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首页> 外文期刊>Molecular and Cellular Biology >A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity
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A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity

机译：本构Androstane受体的结构模型定义介导配体独立活动的新型相互作用。

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Unlike classical nuclear receptors that require ligand for transcriptional activity, the constitutive androstane receptor (CAR) is active in the absence of ligand. To determine the molecular contacts that underlie this constitutive activity, we created a three-dimensional model of CAR and verified critical structural features by mutational analysis. We found that the same motifs that facilitate ligand-dependent activity in classical receptors also mediated constitutive activity in CAR. This raises a critical question: how are these motifs maintained in an active conformation in unliganded CAR? The model identified several novel interactions that account for this activity. First, CAR possesses a short loop between helix 11 and the transactivation domain (helix 12), as well as a short carboxy-terminal helix. Together, these features favor ligand-independent docking of the transactivation domain in a position that is characteristic of ligand-activated receptors. Second, this active conformation is further stabilized by a charge-charge interaction that anchors the carboxy-terminal activation domain to helix 4. Mutational analysis of these interactions provides direct experimental support for this model. We also show that ligand-mediated repression of constitutive activity reflects both a displacement of coactivator and a recruitment of corepressor. Our data demonstrate that CAR utilizes the same conserved structural motifs and coregulator proteins as originally defined for classical nuclear receptors. Despite these remarkable similarities, our model demonstrates how a few critical changes in CAR can dramatically reverse the transcriptional activity of this protein.
机译：与需要配体具有转录活性的经典核受体不同，组成型雄甾烷受体（CAR）在没有配体的情况下具有活性。为了确定构成此构型活动基础的分子接触，我们创建了CAR的三维模型，并通过突变分析验证了关键的结构特征。我们发现促进经典受体中配体依赖性活性的相同基序也介导了CAR中的组成型活性。这就提出了一个关键问题：在未配体的CAR中，这些基序如何保持在活性构象中？该模型确定了几种新颖的相互作用来解释这一活动。首先，CAR在螺旋11和反式激活结构域（螺旋12）之间具有一个短环，以及一个短的羧基末端螺旋。总之，这些特征有利于反式激活域的配体非依赖性对接，该位置是配体激活受体的特征。其次，通过将羧基末端活化域锚定到螺旋4上的电荷相互作用进一步稳定了这种活性构象。这些相互作用的突变分析为该模型提供了直接的实验支持。我们还表明，配体介导的组成性抑制作用反映了共激活剂的置换和corepressor的募集。我们的数据表明，CAR利用与最初为经典核受体定义的相同的保守结构基序和共调节蛋白。尽管有这些惊人的相似性，我们的模型还是证明了CAR的一些关键变化如何能够显着逆转该蛋白的转录活性。

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