Human ADA3 regulates RARalpha transcriptional activity through direct contact between LxxLL motifs and the receptor coactivator pocket.
Human ADA3 regulates RARalpha transcriptional activity through direct contact between LxxLL motifs and the receptor coactivator pocket.
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DOI：
10.1093/nar/gkq269
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发表时间：
2010-09
影响因子：
14.9
通讯作者：
Chen JD
中科院分区：
文献类型：
--
作者：
Li CW;Ai N;Dinh GK;Welsh WJ;Chen JD
激活-3（ADA 3）的交替/缺陷是人p300/CBP相关因子（PCAF）和酵母Spt-Ada-Gcn 5-乙酰转移酶（佐贺）组蛋白乙酰转移酶复合物的重要组成部分。这些复合物通过与转录因子的结合和局部染色质结构的修饰促进靶基因的反式激活。已知酵母细胞中核受体（NR）介导的反式激活需要酵母ADA 3;然而，哺乳动物ADA 3在NR信号传导中的作用仍然难以捉摸。在这项研究中，我们研究了人（h）ADA 3如何调节视黄酸受体（RAR）α介导的反式激活。我们发现，hADA 3直接相互作用与RARα在一个依赖的方式，这种相互作用有助于RARα的反式激活。有趣的是，这种相互作用涉及hADA 3中的经典LxxLL基序，如通过功能突变的“丧失”和“获得”以及受体的功能性辅激活因子口袋所证明的。此外，我们还发现hADA 3与RARα靶基因启动子以依赖性的方式结合，并且ADA 3敲低会损害RARβ2的表达。此外，还建立了一个结构模型来说明ADA 3/RARα复合物中的相互作用网络。这些结果表明，hADA 3是RARα的真正转录辅激活因子，通过NR盒和受体辅激活因子口袋之间的直接接触的保守机制起作用。
The alternation/deficiency in activation-3 (ADA3) is an essential component of the human p300/CBP-associated factor (PCAF) and yeast Spt-Ada-Gcn5-acetyltransferase (SAGA) histone acetyltransferase complexes. These complexes facilitate transactivation of target genes by association with transcription factors and modification of local chromatin structure. It is known that the yeast ADA3 is required for nuclear receptor (NR)-mediated transactivation in yeast cells; however, the role of mammalian ADA3 in NR signaling remains elusive. In this study, we have investigated how the human (h) ADA3 regulates retinoic acid receptor (RAR) α-mediated transactivation. We show that hADA3 interacts directly with RARα in a hormone-dependent manner and this interaction contributes to RARα transactivation. Intriguingly, this interaction involves classical LxxLL motifs in hADA3, as demonstrated by both ‘loss’ and ‘gain’ of function mutations, as well as a functional coactivator pocket of the receptor. Additionally, we show that hADA3 associates with RARα target gene promoter in a hormone-dependent manner and ADA3 knockdown impairs RARβ2 expression. Furthermore, a structural model was established to illustrate an interaction network within the ADA3/RARα complex. These results suggest that hADA3 is a bona fide transcriptional coactivator for RARα, acting through a conserved mechanism involving direct contacts between NR boxes and the receptor’s co-activator pocket.
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影响因子：
64.8
作者：
HORLEIN, AJ;NAAR, AM;ROSENFELD, MG
通讯作者：
ROSENFELD, MG
DOI：
10.1073/pnas.092043399
发表时间：
2002-04-30
影响因子：
11.1
作者：
Ghosh, JC;Yang, XF;Chen, JD
通讯作者：
Chen, JD
影响因子：
64.8
作者：
CHEN, JD;EVANS, RM
通讯作者：
EVANS, RM
影响因子：
5.3
作者：
Kumar, A;Zhao, YT;Band, V
通讯作者：
Band, V
影响因子：
64.8
作者：
Nolte, RT;Wisely, GB;Milburn, MV
通讯作者：
Milburn, MV