Willy P J, Mangelsdorf D J
Howard Hughes Medical Institute and the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9050, USA.
Genes Dev. 1997 Feb 1;11(3):289-98. doi: 10.1101/gad.11.3.289.
LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR-LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans-activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.
肝X受体（LXR）是一种孤儿核受体，它通过与一种名为LXRE的特定反应元件相互作用，赋予视黄酸X受体（RXR）视黄酸反应性。为了理解这种反应的机制，确定了对RXR-LXR复合物激活至关重要的三个特征。首先，RXR-LXR异二聚体在DNA上的方向表明，作为配体结合伙伴，RXR占据反应元件的5'半位点。其次，确定了LXRE序列特异性，以识别异二聚体视黄酸激活所需的残基。值得注意的是，LXRE半位点核苷酸序列的细微变化（这些变化不会显著改变RXR-LXR异二聚体与DNA的结合）对复合物被配体激活的能力有显著影响。最后，我们表征了每个受体激活域对RXR-LXR异二聚体反式激活潜能的贡献。令人惊讶的是，我们的结果表明，视黄酸激活仅需要LXR的激活域。综上所述，这些结果证明了异二聚体伙伴之间存在一种独特的通讯形式，其中一个受体（LXR）的激活潜能通过配体与其伙伴（RXR）的结合得以实现。此外，我们得出结论，RXR配体激活潜能并非仅由其在DNA上的位置决定，而是受其他因素影响，如受体伙伴和反应元件序列。
