A covalent strategy to profile the reader proteins of glycosylation

Project Summary/Abstract Proteins interact with proteins, carbohydrates, nucleic acids, and lipids. These interactions govern every aspect of life. Deciphering these interactions can contribute to the understanding of the fundamental aspects of life and open up diverse opportunities for therapeutic intervention. While there are efficient tools to probe protein-protein or protein-nucleic acid interactions, it’s a different story for the study of protein-carbohydrate interactions. Certain glycan-binding proteins (GBPs) can read the codes of glycosylation (termed as readers proteins of glycosylation for clarification), initiating downstream signaling via the interactions with the carbohydrates presented on proteins or lipids. These reader proteins interact with glycans to regulate cell–cell communication, organism development, tumor cell metastasis, immune surveillance, and pathogen-host interactions. Despite the critical roles of protein- carbohydrate interactions, the lack of tools greatly hindered the efforts to study such interactions and leverage these interactions for therapeutic purposes. To address these challenges, our lab will leverage our expertise in organic synthesis, molecular biology, and protein science to build a versatile, small molecule-based platform to map the reader proteins of glycosylation. In the next five years, we will first fully demonstrate the feasibility of the proposed platform and then expand this platform to study the reader proteins of critical glycosylation including sialylation and core fucosylation. We will also conduct structural characterization of the key identified reader proteins. The overall goal of this research program is to decipher the protein-carbohydrate interaction code, especially disease-related protein-carbohydrate interactions, which would lay out the foundation for the development of therapeutics targeting carbohydrates.