Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner
Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner
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DOI：
10.1073/pnas.0501204102
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发表时间：
2005-07-05
影响因子：
11.1
通讯作者：
Xu, HE
中科院分区：
文献类型：
--
作者：
Li, Y;Choi, M;Xu, HE
孤儿核受体小异二聚体伴侣（SHP）和肝受体同源物1 （LRH-1）之间的功能相互作用，其中SHP与LRH-1结合并抑制其组成转录活性，对于调节参与胆固醇稳态的基因至关重要。在这里，我们报告了LRH-1/SHP相互作用的结构和生化分析。结合SHP的两个lxxll相关基序的LRIH-11配体结合域的晶体结构和建模研究表明，受体经历构象变化以适应SHP对接，并揭示了决定SHP结合效价和选择性的关键残基。通过诱变和结合研究的结合，我们证明了抑制LRH-1只需要第二个SHP LXXLL基序，并且该基序比密切相关的受体甾体生成因子1 （SF-1）更倾向于与LRH-1结合。结构比较表明，这种结合选择性是由核心LXXLL基序两侧的残基决定的。这些结果为理解SHP如何与LRH-1相互作用以调节胆固醇稳态建立了一个结构模型，并为如何实现核受体/共调节物选择性提供了新的见解。
The functional interaction between the orphan nuclear receptors small heterodimer partner (SHP) and liver receptor homolog 1 (LRH-1), where SHP binds to LRH-1 and represses its constitutive transcriptional activity, is crucial for regulating genes involved in cholesterol homeostasis. Here, we report structural and biochemical analyses of the LRH-1/SHP interaction. The crystal structure and modeling studies of the LRIH-11 ligand-binding domain bound to either of the two LXXLL-related motifs of SHP show that the receptor undergoes conformational changes to accommodate the SHP docking and reveal key residues that determine the potency and selectivity of SHP binding. Through a combination of mutagenesis and binding studies, we demonstrate that only the second SHP LXXLL motif is required for repressing LRH-1, and this motif displays a strong preference for binding to LRH-1 over the closely related receptor steroidogeneic factor 1 (SF-1). Structural comparisons indicate that this binding selectivity is determined by residues flanking the core LXXLL motifs. These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved.