Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change
Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change
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DOI：
10.1073/pnas.0510664103
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发表时间：
2006-02-07
影响因子：
11.1
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Gallagher, E;Gao, M;Karin, M
E3泛素（Ub）连接酶Itch通过其诱导Ub依赖性JunB降解的能力是辅助性T细胞2（Th 2）细胞因子产生的关键调节剂。在T细胞受体参与后，瘙痒经历JINK 1介导的磷酸化，大大增强了其酶活性。为了研究磷酸化是如何激活E3 Ub连接酶的，我们鉴定了Itch中的JNK 1磷酸化位点S199、S232和T222，它们位于富含Pro的区域内。这些位点的磷酸化对于破坏Itch的WW结构域与其催化HECT（Homelands to E6-AP C Terminus）结构域之间的抑制性相互作用是必要且足够的，并且诱导极大地增强Itch的催化活性的构象变化，Itch是一种HECT E3连接酶，发现其磷酸化后直接活化。
The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-dependent JunB degradation. After T cell receptor engagement, Itch undergoes JINK1-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 S199, 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.