Structural features discriminate androgen receptor N/C terminal and coactivator interactions.
Structural features discriminate androgen receptor N/C terminal and coactivator interactions.
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DOI：
10.1016/j.mce.2011.03.026
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发表时间：
2012-01-30
影响因子：
4.1
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Askew, Emily B.;Minges, John T.;Hnat, Andrew T.;Wilson, Elizabeth M.
人雄激素受体（AR）转录活性涉及与激动剂结合的AR配体结合域（LBD）的域间和共激活因子相互作用。先前通过晶体学显示了LBD中AR NH 2-末端FXXLF基序和激活功能2（AF 2）之间AR NH 2-和羧基末端相互作用的结构决定因素。在这份报告中，我们提供的证据表明，在AR LBD螺旋12的AF 2结合裂缝，促进与FXXLF和LXXLL基序的相互作用以外的区域。在AR LBD螺旋12（Q902 A）中谷氨酰胺902突变为丙氨酸破坏了AR FXXLF基序与AF 2的结合，但增强了辅激活因子LXXLL基序的结合。结合雄激素的解离速率较慢，表明AR-Q902 A对缺陷性FXXLF基序结合的功能补偿。谷氨酰胺902的功能重要性由引起部分雄激素不敏感的带电残基种系突变Q902 R和前列腺癌中报告的类似体细胞突变Q902 K指示，这两者都增加雄激素解离速率并降低AR转录活性。高亲和力平衡雄激素结合保留丙氨酸取代突变的Tyr-739在AR LBD螺旋5或Lys-905在螺旋12结构上相邻的AF 2，而转录活性降低和雄激素解离增加。这些功能丧失突变的有害作用被螺旋稳定化AR前列腺癌体细胞突变H874 Y挽救。基于AR-2-30 FXXLF基序肽与激动剂结合的AR LBD的结合大于较短的AR-20- 30 FXXLF基序肽，AR FXXLF基序的序列NH 2末端有助于AR NH 2末端和羧基末端相互作用。我们的结论是，螺旋12残基以外的AF 2结合裂缝调节AR转录活性，提供灵活性，以适应FXXLF或LXXLL基序结合。
Human androgen receptor (AR) transcriptional activity involves interdomain and coactivator interactions with the agonist-bound AR ligand binding domain (LBD). Structural determinants of the AR NH2- and carboxyl-terminal interaction between the AR NH2-terminal FXXLF motif and activation function 2 (AF2) in the LBD were shown previously by crystallography. In this report, we provide evidence for a region in AR LBD helix 12 outside the AF2 binding cleft that facilitates interactions with the FXXLF and LXXLL motifs. Mutagenesis of glutamine 902 to alanine in AR LBD helix 12 (Q902A) disrupted AR FXXLF motif binding to AF2, but enhanced coactivator LXXLL motif binding. Functional compensation for defective FXXLF motif binding by AR-Q902A was suggested by the slower dissociation rate of bound androgen. Functional importance of glutamine 902 was indicated by the charged residue germline mutation Q902R that caused partial androgen insensitivity, and a similar somatic mutation Q902K reported in prostate cancer, both of which increased the androgen dissociation rate and decreased AR transcriptional activity. High affinity equilibrium androgen binding was retained by alanine substitution mutations at Tyr-739 in AR LBD helix 5 or Lys-905 in helix 12 structurally adjacent to AF2, whereas transcriptional activity decreased and the androgen dissociation increased. Deleterious effects of these loss of function mutations were rescued by the helix stabilizing AR prostate cancer somatic mutation H874Y. Sequence NH2-terminal to the AR FXXLF motif contributed to the AR NH2- and carboxyl-terminal interaction based on greater AR-2-30 FXXLF motif peptide binding to the agonist-bound AR LBD than a shorter AR-20-30 FXXLF motif peptide. We conclude that helix 12 residues outside the AF2 binding cleft modulate AR transcriptional activity by providing flexibility to accommodate FXXLF or LXXLL motif binding.
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影响因子：
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