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首页> 外文期刊>Molecular and Cellular Biology >Ligand Binding to the Androgen Receptor Induces Conformational Changes That Regulate Phosphatase Interactions
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Ligand Binding to the Androgen Receptor Induces Conformational Changes That Regulate Phosphatase Interactions

机译：配体结合到雄激素受体诱导构象变化，调节磷酸酶的相互作用。

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We describe a mechanism for protein phosphatase 2A (PP2A) targeting to the androgen receptor (AR) and provide insight into the more general issue of kinase and phosphatase interactions with AR. Simian virus 40 (SV40) small t antigen (ST) binding to N-terminal HEAT repeats in the PP2A A subunit induces structural changes transduced to C-terminal HEAT repeats. This enables the C-terminal HEAT repeats in the PP2A A subunit, including HEAT repeat 13, to discriminate between androgen- and androgen antagonist-induced AR conformations. The PP2A-AR interaction was used to show that an AR mutant in prostate cancer cells (T877A) is activated by multiple ligands without acquiring the same conformation as that induced by androgen. The correlation between androgen binding to AR and increased phosphorylation of the activation function 1 (AF-1) region implies that changes in AR conformation or chaperone composition are causal to kinase access to phosphorylation sites. However, AF-1 phosphorylation sites are kinase accessible prior to androgen binding. This suggests that androgens can enhance the phosphorylation state of AR either by negatively regulating the ability of the ligand-binding domain to bind phosphatases or by inducing an AR conformation that is resistant to phosphatase action. SV40 ST subverts this mechanism by promoting the direct transfer of PP2A onto androgen-bound AR, resulting in multisite dephosphorylation.
机译：我们描述了针对男性激素受体（AR）的蛋白质磷酸酶2A（PP2A）的机制，并提供了对激酶和磷酸酶与AR相互作用的更一般性问题的见解。猿猴病毒40（SV40）小t抗原（ST）与PP2A A亚基的N末端HEAT重复序列结合，可诱导转导至C末端HEAT重复序列的结构变化。这使得PP2A A亚基中的C末端HEAT重复序列（包括HEAT重复序列13）能够区分雄激素和雄激素拮抗剂诱导的AR构象。 PP2A-AR相互作用用于显示前列腺癌细胞（T877A）中的AR突变体被多个配体激活，而没有获得与雄激素诱导的构象相同的构象。雄激素与AR的结合与激活功能1（AF-1）区域磷酸化的增加之间的相关性意味着AR构象或分子伴侣组成的变化是激酶接近磷酸化位点的原因。然而，在雄激素结合之前，AF-1磷酸化位点是激酶可及的。这表明雄激素可以通过负调节配体结合域结合磷酸酶的能力或通过诱导抗磷酸酶作用的AR构象来增强AR的磷酸化状态。 SV40 ST通过促进PP2A直接转移到与雄激素结合的AR上而破坏了这种机制，从而导致多位点去磷酸化。

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