Premium
Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch
Author(s) -
Zhu Kang,
Shan Zelin,
Chen Xing,
Cai Yuqun,
Cui Lei,
Yao Weiyi,
Wang Zhen,
Shi Pan,
Tian Changlin,
Lou Jizhong,
Xie Yunli,
Wen Wenyu
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201744454
Subject(s) - allosteric regulation , ubiquitin ligase , nedd4 , dna ligase , ubiquitin protein ligases , microbiology and biotechnology , chemistry , biochemistry , enzyme , biology , genetics , ubiquitin , gene
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 WW 2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2‐E3 transthiolation. Binding of the Ndfip1 adaptor or JNK 1‐mediated phosphorylation relieves the auto‐inhibition of Itch in a WW 2‐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.