The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator
The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator
复制标题
DOI：
10.1074/jbc.274.29.20229
复制
发表时间：
1999-07-16
影响因子：
4.8
通讯作者：
Chang, C
中科院分区：
文献类型：
--
作者：
Hsiao, PW;Lin, DL;Chang, C
虽然雄激素受体（AR）中的多聚谷氨酰胺（poly-Q）重复扩增与肯尼迪病（CX连锁脊髓和延髓肌萎缩症）的联系是一个重大进展，但poly-Q长度变化如何促成该疾病的详细分子机制仍不清楚。在这里，我们报告的核G蛋白，Ras相关的核蛋白/ARA 24，作为第一个AR辅激活剂，可以结合不同长度的聚Q内AR的鉴定。在酵母和哺乳动物相互作用试验中，我们的数据表明AR N-末端结构域与ARA 24的相互作用随着poly-Q长度的增加而减少。ARA 24的共激活也随着AR内的poly-Q扩增而减少。在ARA 24的C末端的酸性六肽（DEDDDL）的缺失进一步增强其AR共活化。总之，我们的数据表明，在X-连锁脊髓和延髓肌肉萎缩AR中，ARA 24与较长的poly-Q AR的弱相互作用和弱共激活可能导致AR的弱反式激活。弱相互作用和弱共激活的结果可能最终导致Kennedy病发展期间的部分雄激素不敏感。
Although the linkage of polyglutamine (poly-Q) repeat expansion in the androgen receptor (AR) to Kennedy's disease CX-linked spinal and bulbar muscular atrophy) was a major step forward, the detailed molecular mechanism of how the change in poly-Q length contributes to the disease remains unclear. Here we report the identification of a nuclear G-protein, Ras-related nuclear protein/ARA24, as the first AR coactivator that can bind differentially with different lengths of poly-Q within AR. In the yeast and mammalian reciprocal interacting assays, our data suggested the interaction of AR N-terminal domain with ARA24 diminishes as the poly-Q length increases. The coactivation of ARA24 also diminishes with the poly-Q expansion within AR. Deletion of the acidic hexapeptide (DEDDDL) at the C terminus of ARA24 further enhances its AR coactivation. Together, our data suggest that poor interaction and weaker coactivation of ARA24 to the longer poly-Q AR in the X-linked spinal and bulbar muscular atrophied AR could contribute to the weaker transactivation of AR, The con sequence of poor interaction and weak coactivation may eventually lead to the partial androgen insensitivity during the development of Kennedy's disease.