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.
