A multifunctional network of basic residues confers unique properties to protein kinase CK2

Protein kinase CK2 is characterized by a number of features, including subs trate specificity, inhibition by polyanionic compounds and intrasteric down -regulation by its beta-subunit, which denote a special aptitude to interac t with negatively charged ligands. This situation may reflect the presence in CK2 catalytic subunits of several basic residues that are not conserved in the majority of other protein kinases. Some of these residues, notably K 49 in the 'Gly rich loop', K74, K75, K76, K77, K79, R80, K83 in the 'Lys ri ch segment' and R191, R195, K198 in the 'p+1 loop', have been shown by muta tional studies to be implicated to various extents and with distinct roles in substrate recognition, inhibition by heparin and by pseudosubstrate and instrasteric regulation. Molecular modelization based on crystallographic d ata provide a rationale for the biochemical observations, showing that seve ral of these basic residues are clustered around the active site where they make contact with individual acidic residues of the peptide substrate. The y can also mediate the effect of polyanionic inhibitors (e.g. heparin) and of regulatory elements present in the beta-subunit, in the N terminal segme nt of the catalytic subunit and possibly in other proteins interacting with CK2. Our data also disclose a unique mode of binding of the phosphoaccepto r substrate which bridges across the catalytic cleft making contacts with b oth the lower and upper lobes of CK2.