Functionally, WWP1 has been postulated to function as an oncogenic factor by regulating the stability of several cancer-related proteins, such as p53, p63, KLF2, JunB, HER4, and KLF5, and its dysregulation has been implicated in cancers, infectious diseases, neurological diseases, and ageing 9, 10, 15. The Nedd4 family E3s have nine members in humans (WWP1/2, Nedd4/4 L, Smurf1/2, NEDL1/2, and Itch), which share a common N-terminal domain architecture comprised of a C2 domain and 2–4 WW domains that are responsible for subcellular localization and substrate recognition, respectively. Each HECT-type E3 contains a characteristic HECT domain at its C terminus, which catalyzes the transfer of ubiquitin from E2 to itself and then to the specific substrate.īased on their distinct N-terminal domains, HECT-type E3s can be further grouped into several subfamilies, and the Nedd4 family is the largest and best characterized of these subfamilies 7, 9. HECT (homologous to E6-AP carboxyl terminus)-type E3s play vital roles in diverse physiological processes, including cell cycle progression, cell proliferation, autophagy, and inflammation, and their dysregulation is closely correlated with human diseases such as cancers, immune disorders, and neurological diseases 9, 10, 11, 12, 13, 14. Ubiquitin ligases (E3s) determine the selectivity and the modification sites of target proteins 1, 2, 3, 4 and are therefore key specificity factors in ubiquitin signaling and have attracted extensive attention as targets for therapeutic applications 5, 6, 7, 8. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes. 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. 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. Removing WW2 or WW34 led to a partial activation of WWP1. 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. 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.
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