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首页> 外文期刊>Molecular and Cellular Biology >Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors β and γ Interferes with Corepressor Recruitment and Prevents Transcriptional Repression
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Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors β and γ Interferes with Corepressor Recruitment and Prevents Transcriptional Repression

机译：同型受限的corepressor招聘：维甲酸受体β和γ的组成性封闭螺旋12构象干扰corepressor招聘并防止转录抑制。

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Retinoic acid receptors (RARs) are ligand-regulated transcription factors that play multiple roles in vertebrate development and differentiation. RARs as a class are capable of both repressing and activating target gene expression. Transcriptional repression is mediated through the recruitment of corepressor proteins such as SMRT. Notably, vertebrates encode three major forms of RARs, α, β, and γ, and these distinct RAR isotypes differ in the ability to recruit a corepressor. RARα strongly interacts with SMRT and can repress target gene transcription, whereas RARβ and -γ interact with SMRT only weakly and fail to repress. We report here the use of a genetic suppressor approach, based on a yeast two-hybrid interaction assay using Saccharomyces cerevisiae, for the isolation of RARβ mutants that have gained the RARα-like corepressor phenotype, i.e., a strong interaction with SMRT and the ability to repress gene expression in vertebrate cells. Analysis of these gain-of-function mutants indicates that the different corepressor interaction properties of RARα, -β and -γ are determined by a gating mechanism through which amino acid differences in the helix 3 region of these receptors influence the position of the receptor C-terminal helix 12 domain. As a consequence, the RARβ and RARγ receptors appear to adopt a constitutively closed helix 12 conformation in the absence of hormone that may approximate the conformation of RARα when bound to hormone agonist. This closed helix 12 conformation in RARβ and RARγ blocks corepressor binding, prevents repression, and permits significant levels of target gene activation even in the absence of hormone. We refer to this phenomenon as a “gate-latch” model of corepressor regulation.
机译：维甲酸受体（RARs）是配体调节的转录因子，在脊椎动物的发育和分化中起多种作用。作为类的RAR能够抑制和激活靶基因表达。转录抑制是通过募集诸如SMRT的共抑制蛋白来介导的。值得注意的是，脊椎动物编码RAR的三种主要形式，即α，β和γ，并且这些不同的RAR同种型在募集抗抑郁药的能力方面也有所不同。 RARα与SMRT强烈相互作用，并且可以抑制靶基因的转录，而RARβ和-γ与SMRT的相互作用很小，不能抑制。我们在此报告了一种遗传抑制方法的使用，该方法基于使用酿酒酵母（Saccharomyces cerevisiae）的酵母两杂交相互作用测定法，用于分离已获得RARα-like核心表达表型的RARβ突变体，即与SMRT的强相互作用以及抑制脊椎动物细胞中基因表达的能力。对这些功能获得突变体的分析表明，RARα，-β和-γ的不同的corepressor相互作用特性是由门控机制决定的，通过门控机制，这些受体的螺旋3区中的氨基酸差异会影响受体C的位置。 -末端螺旋12结构域。结果，在不存在激素的情况下，RARβ和RARγ受体似乎采用组成性封闭的螺旋12构象，当与激素激动剂结合时，其可能近似于RARα的构象。 RARβ和RARγ中这种闭合的螺旋12构象可阻断核心加压因子的结合，防止阻遏，即使在没有激素的情况下也可以显着水平激活靶基因。我们将这种现象称为“ corepressor调节”的“门锁”模型。

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