Dissection of androgen receptor-promoter interactions: steroid receptors partition their interaction energetics in parallel with their phylogenetic divergence.
Dissection of androgen receptor-promoter interactions: steroid receptors partition their interaction energetics in parallel with their phylogenetic divergence.
复制标题
雄激素受体-启动子相互作用的剖析：类固醇受体与其系统发育分歧平行地划分其相互作用能量。
DOI：
10.1016/j.jmb.2013.07.033
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发表时间：
2013
影响因子：
5.6
通讯作者：
Bain,DavidL
中科院分区：
文献类型：
--
作者：
DeAngelis,RolandoW;Yang,Qin;Miura,MichaelT;Bain,DavidL
类固醇受体包括一个同源家族的配体激活的转录因子。其成员包括雄激素受体（AR）、雌激素受体（ER）、糖皮质激素受体（GR）、矿皮质激素受体（MR）和孕激素受体（PR）。系统发育研究表明，AR、GR、MR和PR亲缘关系最为密切，属于3C亚群。ER的亲缘关系较远，属于3A亚群。为了确定受体产生其独特转录反应的定量基础，我们系统地剖析了所有受体在单一“标准状态”条件下的启动子结合能。在这里，我们研究了全长AR和与前列腺癌相关的突变体T877A的自组装和启动子结合能量。我们首先证明了这两种蛋白质仅作为单体存在，没有显示二聚化的证据。虽然这一结果与传统的理解相矛盾，即类固醇受体在没有DNA的情况下二聚化，但它与我们之前的工作完全一致，证明GR和两个PR亚型要么不二聚化，要么二聚化很弱。此外，两种AR蛋白在结合位点之间表现出大量的协同性，与GR和PR的情况相同。与之形成鲜明对比的是，更远的ER-α二聚体非常强烈，以至于只能间接测量能量，但协同性可以忽略不计。因此，同源受体对启动子结合能的分配是完全不同的。此外，由于受体与系统发育分配密切相关，它们的能量分配相似，这种分配似乎是进化上保守的。我们推测，这种能量学上的差异，加上不同的启动子结构，是产生受体特异性启动子占用和功能的基础。
Steroid receptors comprise a homologous family of ligand-activated transcription factors. The members include androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR). Phylogenetic studies demonstrate that AR, GR, MR, and PR are most closely related, falling into subgroup 3C. ER is more distantly related, falling into subgroup 3A. To determine the quantitative basis by which receptors generate their unique transcriptional responses, we are systematically dissecting the promoter-binding energetics of all receptors under a single “standard state” condition. Here, we examine the self-assembly and promoter-binding energetics of full-length AR and a mutant associated with prostate cancer, T877A. We first demonstrate that both proteins exist only as monomers, showing no evidence of dimerization. Although this result contradicts the traditional understanding that steroid receptors dimerize in the absence of DNA, it is fully consistent with our previous work demonstrating that GR and two PR isoforms either do not dimerize or dimerize only weakly. Moreover, both AR proteins exhibit substantial cooperativity between binding sites, again as seen for GR and PR. In sharp contrast, the more distantly related ER-α dimerizes so strongly that energetics can only be measured indirectly, yet cooperativity is negligible. Thus, homologous receptors partition their promoter-binding energetics quite differently. Moreover, since receptors most closely related by phylogeny partition their energetics similarly, such partitioning appears to be evolutionarily conserved. We speculate that such differences in energetics, coupled with different promoter architectures, serve as the basis for generating receptor-specific promoter occupancy and thus function.