Defining, studying, and targeting sulfated tyrosine residues of cell surface receptors for disease treatment

项目总结

Project Summary Protein tyrosine O-sulfation (PTS) of cell surface receptors plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes, including cell adhesion, leukocyte trafficking, hormone activities, and immune responses. Tyrosine-sulfated receptors also participate in the development of various human diseases. Accordingly, PTS could emerge as an important drug target for the treatment of human diseases. Despite substantial advances in our knowledge of PTS, our current understanding of its biological significance is still in its infancy. It is this knowledge gap we seek to fill. In one direction, we will conduct comprehensive and discovery-based sulfoproteomic studies, which will lay the foundation to unveil the entire human receptor sulfointeractome and to identify disease-related sulfoprotein-protein interactions. In the second direction, we seek to define the role of PTS in the function of chemokine receptors. Chemokine signaling is central to chronic inflammatory conditions and participates in the development of many human diseases. At their N-terminal region, chemokine receptors contain tyrosine residues that can be sulfated to different extent (designated as “PTS level”). Our hypothesis is that chemokine receptors (and possibly other cell surface receptors in general) can be sulfated to various PTS levels, which allows the receptors to bind different ligands and leads to altered downstream biological/pathological events. In addition to basic mechanistic studies, we also seek to explore and develop novel therapeutic agents targeting PTS of chemokine receptors, such as C-X-C chemokine receptor type 4 (CXCR4). CXCR4 plays important roles in both physiological and pathological conditions, and it represents a crucial target in drug development. Our proposed work will be enabled by three technological breakthroughs, including the engineering of sulfotyrosine-recognizing small protein scaffolds, the use of state-of-the-art mass spectrometry methods, and the development of genetic method to encode sulfotyrosine in mammalian cells. Overall, the successful completion of the proposed work is expected to yield comprehensive data on receptor sulfoproteome, to gain insights into PTS-associated cellular biology, and to produce novel therapeutic interventions of human diseases.