General Information
Cyclic 3'- 5' Adenosine monophosphate dependent protein kinase is an important enzyme in signal transduction in vertebrates. It takes part in the regulation of glycogen synthesis and breakdown, fatty acid synthesis, the oxidation of pyruvate to acteyl-CoA, mobilization of triacylglycerols, and the reciprocal regulation of glycolysis and gluconeogenesis. As the name implies, the activity of the enzyme is dependent on the presence of cAMP. The enzyme occurs naturally as a 4-membered quanternary structure, with two regulatory (R) and two catalytic (C) subunits. In the holoenzyme form, the regulatory subunits are bound to the active site of the catalytic subunits, inactivating them. When cAMP is present, it binds to the regulatory subunit, causing a conformational change that releases and activates the two C subunits. While the 3D structure of the catalytic subunit and regulatory subunits are known seperately, the holoenzyme form of Protein kinase A, containing two regulatory subunits bound to two catalytic subunits, has not been crystallized However, the structure of the catalytic subunit bound to a synthetic inhibitor has been resolved.The structure of this inhibitor gives insight into the natural regulatory domain of 2CPK and the substrate, because both occupy the active site of the catalytic subunit.

Once seperate from the R subunit, the C subunit can perform its function, which is the phosphorylation of a Ser or Thr residue on the substrate. The phosphorylation causes a change in activity of the substrate, and the substrate can go on to continue the message by performing a function on yet another substrate, or can directly regulate some of the pathways mentioned above. Protein kinase A is classified as a member in the AGC group of protein kinases, because it phosphorylates at Ser and Thr residues, rather than Tyr residues.

Two lobed structure of catalytic subunit of 2CPK

The kinase domain of the catalytic subunit is particularly well conserved among members of the protein kinase superfamily. Because of its relative simplicity, cAMP dependent Protein Kinase is used as the basic structure for comparsion and nomenclature for the catalytic parts of the protein kinase superfamily. The kinase domain is divided up into 12 subdomains which are very similar among the various other related protein kinases. There may be some insertions or deletions, but all of the members of the family are along the same basic lines. The catalytic subunit of folds up into a two lobed structure, which is shown in the above picture.

The red ribbon structure denotes the smaller N-terminal lobe that is comprised of subdomains I-IV of the kinase. Its secondary structure is mainly that of antiparallel beta sheets. This smaller lobe's primary function is orientation and binding the MgATP complex that donates the phoshate. The blue ribbon structure respresents the larger, C-terminal lobe that is made up of subdomains VIA-XI. Its secondary structure is comprised mainly of alpha helices. The larger lobe's function is binding the substrate and initiating the phosphate transfer to the substrate.

The yellow ribbon represents subdomain V, which has the structural function of connecting the two lobes, and also plays roles in the recognition of the peptide substrate and the anchor of the MgATP phospahte donor.

The gray ribbon structures are not part of the kinase domain. These may be structurally important to the protien, but they probably don't play any role in the catalytic activity of the protein.