Protein kinase A

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Protein Kinase A (PKA) is a protein that is dependent on cyclic AMP (cAMP) and without it, is deactivated. PKA is involved in signal-transduction pathways and phosphorylates proteins by adding a phosphate group. The molecule consists of two subunits, a regulatory subunit and a calalytic subunit[1]. These subunits are inactive when cAMP is not bound. When cAMP binds to a regulatory subunit a conformational change occurs. This change means that the catalytic subunit becomes active and is no longer inhibited. This means that the protein can now phosphorylate other proteins by removing a phosphate from ATP, and adding it to a serine residue on the target protein which in turn leads to a cellular respons [2].

Protein Kinase A (PKA) is one of the member of family of enyzmes which is functionally dependent on the levels of cyclic-adenomonophopshate (cAMP). It is also commonly known as the cAMP dependent A kinase, therefore it works through the cAMP signalling pathway. Essentially, PKA is responsible for all the cellular responses induced by cAMP second messenger system.

Protein kinase A (PKA) is activated by the binding of cyclic AMP (cAMP), which causes it to undergo a conformational change. As previously mentioned, PKA then goes on to phosphoylate other proteins in a phosphorylation cascade (which required ATP hydrolysis).

An application in everyday life of PKA is in the 'fight or flight response'. For example, if you were to cross a road and a car was to accelerate as you were doing so, your immediate response would be to run across the road in order to avoid being hit. This response is caused by the following reactions: the nearby car acts as a stimulus, and the response is to run away, which requires energy. This energy is produced in the form of ATP, which is made by aerobic respiration which requires glucose. Glucose is generated by the break down of glycogen.

To begin with, epinephrine is secreted by the adrenal glands[3]. It binds to a trimeric G-protein receptor on the plasma membrane, which induces a conformational change in the G-protein, causing the alpha subunit to let go of GDP and bind GTP, activating the alpha subunit and causing it to dissociate from the beta and gamma subunit. The alpha subunit then binds to adenylyl cyclase, which converts ATP into cAMP. cAMP then binds to protein kinase A, which activates it. Protein kinase A then goes on to phosphorylate glycogen synthase a into glycogen synthase b, which inactivates it (this is done to prevent glycogen synthesis whilst it is being broken down into glucose). PKA also phosphorylates phosphorylase kinase, which then phosphorylates phosphorylase b to phosphorylase a, which causes the breaking down on glycogen into glucose[4], which can be used in aerobic respiration to generate ATP, so you would now have the energy surge to run across the road.

Protein kinases are enzymes which catalyse the phosphorylation of proteins. ATP often supplies the phosphate for the reaction. Protein kinases have differing levels of specificity.  Some will only phosphorylate one particular protein but others, such as protein kinase A, can phosphorylate many different proteins. Protein kinase A is involved in the ‘fight or flight’ response in mammals. In this response, the hormone adrenaline causes the production of cAMP, a secondary messenger. cAMP then activates protein kinase A. Protein kinase A then activates phosphorylase kinase which continues the pathway for the breakdown of glycogen. This pathway occurs in the muscle and in the liver but the hormone is glucagon in the liver.


Protein Kinase A.png[5]

Structure:

PKA is a heterotetramer consists of 4 subunits, of which composed of 2 regulatory and 2 catalytic subunits.

Regulation of activity:

When cAMP levels are low, the catalytic subunits are bound to the regulatoy subunit dimer and are inactive. Each regulatory subunit contains a sequence which matches the phosphorylation consensus sequence - pseudo-substrate motif (Arg-Arg-Gly-Ala-Ile). This sequence therefore enters the active site of the catalytic subunit, preventing any substrate from entering the active site, inhibiting the enzyme[6]. As the concentration of cAMP increases, 2 cAMP molecules[7] bind to each of the regulatory subunits, causing a conformational change of the catalytic subunits from an inactive to an active form[8][9].

References

  1. Berg, J. Tymoczko, J. and Stryer, L. (2007) Biochemistry, 6th edition, New York: WH Freeman
  2. http://www.vivo.colostate.edu/hbooks/molecules/pka.html
  3. April Cashin Garbutt, What is Epinephrine (adrenaline)? 2013; Available from: http://www.news-medical.net/health/What-is-Epinephrine-(Adrenaline).aspx
  4. W.H.Freeman and Company. Biochemistry. Sixth Edition. 2007. Figure 21-17
  5. Linder T, Melby AE. Cyclic AMP. Available at: http://courses.washington.edu/conj/gprotein/cyclicamp.htm
  6. Berg, J. Tymoczko, J. and Stryer, L. (2012) Biochemistry, 7th edition, New York: WH Freeman
  7. Berg, J. Tymoczko, J. and Stryer, L. (2012) Biochemistry, 7th edition, New York: WH Freeman
  8. R. Bowen, November 28 2003, Hypertexts for Biomedical Sciences, a resource of Colorado State University
  9. http://www.vivo.colostate.edu/hbooks/molecules/pka.html

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