Structure and Dimerization Properties of the Aryl Hydrocarbon Receptor PAS-A Domain
Structure and Dimerization Properties of the Aryl Hydrocarbon Receptor PAS-A Domain
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DOI：
10.1128/mcb.00698-13
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发表时间：
2013-09
影响因子：
5.3
通讯作者：
Dalei Wu;N. Potluri;Youngchang Kim;F. Rastinejad
中科院分区：
文献类型：
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作者：
Dalei Wu;N. Potluri;Youngchang Kim;F. Rastinejad
芳烃受体（aryl hydrocarbon receptor，AHR）是一种配体依赖性转录因子，它与外源性物质结合，通过调节解毒和代谢所需的基因程序的表达来应答。AHR及其异源二聚化伴侣芳烃受体核转运子（ARNT）属于碱性螺旋-环-螺旋（bHLH）-PER-ARNT-SIM（PAS）转录因子家族。在这里，我们报告了小鼠AHR PAS-A结构域的2.55-nm分辨率晶体结构，它代表了第一个AHR衍生的蛋白质结构。AHR PAS-A结构域在晶体和溶液中形成螺旋交换的同源二聚体。通过对所有界面残基的详细突变分析，我们确定了几个对AHR二聚化和功能很重要的疏水残基。我们对AHR PAS-A二聚化的晶体学可视化使我们提出了一种由生物化学和细胞数据支持的ARNT异源二聚化模式。我们的研究还强调了其他哺乳动物bHLH-PAS蛋白的残基，可能参与其同源或异源二聚化。
ABSTRACT The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that binds to xenobiotics and responds by regulating the expression of gene programs required for detoxification and metabolism. AHR and its heterodimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT) belong to the basic helix-loop-helix (bHLH)–PER-ARNT-SIM (PAS) family of transcription factors. Here we report the 2.55-Å-resolution crystal structure of the mouse AHR PAS-A domain, which represents the first AHR-derived protein structure. The AHR PAS-A domain forms a helix-swapped homodimer in the crystal and also in solution. Through a detailed mutational analysis of all interface residues, we identified several hydrophobic residues that are important for AHR dimerization and function. Our crystallographic visualization of AHR PAS-A dimerization leads us to propose a mode of heterodimerization with ARNT that is supported by both biochemical and cell-based data. Our studies also highlight the residues of other mammalian bHLH-PAS proteins that are likely involved in their homo- or heterodimerization.