Co-regulator recruitment and the mechanism of retinoic acid receptor synergy
Co-regulator recruitment and the mechanism of retinoic acid receptor synergy
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DOI：
10.1038/415187a
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发表时间：
2002-01-10
期刊：
影响因子：
64.8
通讯作者：
Gronemeyer, H
中科院分区：
文献类型：
--
作者：
Germain, P;Iyer, J;Gronemeyer, H
晶体结构和共调节相互作用的研究已经导致了核受体（NR）作用的初始步骤的一般机制观点。激动剂诱导的配体结合结构域（holo-LBD）的构象转换导致共激活因子复合物的形成，并使与无配体（apo）LBD 1 -3结合的共阻遏因子复合物不稳定。然而，维甲酸-X受体（RXR）在异源二聚体中“从属”的分子基础，避免信号通路混杂的重要机制，仍然难以捉摸。与其异二聚体配偶体相反，RXR不能自主诱导同源激动剂结合时的转录（4-7）。在这里，我们表明，RXR可以结合配体和招募辅激活剂作为异源二聚体与apo-retinoic-acid受体（apo-RAR）。然而，在通常的细胞环境中，辅阻遏物不解离，并且它们阻止辅激活物进入，因为辅调节物结合是相互排斥的。因此，RXR从属性可以在弱结合辅阻遏物的异二聚体中或在具有高辅激活物含量的细胞中克服。我们鉴定了两种类型的RAR拮抗剂，其差异调节共调节因子相互作用，并且我们证明RAR配体和RXR激动剂之间的协同作用（6，8）是由于单个p160与异源二聚体的相互作用效率增加，共激活因子上需要两个完整的受体结合表面。
Crystal structure and co-regulator interaction studies have led to a general mechanistic view of the initial steps of nuclear receptor (NR) action. Agonist-induced transconformation of the ligand-binding domain (holo-LBD) leads to the formation of co-activator complexes, and destabilizes the co-repressor complexes bound to the ligand-free (apo) LBD1-3. However, the molecular basis of retinoid-X receptor (RXR) 'subordination' in heterodimers, an essential mechanism to avoid signalling pathway promiscuity, has remained elusive. RXR, in contrast to its heterodimer partner, cannot autonomously induce transcription on binding of cognate agonists(4-7). Here we show that RXR can bind ligand and recruit co-activators as a heterodimer with apo-retinoic-acid receptor (apo-RAR). However, in the usual cellular environment co-repressors do not dissociate and they prohibit co-activator access because co-regulator binding is mutually exclusive. Accordingly, RXR subordination can be overcome in heterodimers that bind co-repressor weakly or in cells with a high co-activator content. We identify two types of RAR antagonists that differentially modulate co-regulator interaction, and we demonstrate that synergy between RAR ligands and RXR agonists(6,8) results from increased interaction efficiency of a single p160 with the heterodimer, requiring two intact receptor-binding surfaces on the co-activator.