Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities.
Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities.
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DOI：
10.1210/mend.12.2.0065
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发表时间：
1998-02
影响因子：
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通讯作者：
Xiu Fen Ding;Carol M. Anderson;Han Ma;H. Hong;R. M. Uht;Peter J. Kushner;M. Stallcup
中科院分区：
文献类型：
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作者：
Xiu Fen Ding;Carol M. Anderson;Han Ma;H. Hong;R. M. Uht;Peter J. Kushner;M. Stallcup
AF-2核受体（NR）转录激活功能的活性是由部分同源的转录辅激活因子糖皮质激素受体相互作用蛋白1（GRIP 1）/转录中介因子2（TIF 2）和类固醇受体辅激活因子1（SRC-1）介导的。GRIP 1和SRC-1结合9种不同的NR，并表现出相似但不相同的NR结合偏好。最显著的差异是雄激素受体，它与GRIP 1结合良好，但与SRC-1结合较差。GRIP 1和SRC-1在其中心区域含有三个拷贝的NR结合基序LXXLL（称为NR盒）。GRIP 1中NR Box II和NR Box III的突变几乎完全消除了与NR的功能和结合相互作用，表明这两个位点对GRIP 1的大部分NR结合活性至关重要。GRIP 1与雌激素受体的相互作用受NR盒II突变的影响更大，而与雄激素受体和糖皮质激素受体的相互作用受NR盒III突变的影响更大。SRC-1的一种同种型在其末端C端具有额外的NR盒（NR盒IV），其NR结合偏好与SRC-1的中心NR结合结构域的NR结合偏好略有不同。GRIP 1在其C-末端区域没有NR盒，因此没有C-末端NR结合功能。总之，GRIP 1和SRC-1具有重叠的NR结合偏好，但特定的NR显示共激活因子和NR盒偏好，这可能有助于激素反应的特异性。
The activity of the AF-2 transcriptional activation function of nuclear receptors (NR) is mediated by the partially homologous transcriptional coactivators, glucocorticoid receptor interacting protein 1 (GRIP1)/transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator 1 (SRC-1). GRIP1 and SRC-1 bound nine different NRs and exhibited similar, but not identical, NR binding preferences. The most striking difference was seen with the androgen receptor, which bound well to GRIP1 but poorly to SRC-1. GRIP1 and SRC-1 contain three copies of the NR binding motif LXXLL (called an NR Box) in their central regions. Mutation of both NR Box II and NR Box III in GRIP1 almost completely eliminated functional and binding interactions with NRs, indicating that these two sites are crucial for most of GRIP1's NR binding activity. Interactions of GRIP1 with the estrogen receptor were more strongly affected by mutations in NR Box II, whereas interactions with the androgen receptor and glucocorticoid receptor were more strongly affected by NR Box III mutations. One isoform of SRC-1 has an additional NR Box (NR Box IV) at its extreme C terminus with an NR-binding preference somewhat different from that of the central NR-binding domain of SRC-1. GRIP1 has no NR Box in its C-terminal region and therefore no C-terminal NR-binding function. In summary, GRIP1 and SRC-1 have overlapping NR-binding preferences, but specific NRs display both coactivator and NR Box preferences that may contribute to the specificity of hormonal responses.