Bridging the Glycome and Proteome with Chemical Biology

项目总结 糖蛋白和蛋白多糖是细胞内重要的蛋白质糖结合物。他们可以 控制许多生物事件，如生长因子信号、细胞黏附和分化， 来影响癌症的生物学、发展和免疫。虽然对人类健康和生理至关重要， 我们目前还没有全面的分子理解这些分子是如何 协调他们的职能。许多技术孤立地研究这些分子--只关注 单独的蛋白质或多聚糖成分。目前的方法严重低估了 蛋白质糖结合物的结构多样性，这给我们留下了对 蛋白质糖形态如何不同地调节生物学。此外，它还阻碍了道路 利用糖形式依赖的相互作用进行药物发现。我们的研究项目整合了 化学生物学、分子生物学和蛋白质工程的技术，以解决 这些差距。在本应用程序中，我们描述了创建定义的半合成的计划 糖蛋白和蛋白多糖，并使用这些材料来研究它们在活细胞中的相互作用。 识别与糖结合蛋白相关的糖蛋白允许使用靶向 用遗传学方法研究它们的功能贡献。洞察力是从这些方面发展而来的 研究将创造机会，发现可以选择性调制的小分子 糖链结合蛋白与糖蛋白相互作用以调节重要生物 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.