Institut National de Santé et de Recherche Médicale U964/Centre National de Recherche Scientifique, Unité Mixte de Recherche 7104/Université de Strasbourg, 67404 Illkirch, France.
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):E588-94. doi: 10.1073/pnas.1118192109. Epub 2012 Feb 21.
Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 21 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.
甾体激素、维生素衍生物和代谢物的转录调控是由核受体（NRs）介导的，核受体在配体依赖性基因表达和人类健康中发挥重要作用。NRs 作为同源二聚体或异源二聚体发挥作用，并参与核心调节剂（共抑制剂、共激活剂）之间的组合、协调和顺序协调交换。结合功能二聚体的 DNA 结构将核心调节剂蛋白定位。我们之前证明，视黄酸（RAR-RXR）和维生素 D3 受体（VDR-RXR）异源二聚体仅不对称地招募一个共激活剂分子，没有结合第二个辅助因子的空间位阻。现在，我们研究同二聚体的问题，同二聚体中两个相同靶标的存在增强了结合模式的功能重要性。我们使用结构和生物物理方法以及 RAR 作为模型，能够剖析共激活剂募集到同二聚体的分子机制。我们的研究揭示了一种变构机制，其中共激活剂的结合促进了具有 21 个化学计量比的非对称 RAR 同二聚体的形成。配体构象和未结合受体的辅助因子结合位点通过二聚体界面受到影响。在雌激素受体（ER）中也观察到类似的控制机制，从而验证了已建立的功能性同二聚体的负协同作用模型。与其他 NRs 的已发表数据的相关性证实了这种调节途径的一般性。
