Protein kinases are kinases that modify other molecules, primarily proteins, by chemically adding phosphate groups to them. Phosphorylation often results in in a functional change of the target protein (substrate) by altering enzyme activity, cellular localization or binding to other proteins. The human genome contains approximately 518 protein kinase genes, which account for approximately 2% of all human genes. Up to 30% of all human proteins can be modified by kinase activity, and kinases are known to regulate most cellular pathways, especially those involved in signal transduction. Protein kinases are also found in bacteria and plants, and include pseudokinase subfamilies that exhibit unusual characteristics, including atypical nucleotide binding and weak or no catalytic activity, and are "degenerate" enzyme affinities. Part of a larger pseudo-enzyme group. Found throughout life, they actively participate in mechanical cell signaling.
Figure 1. Protein phosphorylation.
The chemical activity of a kinase involves the transfer of a phosphate group from a nucleoside triphosphate (usually ATP) and covalent attachment to a particular amino acid having a free hydroxyl group. Most kinases act on serine and threonine (serine/threonine kinase), other kinases act on tyrosine (tyrosine kinase), and some act on all three (bispecific kinases). There are also protein kinases that phosphorylate other amino acids, including histidine kinases, to phosphorylate histidine residues, resulting in acid and heat labile phosphoramidate linkages. Recent evidence on BioRxiv indicates extensive protein phosphorylation on a variety of non-canonical amino acids, including phosphorylated histidine, aspartic acid, glutamate, arginine and in human HeLa cell extracts. The motif of lysine. Due to the chemical instability of these phosphorylated residues, special procedures and separation techniques are required to preserve them as well as classical Ser, Thr and Tyr phosphorylation.
Serine/threonine-specific protein kinases
The serine/threonine protein kinase phosphorylates the OH group of serine or threonine (having a similar side chain). The activity of these protein kinases can be regulated by specific events (such as DNA damage) as well as a number of chemical signals, including cAMP/cGMP, diacylglycerols and Ca2+/calmodulin. A very important set of protein kinases is MAP kinase (from the acronym for "mitogen-activated protein kinase"). An important subgroup is the kinase of the ERK subfamily, which is normally activated by mitogenic signaling and stress-activated protein kinases JNK and p38. Although MAP kinases are serine/threonine specific, they are activated by phosphorylation of a combination of serine/threonine and tyrosine residues. The activity of MAP kinase is limited by a number of protein phosphatases that remove the phosphate group added to the specific serine or threonine residue of the kinase and require maintenance of the kinase in the active conformation. Two major factors affecting MAP kinase activity: a) activation of transmembrane receptors (natural ligands or crosslinkers) and signals associated with them (simulation of mutations in active states) b) signal inactivation limits the phosphatase of a given MAP kinase. These signals include oxidant stress.
Conformation of protein kinases
The active conformation of protein kinases is highly conserved across almost all non-metabolic, eukaryotic protein kinases. Furthermore, the equilibrium of inactive to active conformers differs between kinase domains, resulting in some kinase domains having higher activity levels than others. Numerous kinase catalytic domain structures have been solved in both their catalytically active and inactive conformers. The active conformation of kinases is highly conserved across almost all non-metabolic eukaryotic protein kinases. Furthermore, the equilibrium of inactive to active conformers differs between kinases, resulting in some kinases having higher activity levels than others. Some kinases are intrinsically in the active conformation, whereas others require additional events (e.g. post-translation modification or interactions with other domains or proteins) to drive them into the active form.
1. Manning G, et al.; The protein kinase complement of the human genome. Oncogene. 2002,19 (49): 5548–57.
2. Reiterer V, et al.; Day of the dead: pseudokinases and pseudophosphatases in physiology and disease. Trends in Cell Biology. 2014,24 (9): 489–505.