The protein kinase super family accounts for nearly 2% of the genes in the human genome and codes for about 545 kinases. The eukaryotic protein kinases are subdivided into three classes: two major classes, the serine/threonine and the tyrosine kinases, and one small class of dual specific kinase (serine/threonine and tyrosine). The classes share extensive sequence and structure homologies. The catalytic domains are typically characterized by a small N-terminal lobe that contains a glycine-rich loop (P-loop) for ATP binding and a larger C-terminal domain that contains a conserved activation loop (also called ‘T-loop’ or activation segment). ATP and substrates bind in the cleft between the two lobes. ATP is bound in a hydrophobic pocket, whereas substrates bind along the cleft and interact with a set of conserved residues that catalyze phosphorylation.
The substrate specificity of protein kinases typically depends on the primary amino acid sequences immediately flanking the site of phosphorylation, called the ‘consensus sequence’. The numbers and types of interactions with residues surrounding the phosphorylation site vary considerably among kinases, reflecting differences in sequence specificity. Protein kinase families are thus classified into basophilic, acedophilic and proline-directed kinases. The first group, which includes kinases such as PKA, PKB and PKC, prefers positively charged residues within the recognition motif. The consensus sequences of acidophilic group kinases, like casein kinase1/2, have acidic residues near the phosphorylation site. The largest family is the proline-directed kinases (MAPK’s, CDK’s, GSK-3) and the recognition motifs of these kinases all include proline.
Although all ‘classical’ protein kinases share a common catalytic fold, these proteins show remarkable diversity in their substrate specificity and signal transmission. This is mainly attributed to additional elements, such as distinct regions located outside the catalytic core, regulatory domains, or adaptor molecules that can directly affect the interaction with substrates or other components within the signaling network.