无尾蛋白，这与组装复合物中独立域运动的损失一致。使用顺磁性自旋标记MTSL [（1-氧基-1,2,2,5,5-四甲基-3-吡咯烷-3-基）甲硫代磺酸甲酯]进行的制图研究证实了我们先前的发现，即尾部结合对两个盒子都有一定程度的特异性。尾巴的末端离蛋白质的主体更远，因此可能自由与其他蛋白质相互作用。在A结构域（C44）中单个位点处的MTSL标记导致B结构域残基可检测到的弛豫增强，表明存在“三明治”式折叠结构，其中尾部使基本结构域能够紧密接近。这些分子内相互作用对于HMGB1与染色质的动态缔合可能很重要，并提供了一种机制，蛋白质-蛋白质相互作用或翻译后修饰可通过该机制调节蛋白质在特定位点或细胞周期特定阶段的功能。

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