EOGT催化Notch受体O-GlcNAcylation的机制与功能研究

Notch信号通路发挥着重要的生物学功能，与疾病发生密切相关。其信号传递受到复杂的糖基化修饰调控。EOGT能特异性催化Notch受体胞外域EGF-like repeats发生O-N-乙酰氨基葡萄糖基化，与Notch信号通路紧密联系，是人类亚当斯-奥利弗综合征（AOS）的致病基因。目前对EOGT催化Notch糖基化的机制认识非常有限，捕捉EOGT的功能结构状态有助于阐明EOGT的功能机制，然而相关研究尚未见报道。.本项目将对新型糖基转移酶EOGT催化Notch受体O-GlcNAc修饰的机制与功能开展研究。我们将借助结构生物学方法，解析EOGT及其与底物形成的复合物的分子结构，阐明其特异识别Notch受体以及催化O-GlcNAcylation的分子机理。在此基础上，分析EOGT对Notch信号通路的作用，并进一步探索EOGT在AOS疾病发生中发挥的作用，为相关疾病诊断和治疗提供新思路。

Notch signaling pathway plays important biological functions and is closely related to human diseases. Notch signaling is regulated by complicated glycosylation. The addition of O-linked β-N-acetylglucosamine to EGF-like repeats of Notch extracellular domain is catalyzed by EOGT (EGF domain-specific O-GlcNAc transferase), which is associated with the Notch signaling pathway. EOGT is the pathogenic gene in Adams-Oliver syndrome (AOS). However, the mechanism of Notch O-GlcNAcylation by EOGT remains poorly understood, limiting our understanding of the important role of this modification on Notch signaling. .This project will focus on the molecular mechanism and function of O-GlcNAcylation on Notch receptor catalyzed by the newly-discovered glycosyltransferase EOGT. We will solve the structures of EOGT and its related complexes, and elucidate how it recognizes Notch receptor and catalyzes O-GlcNAcylation. Based on the structural analysis, we will analyze the role of EOGT in Notch signaling. With the established methods, we will further investigate the pathogenic effects of AOS-related EOGT mutants. The research will bring us implications for diagnosis and therapy insights of related diseases.