Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor
Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor
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DOI：
10.1038/s41467-019-11594-y
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发表时间：
2019-08-08
影响因子：
16.6
通讯作者：
Salvatella, Xavier
中科院分区：
文献类型：
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作者：
Eftekharzadeh, Bahareh;Banduseela, Varuna C.;Salvatella, Xavier
分子伴侣如Hsp40和Hsp70使雄激素受体（AR）处于非活性构象。它们在雄激素存在的情况下被释放，从而激活并使受体变得易于聚集。本研究表明，这些分子伴侣识别AR n端结构域（NTD）的一个区域，包括FQNLF基序，该区域在激活后与AR配体结合结构域（LBD）相互作用。这表明分子伴侣和LBD之间对FQNLF基序的竞争调节了AR的激活。我们还表明，当游离NTD寡聚时，与Hsp70结合增加了其溶解度。在神经肌肉紊乱脊髓性肌萎缩的细胞和小鼠模型中，稳定NTD-Hsp70与小分子的相互作用可减少AR聚集并促进其降解。这些结果有助于解决分子伴侣调节AR聚集、激活和质量控制之间平衡的机制。
Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.