Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain.
Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain.
复制标题
部分雄激素不敏感以及与雄激素受体配体结合域的预测三维结构的相关性。
DOI：
10.1016/s0303-7207(97)00229-3
复制
发表时间：
1998
影响因子：
4.1
通讯作者：
Ratnam,SS
中科院分区：
文献类型：
--
作者：
Yong,EL;Tut,TG;Ghadessy,FJ;Prins,G;Ratnam,SS
人类雄激素受体（AR）的遗传缺陷可导致广泛的雄激素不敏感综合征（AIS），范围从完全AIS的表型女性;部分AIS的生殖器模糊;到轻微AIS的男性不育。这些缺陷中的大多数是由于导致氨基酸取代的点突变。然而，目前尚不清楚为什么某些突变会导致部分AIS，而同一外显子中的其他突变会导致完全综合征。我们提出了一个部分AIS的情况下，由于点突变影响密码子758 AR配体结合域（LBD），改变了从天冬酰胺到苏氨酸（N758 T）的密码子的意义。突变受体显示正常的结合亲和力，但异常的解离动力学在患者的成纤维细胞和转染COS-7细胞的DHT。突变体AR是热不稳定的，并导致在受体反式激活能力减少1050%时，与报告基因纳入雄激素反应元件检查。虽然AR LBD的三维结构尚不清楚，但类固醇受体超家族成员维甲酸-X受体（RXR-α）的同源区域已被结晶化，从而可以比较RXR-α和AR的比对氨基酸序列。突变N758 T位于第五个α-螺旋（H5）和第一个β-链（S1）之间的预测接头区域。通常，导致部分AIS的突变倾向于聚集在位于AR LBD的结构螺旋之间的预测接头区域中。最引人注目的是，预测的接头区域包含超过70%的与LBD中的前列腺癌相关的突变AR。与部分AIS和前列腺癌相关的突变发生在相同的预测接头区域中，表明这种聚类不是巧合的，并且预测接头区域可能在定义雄激素结合和配体特异性方面具有重要但微妙的作用。
Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient’s fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in ≈50% reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-α), has been crystalized, allowing comparison of aligned amino-acid sequences of RXR-α and AR. The mutation, N758T, lies in a predicted linker region between the fifth α-helix (H5) and the first β-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.