Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability.
Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability.
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DOI：
10.1210/mend.9.2.7776971
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发表时间：
1995-02
影响因子：
--
通讯作者：
Zhong-xun Zhou;M. Lane;J. A. Kemppainen;F. S. French;E. M. Wilson
中科院分区：
文献类型：
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作者：
Zhong-xun Zhou;M. Lane;J. A. Kemppainen;F. S. French;E. M. Wilson
利用重组表达的野生型和突变型雄激素受体（AR）研究了睾酮（T）和双氢睾酮（DHT）不同生理效应的分子基础。雄激素从细胞核和细胞质AR的解离速率与激素和浓度依赖性受体降解速率进行了比较。T与AR的解离速度比DHT或methyltrienolone（R1881）快3倍，并且在稳定受体方面效果较差。AR缺失突变体和AR/糖皮质激素受体嵌合体的分析表明，AR NH 2-末端结构域具有通过减缓配体解离和AR降解速率来稳定受体的特定作用。消除受体二聚化、核定位或DNA结合活性的氨基酸突变对雄激素解离或AR降解没有显著影响。一种天然存在的类固醇结合结构域突变（Val 889至Met）导致雄激素不敏感，但不改变平衡雄激素结合亲和力，降低了雄激素结合能力，这是雄激素解离和AR降解速率增加的结果。因此，AR稳定和功能需要雄激素延长受体占用，在较高浓度的快速解离雄激素和较低浓度的较慢解离雄激素下观察到类似程度的稳定。受体结合雄激素的保留通过AR NH 2末端和类固醇结合结构域之间的相互作用而增强。受体稳定的配体特异性和浓度依赖性为T和DHT的作用中的生理差异提供了解释。
The molecular basis for the different physiological effects of testosterone (T) and dihydrotestosterone (DHT) was investigated using recombinantly expressed wild-type and mutant androgen receptor (AR). Rates of androgen dissociation from nuclear and cytoplasmic AR were compared with hormone- and concentration-dependent receptor degradation rates. T dissociates from AR 3 times faster than DHT or methyltrienolone (R1881) and is less effective in stabilizing the receptor. Analysis of AR deletion mutants and AR/glucocorticoid receptor chimeras indicates that the AR NH2-terminal domain has a specific role in stabilizing the receptor by slowing the rate of ligand dissociation and AR degradation. Amino acid mutations that abolish receptor dimerization, nuclear localization, or DNA-binding activity have no significant effect on androgen dissociation or AR degradation. A naturally occurring steroid-binding domain mutation (Val889 to Met) that causes androgen insensitivity, but does not alter equilibrium androgen binding affinity, lowered the androgen-binding capacity as a result of increased rates of androgen dissociation and AR degradation. Thus, AR stabilization and function require prolonged receptor occupancy with androgen, with a similar extent of stabilization observed at higher concentrations of faster dissociating androgens and lower concentrations of slower dissociating androgens. Retention of receptor-bound androgen is enhanced by an interaction between the AR NH2-terminal and steroid-binding domains. The ligand specificity and concentration dependence of receptor stabilization provide an explanation for physiological differences in the actions of T and DHT.