Structure/activity relationships for GMEB-2: The second member of the glucocorticoid modulatory element-binding complex
Structure/activity relationships for GMEB-2: The second member of the glucocorticoid modulatory element-binding complex
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DOI：
10.1021/bi035311b
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发表时间：
2004-01-13
期刊：
影响因子：
2.9
通讯作者：
Simons, S
中科院分区：
文献类型：
--
作者：
Chen, J;He, YZ;Simons, S
糖皮质激素受体激动剂复合体的量效曲线位置和GR拮抗剂复合体的部分激动剂活性可以被两种蛋白质(GMEB-1和GMEB-2)调节，它们以寡聚体的形式结合到被称为糖皮质激素调节元件或GME的DNA元件上。当该元件位于控制报告基因表达的糖皮质激素反应元件的上游时，该元件是活性的。在这里，我们报告了GMEB-2的结构/活性关系，并将它们与我们之前对GMEB-1的发现进行了比较。GMEB-2的大部分活性，如同源和异源齐聚，与GR和CBP的结合，DNA结合，以及上述GR转录特性的调节，都需要蛋白质的大区域。只有内在的反式激活活性才能定位在蛋白质的一小部分区域。这些研究阐明了GMEB-2的作用机制，并进一步支持了我们先前的结论，即调节GR复合体的剂量-反应曲线位置和部分激动剂活性的因素的能力与对GR诱导的基因表达总水平的影响无关。这些研究还确定了GMEB-2的区域，具有对几种活动至关重要的尚未确定的特性。最后，由于GMEB-2和GMEB-1的结构域组织非常相似，我们得出结论，活性的定量差异来自于氨基酸序列的变化，而不是更具全球性的蛋白质结构特征。
The position of the dose-response curve of agonist complexes of glucocorticoid receptors (GRs), and the partial agonist activity of GR-antagonist complexes, can be modulated by two proteins (GMEB-1 and -2), which bind as oligomers to a DNA element that is called a glucocorticoid modulatory element, or GME. This element is active when located upstream of the glucocorticoid response element that controls the expression of a reporter gene. Here, we report the structure/activity relationships of GMEB-2 and compare them to our previous findings for GMEB-1. Most of the activities of GMEB-2, such as homo- and heterooligomerization, binding to GR and to CBP, DNA binding, and modulation of the above GR transcriptional properties, require large regions of the protein. Only the intrinsic transactivation activity could be localized to a small region of the protein. These studies shed light on the mechanism of action of GMEB-2 and further support our previous conclusion that the ability of factors to modulate the position of the dose-response curve, and the partial agonist activity, of GR complexes is unrelated to effects on the total levels of GR-induced gene expression. These studies also identify regions of GMEB-2 possessing yet unidentified properties that are critical for several activities. Finally, as the domain organization of GMEB-2 and -1 is extremely similar, we conclude that the quantitative differences in activities derive from variations in amino acid sequence rather than more global features of protein structure.