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Allosteric auto‐inhibition and activation of the Nedd4 family E3 ligase Itch |
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| Authors: | Yuqun Cai Lei Cui Weiyi Yao Zhen Wang Pan Shi Changlin Tian Jizhong Lou Yunli Xie Wenyu Wen |
| Institution: | 1. Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China;2. Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;3. Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China;4. School of Life Sciences, University of Science and Technology of China, Hefei, China |
| 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. |
| Keywords: | allosteric regulation crystal structure Itch Ndfip1 Nedd4 family E3 ligases |