Protein Kinase
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p512-513
2025-12-01
17
As discussed in Chapter 38, in prokaryotic cells, cAMP binds to a specific protein called cAMP activator protein (CAP) that binds directly to DNA and influences gene expression. By contrast, in eukaryotic cells, cAMP binds to a protein kinase called protein kinase A (PKA), a heterotetrameric molecule consisting of two regulatory subunits (R) that inhibit the activity of the two catalytic subunits (C) when bound as a tetrameric complex. cAMP binding to the R2 C2 tetramer results in the following reaction:
4cAMP + R2C2 ⇄ R2-4cAMP + 2C
The R2C2 complex has no enzymatic activity, but the binding of cAMP to the R subunit induces dissociation of the R-C complex, thereby activating the latter (Figure1). The active C subunit catalyzes the transfer of the γ phosphate of ATP to a serine or threonine residue in a variety of proteins. The consensus PKA phosphorylation sites are-ArgArg/Lys-X-Ser/Thr- and -Arg-Lys-X-X-Ser-, where X can be any amino acid.
Fig1. Hormonal regulation of cellular processes through cAMP-dependent protein kinase (PKA). PKA exists in an inactive form as an R2C2 heterotetramer consisting of two regulatory (R) and two catalytic (C) subunits. The cAMP generated by the action of adenylyl cyclase binds to the regulatory subunit of PKA. This results in dissociation of the regulatory and catalytic subunits and activation of the latter. The active catalytic subunits phosphorylate a number of target proteins on serine and threonine residues. Phosphatases remove phosphate from these residues and thus terminate the physiologic response. A phosphodiesterase can also terminate the response by converting cAMP to 5′-AMP.
Historically protein kinase activities were described as being “cAMP-dependent” or “cAMP-independent.” This classification has changed, as protein phosphorylation is now recognized as being a major and ubiquitous regulatory mechanism.
Several hundred protein kinases have now been described. These kinases are related in sequence and structure within the catalytic domain, but each is a unique molecule with consider able variability with respect to subunit composition, molecular weight, autophosphorylation, Km for ATP, and substrate specificity. Both kinase and protein phosphatase activities can be targeted by interaction with specific kinase-binding proteins. In the case of PKA, such targeting proteins are termed A kinase anchoring proteins, or AKAPs. AKAPs serve as scaffolds, which localize PKA near to substrates thereby focusing PKA activity toward physiologic substrates and facilitating spatiotemporal biologic regulation while also allowing for common, shared proteins to elicit specific physiologic responses. Multiple AKAPs have been described and importantly they can bind PKA and other kinases as well as phosphatases, phosphodiesterases (which hydrolyze cAMP), and protein kinase substrates. The multifunctionality of AKAPs facilitates signaling localization, rate (production and destruction of signals), specificity, and dynamics.
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