Protein Kinase-A

Protein Kinase-A

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About Protein Kinase A / PKA:

Protein Kinase A, also known as PKA, is a family of enzymes that are dependent on cellular levels of cyclic AMP (cAMP) for activity. PKA is also known as a cAMP-dependent protein kinase. PKA has several important functions in cell biology including regulation of glycogen, sugar and lipid metabolism.

Protein Kinase A Structure
The PKA holoenzyme exists as a tetramer, but higher-order structures can form in cells where PKA is targeted to specific components. The most common PKA holoenzyme structure consists of two regulatory subunits and two catalytic subunits. The regulatory subunit has domains which bind to the cyclic AMP, a domain that interacts with the catalytic subunit and an autoinhibitory domain. The catalytic subunit contains a series of canonical residues found in protein kinases known as the active site. These residues bind and hydrolyse ATP and a domain to bind the regulatory subunit.

PKA Mechanism
PKA has traditionally been thought to be activated through the release of catalytic subunits when levels of the second messenger cAMP rise. This has led to PKA being commonly known as a cAMP-dependent protein kinase. More recent studies have suggested that the local subcellular activation of the catalytic activity of PKA could proceed without physical separation of the regulatory and catalytic components. This contrasts experimentally induced supraphysiological concentrations of cAMP which are able to cause the separation of holoenzymes, releasing the catalytic subunits.
By binding to a G protein-coupled receptor on the target cell, extracellular hormones being an intracellular signalling cascade that triggers protein kinase A activation. This can include extracellular hormones such as glucagon and epinephrine. When a G protein-coupled receptor is activated by its extracellular ligand, it induces a conformational change that is transmitted to an attached intracellular heterotrimeric G protein complex by protein domain dynamics. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is then released from the complex.
The activated Gs alpha subunit then binds to and activates adenylyl cyclase. This results in the catalyzation of the conversion of ATP into cyclic adenosine monophosphate (cAMP), increasing the cAMP level. A total of four cAMP molecules can bind to the two R-subunits. This is achieved through two cAMP molecules binding to each of the two cAMP binding sites (CNB-B and CNB-A) which causes a conformational change in the regulatory subunits of PKA. This results in the subunits detaching and unleashing the two now activated catalytic subunits.
Once they have been released from their inhibitory regulatory subunit, the catalytic subunits then go on to phosphorylate a large number of other proteins in the minimal substrate context Arg-Arg-X-Ser/Thr. However, they’re still subject to other layers of regulation such as modulation by the heat-stable pseudosubstrate inhibitor of PKA known as PKI.

Protein Kinase A Interactions
The steps involved in PKA activation; Cytosolic cAMP increases, Two cAMP molecules bind to each of the PKA regulatory subunits, the regulatory subunits move away from the active sites of the catalytic subunits, The R2C2 complex dissociates, The free catalytic subunits then interact with the proteins to phosphorylate Ser or Thr residues, etc.