Structural and functional consequences of glutamine tract variation in the androgen receptor
Structural and functional consequences of glutamine tract variation in the androgen receptor
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DOI：
10.1093/hmg/ddh181
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发表时间：
2004-08-15
影响因子：
3.5
通讯作者：
Tilley, WD
中科院分区：
文献类型：
--
作者：
Buchanan, G;Yang, M;Tilley, WD
雄激素受体（AR）基因在其N-末端反式激活结构域（NTD）中含有多态性三核苷酸重复区（CAG）（n），其编码受体蛋白中的多聚谷氨酰胺（polyQ）区。健康个体中CAG重复序列的长度范围为6至39，而在正常范围内和正常范围外的重复序列长度的变化与疾病相关，包括精子发生受损和肯尼迪病，以及发展乳腺癌和前列腺癌的风险。尽管已经提出，在正常范围内的polyQ束长度与AR反式激活潜力之间的反比关系可能是改变疾病风险的原因，但尚未阐明polyQ长度调节AR功能的分子机制。在这项研究中，我们提供了在人前列腺肿瘤中检测到的体细胞AR基因突变的详细表征，该突变导致两个非连续亮氨酸残基（AR-polyQ 2L）中断polyQ道。与wtAR相比，AR-polyQ 2L表现出破坏的结构域间通讯（N/C相互作用）和较低的蛋白水平，但矛盾的是具有显著增加的反式激活活性。分子建模和对辅因子的响应表明，AR-polyQ 2L的活性增加是由于提供了比野生型AR更稳定的辅助蛋白募集平台。分析polyQ束长度和AR功能之间的关系，揭示了维持N/C相互作用的临界尺寸（Q16-Q29）。在不同种族-族群中，91 - 99%的AR等位基因编码Q16-Q29范围内的polyQ片段，这表明N/C相互作用作为雄激素诱导的AR信号传导的重要组成部分被保留下来。
The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat region, (CAG)(n), in its N-terminal transactivation domain (NTD) that encodes a polyglutamine (polyQ) tract in the receptor protein. Whereas the length of the CAG repeat ranges from 6 to 39 in healthy individuals, the variations in repeat length both within and outside the normal range are associated with disease, including impaired spermatogenesis and Kennedy's disease, and with the risk of developing breast and prostate cancer. Whereas it has been proposed that the inverse relationship between polyQ tract length within the normal range and AR transactivation potential may be responsible for altered risk of disease, the molecular mechanisms underlying polyQ length modulation of AR function have not been elucidated. In this study, we provide detailed characterization of a somatic AR gene mutation detected in a human prostate tumor that results in interruption of the polyQ tract by two non-consecutive leucine residues (AR-polyQ2L). Compared with wtAR, AR-polyQ2L exhibits disrupted inter-domain communication (N/C interaction) and a lower protein level, but paradoxically has markedly increased transactivation activity. Molecular modeling and the response to cofactors indicate that the increased activity of AR-polyQ2L results from the presentation of a more stable platform for the recruitment of accessory proteins than wild-type AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (Q16-Q29) for maintenance of N/C interaction. That between 91 and 99% of AR alleles in different racial-ethnic groups encode a polyQ tract in the range of Q16-Q29 suggests that N/C interaction has been preserved as an essential component of androgen-induced AR signaling.