Protein kinases catalytic domain fold

All related serine/threonine kinases and protein tyrosine kinases share a structurally conserved catalytic domain of about 270 amino acids. Numerous kinase catalytic domains have been structurally characterized by X-ray crystallography [14-18]. All of them share the highly conserved bilobal fold that is depicted in Fig. 15.2-1. In this fold, the N-terminal lobe is composed almost entirely of -sheets, whereas the C-terminal lobe is dominated by a-helices. The two lobes are joined by a polypeptide chain, which functions... 

All catalytic domains of protein kinases exhibit the same characteristic fold, with the ATP-binding niche being located in the cleft between the N-terminal and C-terminal subdomains (for kinases operating on non-protein substrates, however, other folds are also found [109]). The uniqueness of this picture is even more surprising, given that the human genome is estimated to include approximately 520 protein kinases [110], compared to a mere 150 protein phosphatases [111],... 

Figure 2 Snapshots of the overall structure and catalytic machinery of protein kinase A. (a) The overall fold of the catalytic domain is formed by two subdomains, a beta sheet N-terminus (gray) and a C-terminal helical domain (green). ATP binds a cleft between the two lobes, and the phosphoacceptor substrate binds the C-terminal lobe, (b) N-terminal residues Lys 72 and Glu 91 orient the phosphates toward the phosphoacceptor peptide (pink/yellow) in concert with one of two magnesium ions, (c) C-terminal residue Lys 168 acts as an electrostatic catalyst to stabilize the y-phosphate during the reaction while asparagine 171 and aspartate 184 position the phosphates within the active site.

Comparison (or alignment) of amino acid sequences, also called homology search, often provides first-hand information on such conserved structural features and enables one to classify enzymes into families and predict the possible function of a new enzyme (86). A family of enzymes usually folds into similar 3-D structures, at least at the active site region. A typical example is the serine protease family whose members—trypsin, chymotrypsin, elastase, and subtilisin—commonly contain three active-site residues, Asp/His/Ser, which are known as the catalytic triad or charge relay system. Another example is the conserved features of catalytic domains of the highly diverse protein kinase family. In this kinase family, the ATP-binding (or phosphate-anchoring) sites present a consensus sequence motif of Gly-X-Gly-X-X-Gly (67,87). 

C-terminal to the kinase domain the receptor appears to be proteolytically sensitive, suggesting that these sequences are exposed [6], The most C-terminal domain of the molecule is, however, less sensitive to proteolysis and may be more highly folded. The receptor not only catalyses the phosphorylation of exogenous substrate proteins but can also modify itself by phosphorylating three tyrosine residues within the cytoplasmic domain at positions 1068, 1148 and 1173 [1], The functional significance of this autophosphorylation is not clear. Some reports suggest that autophosphorylation leads to a three-fold stimulation of catalytic rate [16], while others have found no effect [6,10]. 

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