Dual effect of lysine-rich polypeptides on the activity of protein kinase CK2

Protein kinase CK2 (casein kinase II) is normally a heterotetramer composed of catalytic (alpha, alpha') and regulatory subunits (beta). CK2 is able to phosphorylate a large number of protein substrates but the physiological mechanisms of its regulation are still unresolved. Lysine-rich peptides such as polylysine and histone H1 are known to stimulate the catalytic activity of the holoenzyme. This activation is mediated through the CK2beta regulatory subunit. In this communication, we report that the same concentrations of lysine-rich peptides or proteins that activate the holoenzyme cause strong inhibition of the phosphorylation of proteins catalyzed by the free catalytic CK2alpha subunit. The inhibitory effect of polylysine and histone H1 is observed with several protein substrates of CK2alpha (casein, adeno E1A, transcription factor II A, and CK2beta itself). With calmodulin, however, the inhibition of CK2alpha phosphorylation caused by polylysine is much lower while with a model peptide substrate of CK2 the inhibition caused by this polycation is negligible. The inhibition of CK2alpha by polylysine is observed only at limiting concentrations of the target substrate proteins. The dual effect of polylysine and of histone H1, which results in the inhibition of CK2alpha and stimulation of the CK2 alpha(2)beta(2) tetrameric holoenzyme, has the consequence that the addition of the CK2beta, in the presence of polylysine and low concentrations of substrate protein, can cause a 242-fold stimulation of the activity of CK2alpha. Other polycationic compounds such as polyarginine and spermine do not inhibit the phosphorylation of casein by CK2alpha, indicating that the effect is specific for lysine-rich peptides. Since there is evidence that there may be free CK2alpha subunits in the nuclei of cells, where there is abundant histone H1, the inhibition of CK2alpha by this lysine-rich protein may have physiological relevance.