A single nucleotide in an estrogen-related receptor α site can dictate mode of binding and peroxisome proliferator-activated receptor γ coactivator 1α activation of target promoters
A single nucleotide in an estrogen-related receptor α site can dictate mode of binding and peroxisome proliferator-activated receptor γ coactivator 1α activation of target promoters
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DOI：
10.1210/me.2005-0313
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Giguère, V
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文献类型：
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作者：
Barry, JB;Laganière, J;Giguère, V
孤儿核受体雌激素相关受体α（ERR α，NR 3B 1）是一种组成型活性转录因子，控制多个过程，最显着的线粒体功能。ERR α优先结合9个核苷酸的延伸半位点序列TNAAGGTCA，称为埃雷，作为单体或二聚体，尽管DNA结合的模式如何决定仍有待确定。在这里，我们使用的ERR α的延伸半位点序列和选择性DNA结合结构域突变体的变体，以调查的影响，埃雷序列特异性ERR α DNA结合模式，反式激活和相互作用的辅激活蛋白过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）。我们发现TNAAGGTCA序列N位的碱基决定了ERR α作为单体或二聚体的结合偏好。此外，我们证明了124位的苏氨酸残基（Thr（124））是ERR α DNA依赖性二聚化的决定因素。转染实验还表明，在天然ERR α靶启动子三叶因子1（TFF 1）的埃雷中的N位用胸苷取代胞嘧啶显著降低了ERR α/PGC-1 α复合物的转录应答。这些结果表明，ERR α结合位点中的单个核苷酸可以决定受体的特异性构型以及与辅激活因子PGC-1 α的有效相互作用。
The orphan nuclear receptor estrogen-related receptor alpha (ERR alpha, NR3B1) is a constitutively active transcription factor that controls multiple processes, most notably mitochondrial function. ERR alpha preferentially binds to a nine-nucleotide extended half-site sequence TNAAGGTCA, referred to as the ERRE, as either a monomer or a dimer, although how the mode of DNA binding is dictated remains to be determined. Here, we used variants of the extended half-site sequence and selective DNA binding domain mutants of ERR alpha to investigate the effects of ERRE sequence specificity on ERR alpha DNA binding mode, transactivation and interaction with the coactivator protein peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). We found that the base at the N position of the TNAAGGTCA sequence dictated ERR alpha binding preference as a monomer or dimer. In addition, we demonstrated that the threonine residue at position 124 (Thr(124)) was a determinant of ERR alpha DNAdependent dimerization. Transfection experiments also indicated that substituting a thymidine for a cytosine at the N position in the ERRE of the native ERR alpha target promoter trefoil factor 1 (TFF1) considerably diminished the transcriptional response of the ERR alpha/PGC-1 alpha complex. These results suggest that a single nucleotide in an ERR alpha binding site can determine specific configuration to the receptor and productive interaction with the coactivator PGC-1 alpha.