Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor
Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor
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DOI：
10.1210/me.2003-0375
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发表时间：
2004-09-01
影响因子：
--
通讯作者：
Trapman, J
中科院分区：
文献类型：
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作者：
Dubbink, HJ;Hersmus, R;Trapman, J
在核受体中，雄激素受体（AR）是独特的，因为其配体结合结构域（LBD）与N-末端结构域中的FXXLF基序相互作用，类似于辅激活因子LXXLL基序。我们比较了野生型AR FXXLF基序和共激活转录中介因子2 LXXLL基序和这些基序的变体的AR和雌激素受体α-LBD相互作用。随机诱变揭示了FXXLF基序中的F残基在高亲和力和选择性AR LBD相互作用中的关键作用。全长AR中的FXXLF基序和转录中介因子2 LXXLL基序竞争重叠结合位点。AR LBD/AR FXXLF复合物的计算机模型表明，庞大的F残基被埋在一个深的辅激活剂结合沟。雌激素受体α LBD中相应的凹槽相当浅，解释了测试的任何FXXLF基序缺乏结合。FXXLF和LXXLL基序的相互作用依赖于不同的带电氨基酸残基的AR LBD存在于相对两端的辅激活剂沟。总之，我们的数据证明了深疏水沟和带电氨基酸的替代使用在指定肽与AR LBD结合中的重要性。
Among nuclear receptors, the androgen receptor (AR) is unique in that its ligand-binding domain (LBD) interacts with the FXXLF motif in the N-terminal domain, resembling coactivator LXXLL motifs. We compared AR- and estrogen receptor alpha-LBD interactions of the wild-type AR FXXLF motif and coactivator transcriptional intermediary factor 2 LXXLL motifs and variants of these motifs. Random mutagenesis revealed a key role for the F residues in FXXLF motifs in high-affinity and selective AR LBD interaction. The FXXLF motif in full-length AR and transcriptional intermediary factor 2 LXXLL motifs competed for an overlapping binding site. A computer model of the AR LBD/AR FXXLF complex showed that the bulky F residues are buried in a deep coactivator-binding groove. The corresponding groove in estrogen receptor alpha LBD is considerably shallower, explaining lack of binding of any of the FXXLF motifs tested. FXXLF and LXXLL motif interaction depended on different charged amino acid residues in the AR LBD present at opposite ends of the coactivator groove. In conclusion, our data demonstrate the importance of a deep hydrophobic groove and alternative usage of charged amino acids in specifying peptide binding to the AR LBD.