Protein kinases principles

The principle underlying the changes in activity of a G-protein is similar to that of an interconversion cycle (Chapter 3). The classic example of an interconversion cycle is that between the two forms of the enzyme phos-phorylase phosphorylase a and b. The interconversions between b and a are catalysed by a protein kinase and a protein phosphatase. The similarities are as follows. 

Figure 20.31 The principle of interconversion cycles in regulation of protein activity or changes in protein concentration as exemplified by translation/proteolysis or protein kinase/protein phosphatase. They result in very marked relative changes in regulator concentration or enzyme activity. The significance of the relative changes (or sensitivity in regulation) is discussed in Chapter 3. The principle of regulation by covalent modihcation is also described in Chapter 3. The modifications in cyclin concentration are achieved via translation and proteolysis, which, in effect, is an interconversion cycle. For the enzyme, they are achieved via phosphorylation and dephosphorylation reactions. In both cases, the relative change in concentration/activity by the covalent modification is enormous. This ensures, for example, that a sufficient increase in cyclin can occur so that an inactive cell cycle kinase can be converted to an active cell cycle kinase, or that a cell cycle kinase can be completely inactivated. Appreciation of the common principles in biochemistry helps in the understanding of what otherwise can appear to be complex phenomena.

The principle of targeted localization is shown in Fig. 7.22. In addition to the binding site for the corresponding protein kinase (or protein phosphatase), the localization subunit also has a specific binding site for an anchor protein, found at a subceUular site in the region where protein phosphorylation should take place. Through the interaction of anchor protein and localization subunit, the catalytic subunit is fixed at the desired location and is able to preferentially convert substrate localized at the same location. 

Src kinase was discovered during the search for the tumor-causing principle of retroviruses. The viral oncogene product of these viruses, v-Src kinase, was the first tyrosine kinase to be identified. In comparison to its cellular coimterpart, c-Src kinase, v-Src lacks the autoinhibitory structural element that controls protein kinase activity. As a consequence of this loss, v-Src kinase is constitutively active and is a potent transforming protein. 

Fig. 10.1. Principle of signal transduction through intracellular protein kinase cascades. The intracellular protein kinase cascades are organized in modules composed in most cases of three proteinkinases and a scaffold protein. The modules process signals that are registered, integrated and passed on at the inner side of the cell membrane by central switching stations such as the Ras protein or the Rac protein. In the case of the MAP kinase pathway, the cascade includes at least three different protein kinases. Specific regulatory processes may take effect at every level of the cascade in addition, signals may be passed from the different protein kinases to other signaling pathways.

Fig. 7.20 The principle of targeted localization of protein kinases and protein phosphatases. The spatial configuration between the catalytic subunit of a protein kinase or protein phosphatase and a membrane-associated substrate is mediated by localization subunits that specifically bind to membrane-localized anchor proteins. The specificity of...

Fig. 13.5 P rinciples of regulation of cyclin-de-pendent protein kinases. The figure shows the principles of CDK regulation, usingthe CDC2 kinase (here simply referred to as CDK) as an example. The active form of CDK (a) is associated with the corresponding cyclin Thrl 60 of CDK (or equivalent positions in other CDKs) is phosphorylated, and Thrl4 and Tyrl 5 are unphosphorylated. Inactivation...

In principle, one can classify the phosphoproteins into two groups (1) functional, whose phosphorylation is correlated with contraction, and (2) structural, whose phosphate content remains rather steady during the contraction cycle. Structural phosphoproteins could make contact with other proteins to form a specific protein network. Alternatively, they may bind divalent metals, Ca + or Mg2+. The common experience of the slow turnover of phosphate in these proteins also suggests that the covalently bound phosphate is not free and, therefore, not readily available for protein kinases and phosphatases. Future investigation should provide information about the role of the structural phosphoproteins in smooth muscle. 

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