Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case.
Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case.
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DOI：
10.1371/journal.pone.0144284
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Turjanski AG
中科院分区：
文献类型：
--
作者：
Ithuralde RE;Turjanski AG
无序区域和胞内无序蛋白（IDP）参与关键的细胞过程，并且只有在与它们的伴侣结合时才可能获得稳定的三维结构。IDP可以遵循称为诱导折叠的结合后折叠过程，或称为构象选择的结合前折叠过程。转录因子p53参与调节应激或DNA损伤引起的细胞事件。p53结构域结构由N-末端反式激活结构域（p53）、DNA结合结构域和四聚化结构域组成。β-淀粉样蛋白的活性受到辅因子、抑制剂和磷酸化相互作用的严格调节。为了启动转录，p53 β与CBP的TAZ 2结构域结合，CBP是一种共转录因子，并经历了折叠和结合过程，正如最近的NMR结构所揭示的复合物。p53的活性受p53结构域上多个位点的磷酸化调节，最近的研究表明，三个残基的修饰影响与TAZ 2的结合。然而，我们仍然不知道这些磷酸化如何影响结合态的结构，因此，它们如何调节p53功能。在这项工作中，我们使用计算机模拟来了解磷酸化如何影响p53蛋白：TAZ 2复合物的结构并调节识别机制。已经提出磷酸化通过与折叠的蛋白质直接相互作用或通过改变IDP的未结合构象（例如通过预折叠有利于识别机制的蛋白质）来增强结合。在这里，我们展示了一个有趣的转折在p53的情况下：磷酸化主要影响p53蛋白的结合结构，突出了IDP蛋白质-蛋白质相互作用的复杂性。我们的研究结果与以前的实验研究一致，允许一个清晰的图片如何p53的磷酸化调节，并提供新的见解如何翻译后修饰可以调节IDP的功能。
Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD:TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs.