5XMC

Crystal structure of the auto-inhibited Nedd4 family E3 ligase Itch

5XMC の概要

• エントリーDOI: 10.2210/pdb5xmc/pdb
• 分子名称: E3 ubiquitin-protein ligase Itchy (2 entities in total)
• 機能のキーワード: auto-inhibited itch, ligase
• 由来する生物種: Mus musculus (Mouse)
• 細胞内の位置: Cell membrane : Q8C863
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 83412.20

構造登録者

Shan, Z.,Wen, W. (登録日: 2017-05-13, 公開日: 2017-08-02, 最終更新日: 2023-11-22)

主引用文献

Zhu, K.,Shan, Z.,Chen, X.,Cai, Y.,Cui, L.,Yao, W.,Wang, Z.,Shi, P.,Tian, C.,Lou, J.,Xie, Y.,Wen, W.
Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch
EMBO Rep., 18:1618-1630, 2017

PubMed Abstract: The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. However, the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation is poorly understood. Here, we show that the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT in the Nedd4 E3 family member Itch. Our structural and biochemical analyses of Itch reveal that the WW2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2-E3 transthiolation. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW2-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Our study provides a new mechanism governing the regulation of Itch.

PubMed: 28747490
DOI: 10.15252/embr.201744454

実験手法

X-RAY DIFFRACTION (2.6 Å)