Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Fudan University, Shanghai, 200032, China.
Nat Commun. 2019 Jul 18;10(1):3162. doi: 10.1038/s41467-019-11224-7.
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.
HECT E3 连接酶控制着众多致癌/肿瘤抑制因子和信号蛋白的降解和功能，其活性必须受到严格调控，以预防癌症和其他疾病。在这里，我们表明 Nedd4 家族的 HECT E3 WWP1 采用了一种自动抑制状态，其中其多个 WW 结构域使用多锁机制将 HECT 封闭。去除 WW2 或 WW34 导致 WWP1 的部分激活。完全抑制的 WWP1 结构揭示了许多在癌症患者中发现的 WWP1 突变导致部分激活状态，从而增加 E3 连接酶活性，并且 WWP1 突变体可能通过增强 ∆Np63α 降解来促进细胞迁移。我们进一步证明 WWP2 和 Itch 利用与 WWP1 非常相似的多锁自动抑制机制，而 Nedd4/4L 和 Smurf2 则利用略有不同的版本。总体而言，这些结果揭示了精细调节 HECT 家族酶的连接酶活性的多功能自动抑制机制。
