A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases
A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases
复制标题
用于微调 HECT 家族 E3 连接酶酶活性的多锁抑制机制
DOI：
10.1038/s41467-019-11224-7
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发表时间：
2019-07-18
影响因子：
16.6
通讯作者：
Wen, Wenyu
中科院分区：
文献类型：
--
作者：
Wang, Zhen;Liu, Ziheng;Wen, Wenyu
HECT E3连接酶控制许多致癌/肿瘤抑制因子和信号传导蛋白的降解和功能，并且必须严格调节其活性以预防癌症和其他疾病。在这里，我们表明，Nedd 4家庭HECT E3 WWP 1采用自动抑制状态，其中其多个WW域隔离HECT使用多锁机制。删除WW 2或WW 34导致WWP 1部分激活。完全抑制的WWP 1的结构表明，在癌症患者中鉴定的许多WWP 1突变导致部分活性状态，E3连接酶活性增加，并且WWP 1突变体可能通过增强Np 63 α降解促进细胞迁移。我们进一步证明，WWP 2和Itch利用了与WWP 1所利用的高度相似的多锁自抑制机制，而Nedd 4/4 L和Smurf 2利用了稍微不同的版本。总的来说，这些结果揭示了微调HECT家族酶的连接酶活性的多功能自抑制机制。
HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes.