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J. Biol. Chem., Vol. 268, Issue 19, 13906-13913, Jul, 1993

Activation of protein kinase C by selective binding of arginine-rich polypeptides

PS Leventhal and PJ Bertics
Department of Biomolecular Chemistry, University of Wisconsin-Madison 53706.

Protein substrates for protein kinase C (PKC) have phosphorylation domains that are typically rich in the basic amino acids arginine and lysine. However, arginine-rich proteins may interact with PKC differently than lysine-rich proteins, i.e. lysine-rich histone requires phospholipid and Ca2+ to be phosphorylated, whereas the arginine-rich protein, protamine, can bypass these effector requirements. We have studied the interaction of PKC with protamine, histone, poly-L-arginine, and poly-L-lysine to better understand the role of basic protein domains in PKC activation, effector dependence, and substrate specificity. Using a microtiter binding assay, PKC was found to bind tightly to protamine and poly-L-arginine, but not to histone or poly-L-lysine, in the absence of phospholipid, Ca2+, and MgATP. Furthermore, poly-L-arginine was much more potent than poly-L- lysine at inhibiting protamine phosphorylation; i.e. 1-2 nM poly-L- arginine was sufficient to cause 50% inhibition of protamine phosphorylation, whereas over 300 microM poly-L-lysine was needed to reach 50% inhibition. Autophosphorylation of PKC in the absence of activators was potently stimulated by protamine and poly-L-arginine, but not by histone or poly-L-lysine, suggesting selective stimulation of PKC by arginine-rich polypeptides. Double-reciprocal plots of protamine phosphorylation using either a mixture of isozymes (alpha/beta/gamma) or isolated PKC-beta were parabolic, and analysis of the kinetic data on velocity/[protamine] versus velocity plots indicated positive cooperativity with respect to protamine. These findings are consistent with those from autophosphorylation experiments in that PKC appears to be selectively stimulated by arginine-rich polypeptides. These results suggest that PKC can preferentially bind arginine-rich proteins in the absence of phospholipid and Ca2+. This interaction appears to be distal to the catalytic site and thus binding of arginine-rich proteins may allosterically activate PKC. Selective stimulation of PKC by arginine-rich proteins may be a mechanism by which protamine can bypass activator requirements. Furthermore, control of PKC activity by activator-independent binding of arginine-rich polypeptides suggests that altering access to certain cellular proteins may be a mechanism for PKC regulation in vivo.
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