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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change
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Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change

机译：E3泛素连接酶痒的活化通过磷酸化诱导的构象变化

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摘要

The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-depen-dent JunB degradation. After T cell receptor engagement, Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as 5199, S232, and T222, which are located within a Pro-rich region. Phosphorylation of these sites is necessary and sufficient for disrupting an inhibitory interaction between the WW domain of Itch and its catalytic HECT (Homologous to E6-AP C Terminus) domain and induces a conformational change that greatly enhances the catalytic activity of Itch, a HECT E3 ligase found to be directly activated upon its phosphorylation.
机译：E3泛素（Ub）连接酶Itch通过诱导Ub依赖性JunB降解的能力，是T辅助2（Th2）细胞因子产生的关键调节剂。在T细胞受体参与后，Itch经历JNK1介导的磷酸化，大大增强了其酶促活性。为了研究磷酸化如何激活E3 Ub连接酶，我们确定了Itch内的JNK1磷酸化位点为5199，S232和T222，位于Pro-rich区域内。这些位点的磷酸化对于破坏Itch的WW域与其催化性HECT（与E6-AP C末端同源）域之间的抑制性相互作用是必要且充分的，并诱导构象变化，从而大大增强了Itch（HECT E3）的催化活性。发现连接酶在其磷酸化后被直接激活。

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