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首页> 外文期刊>Molecular and Cellular Biology >Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors α and β
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Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors α and β

机译：使用组合肽库解剖LXXLL核受体-共激活因子相互作用的母题：雌激素受体α和β的肽拮抗剂的发现。

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Recruitment of transcriptional coactivators following ligand activation is a critical step in nuclear receptor-mediated target gene expression. Upon binding an agonist, the receptor undergoes a conformational change which facilitates the formation of a specific coactivator binding pocket within the carboxyl terminus of the receptor. This permits the α-helical LXXLL motif within some coactivators to interact with the nuclear receptors. Until recently, the LXXLL motif was thought to function solely as a docking module; however, it now appears that sequences flanking the core motif may play a role in determining receptor selectivity. To address this issue, we used a combinatorial phage display approach to evaluate the role of flanking sequences in influencing these interactions. We sampled more than 108 variations of the core LXXLL motif with estradiol-activated estrogen receptor alpha (ERα) as a target and found three different classes of peptides. All of these peptides interacted with ERα in an agonist-dependent manner and disrupted ERα-mediated transcriptional activity when introduced into target cells. Using a series of ERα-mutants, we found that these three classes of peptides showed different interaction patterns from each other, suggesting that not all LXXLL motifs are the same and that receptor binding selectivity can be achieved by altering sequences flanking the LXXLL core motif. Most notable in this regard was the discovery of a peptide which, when overexpressed in cells, selectively disrupted ERβ- but not ERα-mediated reporter gene expression. This novel ERβ-specific antagonist may be useful in identifying and characterizing the ERβ-regulated process in estradiol-responsive cells. In conclusion, using a combinatorial approach to define cofactor-receptor interactions, we have clearly been able to demonstrate that not all LXXLL motifs are functionally equivalent, a finding which suggests that it may be possible to target receptor-LXXLL interactions to develop receptor-specific antagonists.
机译：配体激活后转录共激活子的募集是核受体介导的靶基因表达中的关键步骤。结合激动剂后，受体发生构象变化，这有利于在受体的羧基末端内形成特定的共激活因子结合口袋。这使得某些共激活剂中的α-螺旋LXXLL基序与核受体相互作用。直到最近，LXXLL母题还被认为仅用作对接模块。然而，现在看来，位于核心基序侧翼的序列可能在确定受体选择性中起作用。为了解决此问题，我们使用了组合噬菌体展示方法来评估侧翼序列在影响这些相互作用中的作用。我们以雌二醇激活的雌激素受体α（ERα）为靶标，对核心LXXLL核心的10 8 变异进行了采样，发现了三种不同类别的肽。当引入靶细胞时，所有这些肽都以激动剂依赖性方式与ERα相互作用并破坏ERα介导的转录活性。使用一系列ERα突变体，我们发现这三类肽彼此显示出不同的相互作用模式，这表明并非所有的LXXLL基序都相同，并且可以通过改变LXXLL核心基序两侧的序列来实现受体结合选择性。在这方面，最值得注意的是发现了一种肽，该肽在细胞中过度表达后，选择性地破坏了ERβ-而不是ERα-介导的报告基因表达。这种新颖的ERβ特异性拮抗剂可用于鉴定和表征雌二醇反应性细胞中ERβ调控的过程。总之，使用组合方法定义辅因子-受体相互作用，我们已经清楚地证明并非所有的LXXLL基序在功能上都是等同的，这一发现表明，有可能靶向受体-LXXLL相互作用来发展受体特异性拮抗剂。

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