Auto-silencing by the retinoid X receptor
Auto-silencing by the retinoid X receptor
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DOI：
10.1006/jmbi.1998.2168
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发表时间：
1998-11-20
影响因子：
5.6
通讯作者：
Noy, N
中科院分区：
文献类型：
--
作者：
Kersten, S;Dong, D;Noy, N
基因转录通常由小配体调节，使细胞能够对外部和代谢刺激做出反应。特别感兴趣的是疏水激素调节核受体超家族蛋白质转录活性的机制。先前显示，在不存在配体的情况下，类维生素A X受体（RXR α）形成具有高亲和力和显著正协同性的四聚体，使得四聚体成为受体的主要种类达特浓度低至60-70 nM。进一步显示，虽然RXR四聚体在不存在配体的情况下非常稳定，但配体结合诱导它们快速解离成较小的物质、二聚体和单体。在这里，通过检查显示异常寡聚化行为的RXR的两个点突变体来研究RXR的自缔合特性的功能后果。发现一种突变体mRXR α-R321 A形成具有野生型亲和力的四聚体，但这些四聚体在配体结合时未能解离。发现该突变体与核受体活化剂p/CIP结合并响应RXR配体9-顺式视黄酸激活转录的能力受损。另一个突变体mRXR α-F318 A，自结合成具有野生型亲和力的二聚体，但不能形成四聚体。该突变体即使在没有配体的情况下也显示出显著的转录活性。我们先前提出，基于体外研究，RXR通过将自身隔离成四聚体而充当自动沉默物，并且配体在激活该受体中的重要作用是从转录非活性四聚体池释放活性物质，二聚体和单体。本文报道的观察结果提供了支持该模型的细胞内证据，并表明配体诱导的四聚体解离是RXR信号传导的第一步。(C)北京：科学出版社.
Gene transcription is often regulated by small ligands, enabling cells to respond to external and metabolic stimuli. Of particular interest are the mechanisms by which hydrophobic hormones modulate the transcriptional activities of proteins of the nuclear receptor superfamily. It was previously shown that, in the absence of ligand, the retinoid X receptor (RXR alpha) forms tetramers with a high affinity and a pronounced positive co-operativity such that tetramers become the receptor's predominant species tat concentrations as low as 60-70 nM. It was shown further that while RXR tetramers are remarkably stable in the absence of ligand, ligand-binding induces their rapid dissociation into smaller species, dimers and monomers. Here, the functional consequences of the self-association properties of RXR were studied by examining two point mutants of RXR that displayed aberrant oligomerization behaviors. One mutant, mRXR alpha-R321A, was found to form tetramers with a wild-type affinity, but these tetramers failed to dissociate upon ligand-binding. This mutant was found to be impaired in its ability to associate with the nuclear receptor to-activator p/CIP and to activate transcription in response to the RXR Ligand 9-cis-retinoic acid. The other mutant, mRXR alpha-F318A, self-associated into dimers with a wild-type affinity, but was unable to form tetramers. This mutant displayed substantial transcriptional activity even in the absence of ligand. We previously proposed, based on in vitro studies that RXR acts as an auto-silencer by sequestering itself into tetramers, and that an important role for the ligand in activating this receptor is to release active species, dimers and monomers, from the transcriptionally inactive tetrameric pool. The observations reported here provide in-cell evidence in support of this model and indicate that Ligand induced dissociation of tetramers is the first step in signalling by RXR. (C) 1998 Academic Press.