Precision Substrate Targeting of Protein Kinases

The cAMP-dependent (PKA) and cGMP-dependent protein kinases (PKG) share a strong primary sequence homology within their respective active site regions. Not surprisingly, these enzymes also exhibit overlapping substrate specificities, a feature that often interferes with efforts to elucidate their distinct biological roles. In this report, we demonstrate that PKA and PKG exhibit dramatically different behavior with respect to the phosphorylation of α-substituted alcohols. Although PKA will phosphorylate only residues that contain an α-center configuration analogous to that found in L-serine, PKG utilizes residues that correspond to both L- and D-serine as substrates. The PKG/PKA selectivity of these substrates is the highest ever reported. The cAMP-dependent (PKA) and cGMP-dependent protein kinases (PKG) share a strong primary sequence homology within their respective active site regions. Not surprisingly, these enzymes also exhibit overlapping substrate specificities, a feature that often interferes with efforts to elucidate their distinct biological roles. In this report, we demonstrate that PKA and PKG exhibit dramatically different behavior with respect to the phosphorylation of α-substituted alcohols. Although PKA will phosphorylate only residues that contain an α-center configuration analogous to that found in L-serine, PKG utilizes residues that correspond to both L- and D-serine as substrates. The PKG/PKA selectivity of these substrates is the highest ever reported.