Homologous steroid receptors assemble at identical promoter architectures with unique energetics of cooperativity.
Homologous steroid receptors assemble at identical promoter architectures with unique energetics of cooperativity.
复制标题
同源类固醇受体在相同的启动子结构上组装，具有独特的协同能量。
DOI：
10.1002/prot.24563
复制
发表时间：
2014
期刊：
影响因子：
2.9
通讯作者：
Bain,DavidL
中科院分区：
文献类型：
--
作者：
Connaghan,KeithD;Yang,Qin;Miura,MichaelT;Moody,AmieD;Bain,DavidL
类固醇受体包括配体激活的转录因子的同源家族。这些受体在体外结合基本相同的反应元件，但在体内调节不同的基因网络。这个悖论提出了如何实现转录特异性的问题，特别是如果多个受体群体竞争相同的位点。注意到受体-DNA能量学是驱动转录活性的主要力量，受体之间相互作用能量学的差异可能是受体特异性转录控制的基础。热力学解剖支持这一前提-在相同的启动子结构组装后，单个受体在合作和自缔合能量学方面表现出巨大的差异。更有趣的是，这些参数的分布方式反映了类固醇受体家族的进化分歧。例如，密切相关的孕酮和糖皮质激素受体（PR和GR）显示很少或没有自缔合，但具有很强的位点间协同性，而关系更远的雌激素受体（ER-α）则显示相反的行为。这些发现表明受体将基因组启动子架构视为亲和景观的集合;受体通过其独特的相互作用能量学从该景观中进行选择。为了验证这个想法，我们分析了上述三个受体的合作结合能量使用一系列的启动子。我们发现协同性不仅是受体特异性的，而且是高度启动子特异性的。因此，PR在具有紧密间隔和同相结合位点的启动子处显示出最大的协同性。GR协同保持在更大的距离，是更大的精力，并显示出显着不同的相位依赖性。最后，ER-α似乎不能与启动子结构无关的协同性，与其更远的同源性一致。Proteins 2014; 82：2078-2087.© 2014 Wiley Periodicals，Inc.
Steroid receptors comprise a homologous family of ligand‐activated transcription factors. The receptors bind largely identical response elementsin vitro, yet regulate distinct gene networksin vivo. This paradox raises the issue of how transcriptional specificity is achieved, particularly if multiple receptor populations are competing for identical sites. Noting that receptor‐DNA energetics are a primary force in driving transcriptional activity, differences in interaction energetics among the receptors might underlie receptor‐specific transcriptional control. Thermodynamic dissections support this premise—upon assembling at an identical promoter architecture, individual receptors exhibit vast differences in cooperative and self‐association energetics. More intriguingly, these parameters distribute in a way that mirrors the evolutionary divergence of the steroid receptor family. For example, the closely related progesterone and glucocorticoid receptors (PR and GR) display little or no self‐association but strong intersite cooperativity, whereas the more distantly related estrogen receptor (ER‐α) shows inverse behavior. These findings suggest that receptors view genomic promoter architectures as a collection of affinity landscapes; receptors select from this landscape via their unique interaction energetics. To test this idea, we analyzed the cooperative binding energetics of the above three receptors using an array of promoters. We find that cooperativity is not only receptor‐specific but also highly promoter‐specific. Thus PR shows maximal cooperativity at promoters with closely spaced and in phase binding sites. GR cooperativity is maintained over greater distances, is larger energetically, and shows markedly different phase dependency. Finally, ER‐α appears incapable of cooperativity regardless of promoter architecture, consistent with its more distant phylogeny. Proteins 2014; 82:2078–2087. © 2014 Wiley Periodicals, Inc.