Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
J Biol Chem. 2010 Mar 19;285(12):9161-71. doi: 10.1074/jbc.M109.085779. Epub 2010 Jan 19.
Transcription activation by androgen receptor (AR), which depends on recruitment of coactivators, is required for the initiation and progression of prostate cancer, yet the mechanisms of how hormone-activated AR interacts with coactivators remain unclear. This is because AR, unlike any other nuclear receptor, prefers its own N-terminal FXXLF motif to the canonical LXXLL motifs of coactivators. Through biochemical and crystallographic studies, we identify that steroid receptor coactivator-3 (SRC3) (also named as amplified in breast cancer-1 or AIB1) interacts strongly with AR via synergistic binding of its first and third LXXLL motifs. Mutagenesis and functional studies confirm that SRC3 is a preferred coactivator for hormone-activated AR. Importantly, AR mutations found in prostate cancer patients correlate with their binding potency to SRC3, corroborating with the emerging role of SRC3 as a prostate cancer oncogene. These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer.
雄激素受体（AR）的转录激活依赖于共激活因子的募集，这是前列腺癌发生和发展所必需的，然而，激素激活的 AR 如何与共激活因子相互作用的机制尚不清楚。这是因为 AR 与其他核受体不同，它更喜欢自身的 N 端 FXXLF 基序而不是共激活因子的典型 LXXLL 基序。通过生化和晶体学研究，我们确定类固醇受体共激活因子-3（SRC3）（也称为乳腺癌扩增蛋白 1 或 AIB1）通过其第一个和第三个 LXXLL 基序的协同结合与 AR 强烈相互作用。突变和功能研究证实，SRC3 是激素激活的 AR 的首选共激活因子。重要的是，在前列腺癌患者中发现的 AR 突变与它们与 SRC3 的结合能力相关，这与 SRC3 作为前列腺癌致癌基因的新兴作用相一致。这些结果为激素激活的 AR 对 SRC3 的选择性利用提供了分子机制，并将 AR 和 SRC3 之间的功能关系与前列腺癌的发生和发展联系起来。
