The protein kinase complement of the human genome. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. In addition mutations in certain AGC kinases are linked to some inherited syndromes. Several AGC family members have been implicated in disease, and numerous drugs targeting these kinases have been developed to treat conditions such as cancer and diabetes. Some substrates are phosphorylated only by one AGC kinase, whereas others can be phosphorylated by multiple AGC kinases. The functions of some of these domains have not been fully defined.ĪGC kinases are involved in numerous cellular processes, exemplified by the large number of proteins that they can phosphorylate.
#Kinases with known consensus sequences full
Most described structures to date are of the catalytic domain further work is required to elucidate the structure of full length AGC kinases.ĪGC family members are regulated in various ways, but most require phosphorylation and/or conformational changes to be activated.įunctional domains, other than the kinase domain, have important roles in regulating the activity and localization of AGC kinases. Structural studies have revealed that although the structures of active AGC kinases are highly similar, inactive AGC kinases can adopt several conformations. 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.There are 60 members of the AGC family of protein kinases, which all share a conserved catalytic kinase domain. The largest family is the proline-directed kinases (MAPK’s, CDK’s, GSK-3) and the recognition motifs of these kinases all include proline.Īlthough all ‘classical’ protein kinases share a common catalytic fold, these proteins show remarkable diversity in their substrate specificity and signal transmission. The consensus sequences of acidophilic group kinases, like casein kinase1/2, have acidic residues near the phosphorylation site. The first group, which includes kinases such as PKA, PKB and PKC, prefers positively charged residues within the recognition motif. Protein kinase families are thus classified into basophilic, acedophilic and proline-directed kinases. The numbers and types of interactions with residues surrounding the phosphorylation site vary considerably among kinases, reflecting differences in sequence specificity. The substrate specificity of protein kinases typically depends on the primary amino acid sequences immediately flanking the site of phosphorylation, called the ‘consensus sequence’. ATP is bound in a hydrophobic pocket, whereas substrates bind along the cleft and interact with a set of conserved residues that catalyze phosphorylation. ATP and substrates bind in the cleft between the two lobes.
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). The classes share extensive sequence and structure homologies. 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 protein kinase super family accounts for nearly 2% of the genes in the human genome and codes for about 545 kinases.
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