Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators
Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators
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DOI：
10.1038/415549a
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发表时间：
2002-01-31
期刊：
影响因子：
64.8
通讯作者：
Wright, PE
中科院分区：
文献类型：
--
作者：
Demarest, SJ;Martinez-Yamout, M;Wright, PE
核激素受体是配体激活的转录因子，调节发育、生殖和稳态所必需的基因表达（1）。激素反应通过募集p160受体共激活因子和一般转录共激活因子CBP/p300介导，其协同作用以激活转录（2）。这些辅激活因子表现出内在的组蛋白乙酰转移酶活性，在染色质重塑中发挥作用，并促进RNA聚合酶II和基础转录机制的募集（3）。p160共激活因子的活性依赖于CBP。这两种辅激活因子对于适当的细胞周期控制、分化和凋亡是必需的，并且与癌症和其他疾病有关（4-7）。为了阐明组装多蛋白活化复合物的分子基础，我们对CBP与甲状腺激素和类维生素A受体活化剂的相互作用结构域进行了结构和热力学分析（8）。在这里，我们表明，虽然孤立的结构域本质上是无序的，他们联合收割机结合具有高亲和力，形成一个合作折叠的螺旋异二聚体。我们的研究揭示了一种独特的机制，称为“协同折叠”，通过这种机制，p160共激活因子招募CBP/p300，以允许将激素信号传递给转录机制。
Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of genes that are essential for development, reproduction and homeostasis(1). The hormone response is mediated through recruitment of p160 receptor coactivators and the general transcriptional coactivator CBP/p300, which function synergistically to activate transcription(2). These coactivators exhibit intrinsic histone acetyltransferase activity, function in the remodelling of chromatin, and facilitate the recruitment of RNA polymerase II and the basal transcription machinery(3). The activities of the p160 coactivators are dependent on CBP. Both coactivators are essential for proper cell-cycle control, differentiation and apoptosis, and are implicated in cancer and other diseases(4-7). To elucidate the molecular basis of assembling the multiprotein activation complex, we undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors(8). Here we show that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. Our study uncovers a unique mechanism, called 'synergistic folding', through which p160 coactivators recruit CBP/p300 to allow transmission of the hormonal signal to the transcriptional machinery.