Differential Specificity of Protein Kinases A and C in Reaction with Synthetic Peptides

Abstract

A set of peptides Lys-Arg-Pro-Ser-X-Arg-Ala-Lys-Ala, where X stands for Gly, Ala, Val, Leu, Ile, Phe, Lys, Glu, and Gln was studied as protein kinase A substrates. Although the lead peptide of this series was designed as a specific substrate for protein kinase C, all the compounds listed were also phosphorylated by protein kinase A. The data were analyzed by means of quantitative structure–activity relationships, taking into account hydrophobicity of the variable amino acids, bulkiness of their side-groups quantified by the molecular refractivity constants MR. Differently from similar correlation, obtained previously for protein kinase C, there was no influence of the ionic status of the variable amino acid on peptide reactivity in reaction with protein kinase A. The results of correlation analysis were used to compare substrate specificity patterns of protein kinase A and protein kinase C, focusing on details of the molecular recognition of peptide structure in vicinity of the phosphorylatable serine residue. A quantitative structure–activity relationship was formulated to characterize differences in specificity of these enzymes at the peptide position +1.