TBP binding-induced folding of the glucocorticoid receptor AF1 domain facilitates its interaction with steroid receptor coactivator-1.
TBP binding-induced folding of the glucocorticoid receptor AF1 domain facilitates its interaction with steroid receptor coactivator-1.
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DOI：
10.1371/journal.pone.0021939
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Khan SH;Ling J;Kumar R
糖皮质激素受体（GR）调节其靶基因转录的确切机制在很大程度上是未知的。这在一定程度上是由于缺乏关于GR的N-末端激活功能域AF1的结构和功能信息。与许多类固醇激素受体（SHR）一样，GR AF 1以内在无序（ID）构象或构象异构体的集合存在，这些构象异构体共同表现为非结构化的。已知GR AF1募集几种共调节蛋白，包括来自基础转录机制的那些，例如，TATA盒结合蛋白（TBP），形成多蛋白转录起始复合物的基础。然而，这一过程的确切机制尚不清楚。我们先前已经表明，GR AF1的条件性折叠是其与关键辅激活蛋白相互作用的关键。我们假设TBP与AF1的结合导致ID AF1结构域的结构重排，使其表面易于与其他共激活剂相互作用。为了验证这一假设，我们确定TBP结合诱导的GR AF1结构形成是否有助于其与类固醇受体辅激活因子-1（SRC-1）的相互作用，SRC-1是GR介导的转录活性的重要辅激活因子。我们的数据表明，TBP的化学计量结合诱导显着更高的螺旋含量在GR AF1的无规卷曲配置的费用。此外，我们发现，这种诱导的AF1构象促进其与SRC-1的相互作用，以及随后的AF1介导的转录活性。我们的研究结果可能提供了一个潜在的机制，通过GR和大其他SHR可能调节GR靶基因的表达。
The precise mechanism by which glucocorticoid receptor (GR) regulates the transcription of its target genes is largely unknown. This is, in part, due to the lack of structural and functional information about GR's N-terminal activation function domain, AF1. Like many steroid hormone receptors (SHRs), the GR AF1 exists in an intrinsically disordered (ID) conformation or an ensemble of conformers that collectively appears to be unstructured. The GR AF1 is known to recruit several coregulatory proteins, including those from the basal transcriptional machinery, e.g., TATA box binding protein (TBP) that forms the basis for the multiprotein transcription initiation complex. However, the precise mechanism of this process is unknown. We have earlier shown that conditional folding of the GR AF1 is the key for its interactions with critical coactivator proteins. We hypothesize that binding of TBP to AF1 results in the structural rearrangement of the ID AF1 domain such that its surfaces become easily accessible for interaction with other coactivators. To test this hypothesis, we determined whether TBP binding-induced structure formation in the GR AF1 facilitates its interaction with steroid receptor coactivator-1 (SRC-1), a critical coactivator that is important for GR-mediated transcriptional activity. Our data show that stoichiometric binding of TBP induces significantly higher helical content at the expense of random coil configuration in the GR AF1. Further, we found that this induced AF1 conformation facilitates its interaction with SRC-1, and subsequent AF1-mediated transcriptional activity. Our results may provide a potential mechanism through which GR and by large other SHRs may regulate the expression of the GR-target genes.
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