Development of chemical probes for capturing protein arginine kinases

Abstract

Protein arginine phosphorylation, one of the relatively acid-labile N-phosphorylations, has been identified in numerous prokaryotic and eukaryotic proteins. The only known protein Arg kinase is McsB in Gram-positive bacteria, characterized in 2009. McsB is a heat-stress responsive kinase and phosphorylates Arg residues in aggregated cytosolic proteins so that phosphoarginine (pArg) acts as a protein degradation tag recognized by the ClpC/ClpP protease system. Recently, bacterial-PROTAC was developed using pArg and ClpC-binding cyclic peptide to induce the degradation of the target protein in mycobacterium. In contrast, no eukaryotic or mycobacterial protein Arg kinase has been identified despite pArg sites in those organisms, hindering further studies of Arg phosphorylation. Herein, we report our progress in developing mechanism-based chemical probes to label and capture the elusive Arg kinase.