InterPro domain: IPR016149

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [ 1 ]:

• Serine/threonine-protein kinases
• Tyrosine-protein kinases
• Dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human [ 2 ]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [ 3 ]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [ 4 ], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [ 5 ].

Casein kinase, a ubiquitous, well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha- and 2 beta-subunits [ 6 , 7 ]. However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') [ 8 ]. The alpha-subunit is the catalytic unit and contains regions characteristic of serine/threonine protein kinases. The beta-subunit is believed to be regulatory, possessing an N-terminal auto-phosphorylation site, an internal acidic domain, and a potential metal-binding motif [ 9 ]. The beta subunit is a highly conserved protein of about 25kDa that contains, in its central section, a cysteine-rich motif, CX(n)C, that could be involved in binding a metal such as zinc [ 9 ]. The mammalian beta-subunit gene promoter shares common features with those of other mammalian protein kinases and is closely related to the promoter of the regulatory subunit of cAMP-dependent protein kinase [ 10 ].

This superfamily represents the N-terminal alpha-helical domain, which has an orthogonal bundle topology.

1. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42-52
2. The protein kinase complement of the human genome. Science 298, 1912-34
3. Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514-20
4. High-throughput structural biology in drug discovery: protein kinases. Curr. Pharm. Des. 10, 1069-82
5. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screen. 7, 453-72
6. Human phosvitin/casein kinase type II. Molecular cloning and sequencing of full-length cDNA encoding subunit beta. Eur. J. Biochem. 183, 227-33
7. Structure of the gene encoding human casein kinase II subunit beta. J. Biol. Chem. 266, 13706-11
8. Cloning and disruption of CKB1, the gene encoding the 38-kDa beta subunit of Saccharomyces cerevisiae casein kinase II (CKII). Deletion of CKII regulatory subunits elicits a salt-sensitive phenotype. J. Biol. Chem. 270, 10395-404
9. Cloning and disruption of CKB2, the gene encoding the 32-kDa regulatory beta'-subunit of Saccharomyces cerevisiae casein kinase II. J. Biol. Chem. 269, 18192-200