Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor
Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor
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DOI：
10.1128/mcb.00552-09
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发表时间：
2010-01-01
影响因子：
5.3
通讯作者：
Kumar, Raj
中科院分区：
文献类型：
--
作者：
Garza, Anna M. S.;Khan, Shagufta H.;Kumar, Raj
本质上无序 (ID) 区域在细胞信号蛋白中的比例要高得多，并且预计其磷酸化位点的频率比有序区域高得多，这表明其在调节能力中发挥着重要作用。在这项研究中，我们发现 AF1 是糖皮质激素受体 (GR) 的 ID 激活结构域，由于其被 p38 丝裂原激活蛋白激酶进行位点特异性磷酸化，因此采用功能性折叠构象，参与 GR 引发的细胞凋亡和基因诱导事件。此外，我们发现位点特异性磷酸化诱导的二级和三级结构形成特别促进 AF1 与关键共调节蛋白的相互作用，并随后促进其转录活性。这些数据证明了类固醇受体和其他类似转录因子的 ID 激活结构域在生理条件下可能采取功能活性构象的机制。
Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. In this study, we show that AF1, an ID activation domain of the glucocorticoid receptor (GR), adopts a functionally folded conformation due to its site-specific phosphorylation by p38 mitogen-activated protein kinase, which is involved in apoptotic and gene-inductive events initiated by the GR. Further, we show that site-specific phosphorylation-induced secondary and tertiary structure formation specifically facilitates AF1's interaction with critical coregulatory proteins and subsequently its transcriptional activity. These data demonstrate a mechanism through which ID activation domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.