Bridging the Glycome and Proteome with Chemical Biology

项目摘要 糖蛋白和蛋白聚糖是细胞中重要的蛋白质糖复合物。他们可以 控制许多生物学事件，如生长因子信号传导、细胞粘附和分化， 来影响癌症生物学、发育和免疫力。虽然对人体健康和生理至关重要， 我们目前还没有一个全面的分子理解， 协调它们的功能。许多技术孤立地研究这些分子-只关注 单独的蛋白质或聚糖组分。目前的做法严重低估了 蛋白质糖缀合物的结构多样性，它给我们留下了一个狭窄的理解， 蛋白质糖型如何差异调节生物学。此外，它还阻碍了 to use glycoform糖-dependent依赖interactions相互作用for drug药物discovery发现.我们的研究计划整合了 化学生物学，分子生物学和蛋白质工程技术，以解决 这些差距。在本申请中，我们描述了我们的计划，以创建定义的半合成 糖蛋白和蛋白聚糖，并使用这些材料来研究它们在活细胞中的相互作用。 鉴定与聚糖结合蛋白相关的糖蛋白允许使用靶向的 遗传学方法来研究它们的功能贡献。从这些发展而来的见解 研究将创造一个机会，发现小分子，可以选择性地调节 聚糖结合蛋白和糖蛋白相互作用，以调节重要的生物学功能。 事件

PROJECT SUMMARY Glycoproteins and proteoglycans are important protein glycoconjugates in the cell. They can control many biological events, such as growth factor signaling, cell adhesion, and differentiation, to impact cancer biology, development, and immunity. While vital to human health and physiology, we currently do not have a comprehensive molecular understanding of how these molecules orchestrate their functions. Many techniques study these molecules in isolation – focusing on only the protein or glycan component alone. This current approach severely underappreciates the structural diversity of protein glycoconjugates, and it has left us with a narrowed understanding of how protein glycoforms can differentially regulate biology. Furthermore, it has impeded pathways to use glycoform-dependent interactions for drug discovery. Our research program integrates techniques in chemical biology, molecular biology, and protein engineering, in order to address these gaps. In this application, we describe our plans to create defined semi-synthetic glycoproteins and proteoglycans, and to use these materials to study their interactions in live cells. Identifying the glycoproteins associated with glycan-binding proteins allows the use of targeted genetic approaches to study their functional contributions. The insights developed from these studies will create an opportunity to discover small molecules that can selectively modulate glycan-binding protein and glycoprotein interactions in order to regulate important biological events.