Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. … expand

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [ PUBMED:3291115 ]:

• Serine/threonine-protein kinases
• Tyrosine-protein kinases
• Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human [ PUBMED:12471243 ]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [ PUBMED:12368087 ]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [ PUBMED:15078142 ], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [ PUBMED:15320712 ].

In the absence of cAMP, Protein Kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits [ PUBMED:11734894 ]. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. All R subunits have a conserved domain structure consisting of the N-terminal dimerization domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.

Two types of regulatory (R) subunits exist -types I and II -which differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II were further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. This entry represents the dimerization-anchoring domain of types I-alpha, I-beta, II-alpha and II-beta regulatory subunits of PKA proteins.The dimerization-anchoring domain is located within the first 45 residues of each regulatory subunit, and forms a high affinity binding site for A-kinase-anchoring proteins (AKAPs) [ PUBMED:11285229 ].