Abstract
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.
Highlights
HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumorsuppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases
The Nedd[4] 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
Deletion of L (234HECT) caused a striking increase in WWP1 autoubiquitination, indicating that L has a dominant role in ligase regulation
Summary
HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumorsuppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Several recent studies on Itch, WWP2, and their Drosophila orthologue Su(dx) have shown that the WW2 domain and the linker region (referred to as L hereafter) between WW2 and WW3 synergistically interact with HECT to inhibit ligase activity by occupying the noncovalent ubiquitin binding site and restricting the flexibility of the two lobes[31,32,33]. Such WW2L-mediated autoinhibition can be released by binding to three PY-bearing adaptor Ndfip[1] or JNK1-mediated phosphorylation sites through the WW domains or by the phosphorylation of L. We show that this multi-lock regulation mechanism is conserved in WWP2 and Itch, whereas in Nedd4/4 L and Smurf[2], a variant version of the multi-lock autoinhibition mode is utilized
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