通过磷酸化诱导的构象变化激活E3泛素连接酶Itch。
Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change.
作者信息
Gallagher Ewen, Gao Min, Liu Yun-Cai, Karin Michael
机构信息
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
出版信息
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1717-22. doi: 10.1073/pnas.0510664103. Epub 2006 Jan 30.
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 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 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.
E3泛素（Ub）连接酶Itch是通过诱导Ub依赖性JunB降解来调节辅助性T细胞2（Th2）细胞因子产生的关键因子。T细胞受体激活后，Itch会发生JNK1介导的磷酸化，从而大大增强其酶活性。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S199、S232和T222，这些位点位于富含脯氨酸的区域内。这些位点的磷酸化对于破坏Itch的WW结构域与其催化HECT（与E6-AP C末端同源）结构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Itch的催化活性，Itch是一种HECT E3连接酶，被发现磷酸化后可直接激活。
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