Allosteric auto-inhibition and activation of the Nedd4 family E3 Iigase Itch

作者：温文玉

来源：华东地区生物化学与分子生物学学会联合会2017年学术交流会暨安徽省生物化学与分子生物学学会理事会议, 中国安徽合肥, 2017-10-27.

• Allosteric auto-inhibition and activation of the Nedd4 family E3 Iigase Itch

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 E3 s are tightly controlled via auto-inhibition.However,the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation are 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 Ndfipl 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.

• 出版日期2017
• 单位复旦大学