WW domain-mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex
WW domain-mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex
复制标题
Deltex 的 E3 泛素连接酶抑制剂的 WW 结构域介导的调节和激活
DOI：
10.1074/jbc.ra118.003781
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发表时间：
2018-10-26
影响因子：
4.8
通讯作者：
Wen, Wenyu
中科院分区：
文献类型：
--
作者：
Yao, Weiyi;Shan, Zelin;Wen, Wenyu
Nedd 4家族E3连接酶Itch和WWP 1/2在细胞周期进程和细胞凋亡的调控中起着至关重要的作用，与癌症的发生和转移密切相关。最近已经表明，Itch和WWP 1/2的连接酶活性受到严格调节，其中HECT结构域通过连接WW 2和WW 3的接头区域在分子内隔离。在这里，我们表明，一个类似的自抑制机制是利用果蝇的直系同源物痒和WWP 1/2，Deltex（苏（dx））的抑制。我们表明，苏（dx）采用一个不活跃的稳定状态与WW域区域与HECT域相互作用。我们证明，连接子和之前的WW 2都是Su（dx）HECT的有效结合和调节所需的。通过WW结构域募集含有多个PY基序的衔接子dNdfip缓解了Su（dx）的抑制状态并导致底物（例如Notch）泛素化。我们的研究证明了一个进化上保守的机制，一些Nedd 4家族E3连接酶的调节和激活。我们的研究结果还表明，通过dNdfip-Su（dx）介导的Notch泛素化特异性Notch下调的双重调节机制。
The Nedd4 family E3 ligases Itch and WWP1/2 play crucial roles in the regulation of cell cycle progression and apoptosis and are closely correlated with cancer development and metastasis. It has been recently shown that the ligase activities of Itch and WWP1/2 are tightly regulated, with the HECT domain sequestered intramolecularly by a linker region connecting WW2 and WW3. Here, we show that a similar autoinhibitory mechanism is utilized by the Drosophila ortholog of Itch and WWP1/2, Suppressor of Deltex (Su(dx)). We show that Su(dx) adopts an inactive steady state with the WW domain region interacting with the HECT domain. We demonstrate that both the linker and preceding WW2 are required for the efficient binding and regulation of Su(dx) HECT. Recruiting the multiple-PY motif-containing adaptor dNdfip via WW domains relieves the inhibitory state of Su(dx) and leads to substrate (e.g. Notch) ubiquitination. Our study demonstrates an evolutionarily conservative mechanism governing the regulation and activation of some Nedd4 family E3 ligases. Our results also suggest a dual regulatory mechanism for specific Notch down-regulation via dNdfip-Su(dx)-mediated Notch ubiquitination.