Chemosensors for Unconventional Protein Phosphorylations

Abstract

Protein phosphorylation controls the target protein functions, and it plays an important role in cell signaling and other physiological processes. Accordingly, misregulated phosphorylation has been linked to various human diseases including inflammation, diabetes, and cancer. In recent years, serine (Ser), threonine (Thr), and tyrosine (Tyr) phosphorylation have been studied extensively thanks to the advances in phosphoproteomics and other research tools. However, protein N-phosphorylations on histidine (His) and arginine (Arg) residues have been relatively unexplored because of their chemical instability and technical difficulties. Nonetheless, some important functions of these unconventional protein phosphorylations have been identified. For example, histidine phosphorylation is the key event in two component signal transduction systems, the major sensor systems in bacteria, plants, and fungi. And arginine phosphorylation regulates protein degradation and stress responses. Here, we report our progress in the development of fluorescence-based chemosensors for protein His/Arg phosphorylation. These chemosensors can be applied to real-time measurement of the kinase and phosphatase activities, with potential applications in high-throughput screening of the enzyme inhibitors/activators and discovery of novel His/Arg kinases.