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首页> 外文期刊>Molecular and Cellular Biology >Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha.
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Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha.

机译：9-顺式视黄酸的不同结合决定簇位于视黄酸受体α的AF-2内。

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摘要

Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways.
机译：类维生素A通过与两个家族的核受体（维甲酸受体（RAR）和类维生素X受体（RXR））相互作用来发挥其生理作用，它们通过在DNA上形成转录活性异二聚体RAR / RXR或同二聚体RXR / RXR复合物来调节基因表达。类维生素A受体的活性存在于多个区域，包括DNA和配体结合域，二聚化界面以及不依赖配体的（AF-1）和依赖配体的（AF-2）反式激活功能。尽管9-顺式视黄酸（RA）是RXR的同源配体，但9-顺式RA和全反式RA（t-RA）都以与RAR的高亲和力竞争结合。后一个观察结果向我们表明，两种异构体可能与一个共同的结合位点相互作用。在这里我们报告说，RAR alpha具有两个不同但重叠的9-顺式RA和t-RA结合位点。将人RARα截短至419个氨基酸可产生以高亲和力结合t-RA和9-顺式RA的受体，但截短至氨基酸404则产生仅以高亲和力结合t-RA的突变受体。值得注意的是，该区域还为AF-2定义了一个C端边界，因为将氨基酸405添加到419中可将受体介导的基因活性恢复到缺少该区域的截短的人类RARα。有趣的是，类视黄醇立体异构体与RAR内独特位点的结合可能与AF-2一起起作用，从而引起类视黄醇响应基因途径的差异激活。

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