Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif
Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif
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DOI：
10.1074/jbc.m113.534859
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发表时间：
2014-03-28
影响因子：
4.8
通讯作者：
Cato, Andrew C. B.
中科院分区：
文献类型：
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作者：
Jehle, Katja;Cato, Laura;Cato, Andrew C. B.
背景：共激活剂与雄激素受体（AR）的相互作用表面是前列腺癌治疗的重要靶点。结果：鉴定出了由序列（GARRPR）与AR的变构口袋（BF-3）结合形成的新界面。结论：GARRPR结合可调节AR活性。意义：GARRPR/BF-3相互作用是AR活性的一个新的调控中心。雄激素受体（AR）是一种配体激活的转录因子，对前列腺癌的发展至关重要。雄激素通过其配体结合结构域（LBD）激活它，该结构域主要由11 -螺旋组成。配体结合后，最后一个螺旋被重组为一种激动剂构象，称为激活剂功能-2 (AF-2)，用于辅激活剂结合。几种共激活因子通过保守的LXXLL或FXXLF序列与AF-2口袋结合，以增强受体的活性。最近，AF-2附近的一个小的化合物结合表面被确定为AF-2活性的变构调节剂，并被称为结合功能-3 （BF-3）。然而，目前尚不清楚BF-3在体内的作用，也不清楚哪些蛋白质可以与它结合。在这里，我们证明了在伴侣Bag-1L的N端有一个重复的GARRPR基序通过BF-3口袋起作用。这些发现得到了这样一个事实的支持，即BF-3口袋内的选择性BF-3抑制剂或突变消除了GARRPR基序和BF-3之间的相互作用。相反，Bag-1L的两个GARRPR基序中的氨基酸交换会损害Bag-1L与AR之间的相互作用，但不会改变Bag-1L与染色质结合的能力。此外，在全基因组转录组分析中，突变体Bag-1L增加了AR靶点子集的雄激素依赖性激活，证明了GARRPR/BF-3相互作用的抑制功能。因此，我们已经确定GARRPR是一种新的BF-3调控序列，对微调AR的活性很重要。
Background: The interaction surface of coactivators and the androgen receptor (AR) is an important target for prostate cancer therapeutics. Results: A new interface formed by binding of the sequence (GARRPR) and the allosteric pocket (BF-3) of the AR has been identified. Conclusion: GARRPR binding modulates AR activity. Significance: The GARRPR/BF-3 interaction is a novel regulatory hub for AR activity.The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 -helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.