HECT类泛素连接酶E6AP自抑制及病毒蛋白E6对其激活的分子机制研究

E6AP是一种HECT类的泛素连接酶，其活性异常增强是自闭症发生的重要因素，而E6AP基因缺失则与人类天使综合征有关。这表明E6AP表达水平和活性在正常生理环境下需要受到严格调控。我们及他人的实验表明E6AP处于自抑制状态，然而具体的分子机制仍然不清楚。.E6AP会被与宫颈癌相关病毒HPV-16表达的一种早期病毒蛋白E6（16E6）劫持，16E6/E6AP诱导的p53失活在90%以上的宫颈癌进展中起重要作用。在此过程中，16E6不仅起到衔接蛋白的作用，还是E6AP的激活蛋白。由于缺乏相应的结构信息，目前我们仍然不清楚E6AP/16E6/p53复合体组装及16E6介导p53泛素化的分子机制。.本项目在前期研究基础上，测定E6AP自抑制状态以及E6AP/16E6/p53的原子结构，综合运用生物化学、细胞生物学等多种手段，研究E6AP自抑制及16E6劫持E6AP泛素化修饰p53的分子机制。

E6AP is a HECT-type ubiquitin ligase, and the abnormal increase of its activity is an important factor in the occurrence of Autism, while the deletion of E6AP gene is related to human Angel syndrome. This indicates that the expression level and activity of E6AP need to be strictly regulated under normal physiological environment. The results of our previous experiments and other research groups have shown that E6AP is in an auto-inhibitory state, but the specific molecular mechanism is still unclear..E6AP can be hijacked by an early viral protein E6 (16E6) expressed by HPV-16, a virus closely related to cervical cancer. 16E6/E6AP-induced p53 inactivation plays an important role in more than 90% of cervical cancer progression. In this process, 16E6 not only acts as an adaptor protein, but also acts as an activator protein of E6AP. Due to the lack of corresponding structural information, we still do not know the molecular mechanism of E6AP/16E6/p53 complex assembly and 16E6-mediated p53 ubiquitination..Based on our previous research, this project will measure the atomic structure of the auto-inhibition status of E6AP and the E6AP/16E6/p53 complex, and use a variety of methods such as biochemistry and cell biology to study the molecular mechanism of E6AP auto-inhibition and 16E6-mediated p53 ubiquitination.