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首页> 外文期刊>Biochemistry >Binding of the ER alpha Nuclear Receptor to DNA Is Coupled to Proton Uptake
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Binding of the ER alpha Nuclear Receptor to DNA Is Coupled to Proton Uptake

机译：ERα核受体与DNA的结合偶联与质子摄取

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摘要

Nuclear receptors act as ligand-modulated transcription factors and orchestrate a plethora of cellular functions central to health and disease. Although studied for more than half a century, many mysteries surrounding the mechanism of action of nuclear receptors remain unresolved. Herein, using isothermal titration calorimetry (ITC) in conjunction with macromolecular modeling (MM), we provide evidence that the binding of the ER alpha nuclear receptor to its DNA response element is coupled to proton uptake by two ionizable residues, H196 and E203, located at the protein DNA interface. Alanine substitution of these ionizable residues decouples protonation and hampers the binding of ER alpha to DNA by nearly 1 order of magnitude. Remarkably, H196 and E203 are predominantly conserved across similar to 50 members of the nuclear receptor family, implying that proton-coupled equilibrium may serve as a key regulatory switch for modulating protein DNA interactions central to nuclear receptor function and regulation. Taken together, our findings unearth an unexpected but critical step in the molecular action of nuclear receptors and suggest that they may act as sensors of intracellular pH.
机译：核受体充当配体调节的转录因子，并协调血液血管功能核心健康和疾病。虽然学习了半个多世纪以上，但周围的许多神秘围绕核受体的作用机制仍未解决。在此，使用等温滴定热量法（ITC）与大分子建模（MM）结合，我们提供了ERα核受体与其DNA响应元件的结合与定位的两个可电离残留物，H196和E203的质子吸收偶联在蛋白质DNA界面。这些可电离残留物的丙氨酸取代使质子化与ERα与DNA的结合达到近1个级。值得注意的是，H196和E203主要被保守到与核受体家族的50个成员相似，这意味着质子偶联的平衡可以用作调节蛋白DNA相互作用与核受体功能和调节的关键调节开关。我们的研究结果集中在核受体的分子作用中出现了意外但重要的一步，并表明它们可以作为细胞内pH的传感器。

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  • 来源
    《Biochemistry》 |2010年第29期|共11页
  • 作者

    Deegan BJ; Seldeen KL; McDonald CB; Bhat V; Farooq A;

  • 作者单位

    Department of Biochemistry and Molecular Biology and USylvester Braman Family Breast Cancer Institute Leonard Miller School of Medicine University of Miami Miami Florida 33136;

    Department of Biochemistry and Molecular Biology and USylvester Braman Family Breast Cancer Institute Leonard Miller School of Medicine University of Miami Miami Florida 33136;

    Department of Biochemistry and Molecular Biology and USylvester Braman Family Breast Cancer Institute Leonard Miller School of Medicine University of Miami Miami Florida 33136;

    Department of Biochemistry and Molecular Biology and USylvester Braman Family Breast Cancer Institute Leonard Miller School of Medicine University of Miami Miami Florida 33136;

    Univ Miami Dept Biochem &

    Mol Biol Miami FL 33136 USA.;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    ENTHALPY-ENTROPY COMPENSATION; ACTIVATED PROTEIN-KINASE; HEAT-CAPACITY CHANGES; ESTROGEN-RECEPTOR; INTRACELLULAR PH; HORMONE-RECEPTORS; RESPONSE ELEMENTS; STEROID-RECEPTORS; EVOLUTION; PHOSPHORYLATION;

    机译：焓 - 熵补偿;活化蛋白 - 激酶;热容量变化;雌激素受体;细胞内pH;激素受体;反应元素;类固醇受体;进化;磷酸化;磷酸化;磷酸化;

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