Interactions that determine the assembly of a retinoid X receptor/corepressor complex
Interactions that determine the assembly of a retinoid X receptor/corepressor complex
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DOI：
10.1073/pnas.092043399
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发表时间：
2002-04-30
影响因子：
11.1
通讯作者：
Chen, JD
中科院分区：
文献类型：
--
作者：
Ghosh, JC;Yang, XF;Chen, JD
类视黄醇X受体（RXR）是多种信号通路的关键调节因子，它既可以与自身形成同二聚体，也可以与I类核受体成员形成异二聚体。含有rxr的晚餐通过向目标启动子招募共激活子或辅抑制子来调节转录。共激活剂与RXR的结合是通过部分由c端激活螺旋（AF-2）形成的疏水口袋介导的。然而，我们对共阻遏子与RXR的相互作用及其在转录抑制中的作用知之甚少。本研究表明，RXR的抑制活性与其与类视黄醇和甲状腺激素受体（SMRT）的协同抑制因子沉默介质的结合有关。这种内在的抑制活性被AF-2螺旋所掩盖，AF-2螺旋可以拮抗SMRT结合。AF-2螺旋抑制SMRT结合需要特定的氨基酸序列和螺旋结构。此外，RXR上的smrt结合位点独立于螺旋11，但与共激活子结合袋重叠。基于这些结果，我们提出了一个结构模型来帮助理解RXR募集辅抑制因子的分子机制。
The retinoid X receptor (RXR) is a key regulator in multiple signaling pathways because it can form either a homodimer with itself or a heterodimer with members of the class I nuclear receptors. The RXR-containing dinners regulate transcription by recruiting coactivators or corepressors to the target promoters. The binding of coactivators to RXR is mediated through a hydrophobic pocket formed in part by the C-terminal activation helix (AF-2). However, little is known about interactions of corepressors with RXR and its roles in transcriptional repression. Here we show that the repression activity of RXR correlates with its binding to the corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT). This intrinsic repression activity is masked by the AF-2 helix, which antagonizes SMRT binding. Inhibition of SMRT binding by the AF-2 helix requires specific amino acid sequences and the helical structure. Furthermore, the SMRT-binding site on RXR is independent of helix 11 but overlaps with the coactivator-binding pocket. On the basis of these results, we propose a structural model to help understand the molecular mechanism of corepressor recruitment by RXR.