5XMC

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

Summary for 5XMC

• Entry DOI: 10.2210/pdb5xmc/pdb
• Descriptor: E3 ubiquitin-protein ligase Itchy (2 entities in total)
• Functional Keywords: auto-inhibited itch, ligase
• Biological source: Mus musculus (Mouse)
• Cellular location: Cell membrane : Q8C863
• Total number of polymer chains: 1
• Total formula weight: 83412.20

Authors

Shan, Z.,Wen, W. (deposition date: 2017-05-13, release date: 2017-08-02, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)