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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Quaternary structures of tumor suppressor p53 and a specific p53-DNA complex
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Quaternary structures of tumor suppressor p53 and a specific p53-DNA complex

机译：抑癌基因p53和特定p53-DNA复合物的四级结构

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The homotetrameric tumor suppressor p53 consists of folded core and tetramerization domains, linked and flanked by intrinsically disordered segments that impede structure analysis by x-ray crystallography and NMR. Here, we solved the quaternary structure of human p53 in solution by a combination of small-angle x-ray scattering, which defined its shape, and NMR, which identified the core domain interfaces and showed that the folded domains had the same structure in the intact protein as in fragments. We combined the solution data with electron microscopy on immobilized samples that provided medium resolution 3D maps. Ab initio and rigid body modeling of scattering data revealed an elongated cross-shaped structure with a pair of loosely coupled core domain dimers at the ends, which are accessible for binding to DNA and partner proteins. The core domains in that open conformation closed around a specific DNA response element to form a compact complex whose structure was independently determined by electron microscopy. The structure of the DNA complex is consistent with that of the complex of four separate core domains and response element fragments solved by x-ray crystallography and contacts identified by NMR. Electron microscopy on the conforma-tionally mobile, unbound p53 selected a minor compact conformation, which resembled the closed conformation, from the ensemble of predominantly open conformations. A multipronged structural approach could be generally useful for the structural characterization of the rapidly growing number of multidomain proteins with intrinsically disordered regions.
机译：同型四聚体肿瘤抑制物p53由折叠的核心和四聚结构域组成，其连接和侧翼是固有的无序链段，这些链段阻碍了X射线晶体学和NMR的结构分析。在这里，我们通过小角度X射线散射（定义了其形状）和NMR（确定了核心结构域界面并显示折叠结构域在结构中具有相同的结构）的组合解决了溶液中人p53的四级结构。完整的蛋白质，如片段。我们将溶液数据与电子显微镜结合在固定样品上，该样品提供了中分辨率3D地图。散射数据的从头算和刚体建模显示了一个细长的十字形结构，该结构的两端有一对松散耦合的核心结构域二聚体，可与DNA和伴侣蛋白结合。这种开放构象的核心结构域在特定的DNA反应元件周围闭合，形成致密的复合物，其结构由电子显微镜独立确定。 DNA复合物的结构与四个独立的核心结构域和通过X射线晶体学解析的反应元件片段以及通过NMR鉴定的触点的复合物的结构一致。在可移动的，未结合的构象上，电子显微镜从主要为开放构象的集合中选择了一个较小的紧凑构象，类似于封闭构象。多管结构方法通常可用于快速鉴定数量众多且具有内在无序区域的多结构域蛋白的结构特征。

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