Protein kinase Domain structure

Multifunctional Ca2+/calmodulin-dependent protein kinase Domain structure and regulation, H. Schulman and L. 

Figure 15.26. Janus Kiuase Domaiu Structure. A Janus kinase (JAK) includes four recognized domains an ERM domain that favors interactions with membranes, an SH2 domain that binds phosphotyrosine-containing peptides, and two domains homologous to protein kinases. Only the second protein kinase domain appears to be enzymatically functional.

Figure 15.35. Sre Structure. (A) Cellular Sre includes an SH3 domain, an SH2 domain, a protein kinase domain, and a carboxyl-terminal tail that includes a key tyrosine residue. (B) Structure of c-Src in an inactivated form with the key tyrosine residue phosphorylated. The phosphotyrosine residue is bound in the SH2 domain the linker between the SH2 domain and the protein kinase domain is bound by the SH3 domain. These interactions hold the kinase domain in an inactive conformation.

Figure 14.19 Activation of the insulin receptor by phosphorylation. The activation loop is shown in red in this model of the protein kinase domain of the fi subunit of The Insulin receptor. The unphosphorylated structure on the left is not catalytically active. Notice that, when three tyrosine residues in the activation loop are phosphorylated, the activation loop swings across the structure and the kinase structure adopts a more compact conformation. This conformation is catalytically active. [Drawn from lIRK.pdb and IR3.pdb.]...

Although there is no similarity to classical protein kinases on the primary sequence level, the three-dimensional structure of the TRP channel protein kinase domain is very similar to the classical kinase fold. 

Fig. 15.2-1 Ribbon diagram showing the structure of the catalytic domain of murine protein kinase A (PKA) in complex with Mg/ATP (lQ24.pdb). The basic architecture that has been observed in all subsequent kinase domain structures is denoted.

The catalytic subunit of cAPK contains two domains connected by a peptide linker. ATP binds in a deep cleft between the two domains. Presently, crystal structures showed cAPK in three different conformations, (1) in a closed conformation in the ternary complex with ATP or other tight-binding ligands and a peptide inhibitor PKI(5-24), (2) in an intermediate conformation in the binary complex with adenosine, and (3) in an open conformation in the binary complex of mammalian cAPK with PKI(5-24). Fig.l shows a superposition of the three protein kinase configurations to visualize the type of conformational movement. 

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

AKAPs are a diverse family of about 75 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins to cellular compartments and thereby limit and integrate cellular signalling processes at specific sites. This compartmentalization of signalling by AKAPs contributes to the specificity of a cellular response to a given external stimulus (e.g. a particular hormone or neurotransmitter). 

Adaptor Proteins. Figure 1 Adaptor protein domains. A scheme of the domain structures of some well-characterized adaptor proteins is shown. Descriptions of domain characteristics are in main text except C2, binds to phospholipids GTPase activating protein (GAP) domain, inactivates small GTPases such as Ras Hect domain, enzymatic domain of ubiquitin ligases and GUK domain, guanylate kinase domain. For clarity, not all domains contained within these proteins are shown. 

Protein Kinase C. Figure 1 Domain structure of PKC family members showing regulatory modules (pseudosubstrate sequence and C1, C2, and PB1 domains) and the kinase core. Shown below are the structures of the C1 domain of PKC 5 with bound phorbol (purple), the C2 domain of PKC (3 with bound Ca2+ (pink spheres), and the recently solved structure of the kinase domain by Grant and coworkers [1] of PKC pil with phosphorylation sites indicated in pink. Figure adapted from Newton (2003). 

Grodsky N, Li Y, Bouzida D et al (2006) Structure of the catalytic domain of human protein kinase C (311 complexed with a bisindolylmaleimide inhibitor. Biochemistry 45 13970-13981... 

Figure 5-8. Domain structure. Protein kinases contain two domains. The upper, amino terminal domain binds the phosphoryl donor ATP (light blue). The lower, carboxyl terminal domain is shown binding a synthetic peptide substrate (dark blue).

Molecular insight into the protein conformation states of Src kinase has been revealed in a series of x-ray crystal structures of the Src SH3-SH2-kinase domain that depict Src in its inactive conformation [7]. This form maintains a closed structure, in which the tyrosine-phosphorylated (Tyr527) C-terminal tail is bound to the SH2 domain (Fig. 2). The x-ray data also reveal binding of the SH3 domain to the SH2-kinase linker [adopts a polyproline type II (PP II) helical conformation], providing additional intramolecular interactions to stabilize the inactive conformation. Collectively, these interactions cause structural changes within the catalytic domain of the protein to compromise access of substrates to the catalytic site and its associated activity. Significantly, these x-ray structures provided the first direct evidence that the SH2 domain plays a key role in the self-regulation of Src. 

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