Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance
Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance
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DOI：
10.1016/j.molcel.2004.09.036
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发表时间：
2004-11-05
期刊：
影响因子：
16
通讯作者：
Wilson, EM
中科院分区：
文献类型：
--
作者：
He, B;Gampe, RT;Wilson, EM
雄激素受体(AR)是男性性别发育所必需的，并有助于前列腺癌细胞的存活。与其他结合共激活子LxxLL基序的核受体不同，AR配体结合域优先与AR FXXLF基序进行域间相互作用。本文报道了配体激活的AR配体结合域的晶体结构，包括与FXXLF和LxxLL结合的多肽和不结合的FXXLF和LxxLL。通过比较结构功能和突变研究确定了建立基序结合特异性的关键残基。前列腺癌的一种机制是通过特异性决定残基上的功能性AR突变恢复辅活化子LxxLL基序结合。提出了一种激活功能转换假说，即在类固醇受体亚家族中，LxxLL基序结合的进化性下降与NH2末端反式激活结构域的扩展和功能优势平行。
The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH2-terminal transactivation domain in the steroid receptor subfamily.