Edwards D P
University of Colorado Health Sciences Center, Department of Pathology, Denver 80262, USA.
J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):307-24. doi: 10.1023/a:1009503029176.
Steroid hormone receptors are members of a superfamily of ligand-dependent transcription factors. As such they have a DNA binding domain that recognizes specific target gene sequences along with separate transcriptional activation domains. What sets steroid hormone receptors (and other nuclear hormone receptors) apart from other families of sequence specific transcriptional activators is the presence of a ligand binding domain (LBD) that acts as a molecular switch to turn on transcriptional activity when a hormonal ligand induces a conformational change in the receptor. Upon binding hormone, steroid receptors recruit a novel coactivator protein complex with an essential role in receptor-mediated transcriptional activation. Coactivators function as adaptors in a signaling pathway that transmits transcriptional responses from the DNA bound receptor to the basal transcriptional machinery. Hormone agonists induce a conformational change in the carboxyl-terminal transcriptional activation domain, AF-2, that creates a new protein interaction site on the surface of the LBD that is recognized by LXXLL motifs in the p160 family of coactivators. In contrast, steroid antagonists such as the antiestrogen tamoxifen for the estrogen receptor induce an alternate conformation in AF-2 that occludes the coactivator binding site and recruits corepressors that can actively silence steroid responsive genes. Thus, the cellular availability of coactivators and corepressors is an important determinant in the biological response to both steroid hormone agonists and antagonists. This paper provides an update on the properties and mechanism of action of nuclear receptor coactivators, the nature of the coactivator-binding site, and the structural and mechanistic basis for ligand-dependent binding of coactivators to receptors.
类固醇激素受体是配体依赖性转录因子超家族的成员。因此，它们具有一个DNA结合结构域，可识别特定的靶基因序列以及单独的转录激活结构域。类固醇激素受体（和其他核激素受体）与其他序列特异性转录激活因子家族的不同之处在于存在一个配体结合结构域（LBD），当激素配体诱导受体发生构象变化时，该结构域可作为分子开关开启转录活性。在结合激素后，类固醇受体招募一种新型共激活蛋白复合物，该复合物在受体介导的转录激活中起关键作用。共激活因子在信号通路中充当衔接子，将DNA结合受体的转录反应传递至基础转录机制。激素激动剂诱导羧基末端转录激活结构域AF-2发生构象变化，在LBD表面产生一个新的蛋白质相互作用位点，该位点可被共激活因子p160家族中的LXXLL基序识别。相比之下，类固醇拮抗剂，如雌激素受体的抗雌激素他莫昔芬，会诱导AF-2形成另一种构象，从而封闭共激活因子结合位点，并招募可使类固醇反应性基因沉默的共抑制因子。因此，共激活因子和共抑制因子在细胞内的可利用性是对类固醇激素激动剂和拮抗剂生物学反应的重要决定因素。本文提供了关于核受体共激活因子的特性和作用机制、共激活因子结合位点的性质以及共激活因子与受体配体依赖性结合的结构和机制基础的最新信息。
