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Protein Kinase A



Protein kinases are these enzymes found inside our body which are responsible for catalyzing phosphorylation reactions. Phosphorylation is an example of covalent modification and this is a mechanism that our cells use to basically regulate and control the activity of enzymes and the functionality of proteins. The one of protein kinase is cAMP-dependent protein kinase, also known as protein kinase A or PKA.

As epinephrine travels through our cardiovascular system when in stressful situation, it basically stimulates our cells to transform ATP molecules into another molecule known as cyclic adenosine monophosphate or simply cAMP. cAMP is a cyclic nucleotide that serves as an intracellular and, in some cases, extracellular “second messenger” mediating the action of many peptide or amine hormones, regulated by several receptors like GPCRs include Alpha and Beta-ADRs (Adrenergic Receptors), CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor), Smo (Smoothened) etc. It's also an allosteric regulator of protein kinase A and it binds on to the inactive version of protein kinase A and it activates protein kinase A which becomes responsible for activating many different types of enzymes via the process of phosphorylation and it phosphorylates one of two types of residues either the serine residue or the threonine residues.

Protein Kinase A

If the substrate molecule contains consensus amino acids sequence of -arginine-arginine-X-serine or threonine-Y- , in which X is basically any small amino acid for instance glycine and Y is basically any large hydrophobic amino acid this is basically where that protein kinase A will bind to and what it will phosphorylate this target side the serine or threonine. The first arginine in the consensus sequence can be changed to lysine and that will also allow the protein kinase A to bind onto. But the affinity of residue-changed sequence will not be as good as in the case where these two are arginine residues.it can basically change the activity and the functionality of that target substrate molecule.

PKA is composed of two types of subunits, catalytic subunit containing the active side and regulatory subunit containing allosteric site which binds to the cyclic AMP. The catalytic subunit performs the phosphate-adding reaction. The regulatory subunit senses the level of cyclic AMP, then turns the catalytic subunits on or off based on that level. When cAMP levels are low, a dimer of the regulatory subunits binds to two copies of the catalytic subunit, forming an inactive complex. When cAMP levels rise, it binds to the regulatory subunit, releasing the catalytic subunit in an active form. To be more specifically, in the absence of an allosteric effector, the PKA quaternary structure consists of two catalytic subunits and two regulatory subunits (R2C2 complex). Under stressful conditions, epinephrine is released and stimulates the production of cyclic adenosine monophosphate (cAMP), which is an allosteric effector of PKA. When cAMP binds to all of these regulatory sites, resulting in a conformational change that allows regulatory sections dissociate from the catalytic sections. Active sites of catalytic subunits have been occupied by the sequence of amino acids, which is known as pseudo substrate sequence, found on the regulatory subunit in inactive PKA complex. Once the active sites are free, these catalytic subunits catalyze all these different types of target enzymes via the process of phosphorylation.

Protein Kinase A

As for protein kinase A family, there are several genes encoding subunits of PKA complex. PKA-cat alpha (PKACa) and PKA-cat beta (PKACb), as well as PKA-cat gamma (PKACg), encode two catalytic subunits of inactive PKA existing as a tetrameric complex. The other two regulatory subunits of inactive PKA are encoded by PKAR1A and PRKAR1B or PRKAR2A and PKAR2B.

Gene Name Enzymes and Subunits
PKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha subunit
PRKAR1B protein kinase, cAMP-dependent, regulatory, type I, beta subunit
PRKAR2A protein kinase, cAMP-dependent, regulatory, type II, alpha subunit
PKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta subunit
PKACa protein kinase, cAMP-dependent, catalytic, alpha subunit
PKACb protein kinase, cAMP-dependent, catalytic, beta subunit
PKACg protein kinase, cAMP-dependent, catalytic, gamma subunit
PRKX protein kinase, X-linked
PRKY protein kinase, Y-linked, pseudogene

Related Enzyme Products in Creative Enzymes

Cat. No. Product Name
NATE-0571 Protein Kinase A catalytic subunit human, Recombinant
NATE-0572 Protein Kinase A Catalytic Subunit β, Active human, Recombinant

Moreover, protein kinase A plays a key role in a number of cellular processes. It participate in regulation of cell cycle and proliferation, metabolism, transmission of nerve impulses, cytoskeleton remodeling, muscle contraction, cell survival and other cell processes. PKA may be located in the cytoplasm or associated with cellular structures and organelles depending on type of PKA regulatory subunits (PKA-reg). PKA is anchored to specific locations within the cell by specific proteins called A kinase anchor proteins (AKAPs). Moreover, AKAPs may participate in PKA regulation and/or in governing PKA activity. Ribosomal protein S6 kinase 90kDa polypeptide 1 (p90RSK1) may regulate the ability of PKA to be bound to cAMP. Inactive p90RSK1 interacts with PKA regulatory type I subunit. Conversely, active p90RSK1 interacts with the PKA catalytic subunit (PKA-cat). Binding of p90RSK1 to PKA-reg decreases the interactions between PKA-reg and PKA-cat, while the binding of active p90RSK1 to PKA-cat increases interactions between PKA-cat and PKA-reg and decreases the ability of cAMP to stimulate PKA. In addition, PKA-cat may be regulated by 3-phosphoinositide dependent protein kinase-1 (PDK-1), Protein kinase (cAMP-dependent, catalytic) inhibitors (PKI), Protein phosphatase 1, regulatory (inhibitor) subunit 1B (DARPP-32).

Besides, there are two cAMP -independent pathways of PKA regulation. The one is nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB)-dependent cascade. Certain pool of PKA-cat exists in a complex with I-kB alpha and beta (NFKBIA and NFKBIB). Under basal conditions, NFKBIA and NFKBIB retain PKA-cat alpha in the inactive state, presumably by masking its ATP binding site. Phosphorylation and degradation of NFKBIA and NFKBIB result in a release and activation of PKA-cat alpha. This pathway might be a general response to vasoactive peptides. The other one is realized via transforming growth factor-beta (TGF-beta)/ SMAD family member 3 and 4 (SMAD3 and SMAD4). Activated SMAD3 binds to SMAD4, and this complex binds to the PKA-reg. This results in release of PKA-cat and activation of the downstream target genes.

References

  1. Cooper DM. Compartmentalization of adenylate cyclase and cAMP signalling. Biochemical Society transactions 2005 Dec; 33(Pt 6):1319-22.
  2. Dell'Acqua ML, Smith KE, Gorski JA, Horne EA, Gibson ES, Gomez LL. Regulation of neuronal PKA signaling through AKAP targeting dynamics. European journal of cell biology 2006 Jul; 85(7):627-33.
  3. McConnachie G, Langeberg LK, Scott JD. AKAP signaling complexes: getting to the heart of the matter. Trends in molecular medicine 2006 Jul; 12(7):317-23.
  4. Landsverk HB, Carlson CR, Steen RL, Vossebein L, Herberg FW, Tasken K, Collas P. Regulation of anchoring of the RIIalpha regulatory subunit of PKA to AKAP95 by threonine phosphorylation of RIIalpha: implications for chromosome dynamics at mitosis. Journal of cell science 2001 Sep; 114(Pt 18):3255-64.
  5. Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A. A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3 beta) and mediates protein kinase A-dependent inhibition of GSK-3beta. The Journal of biological chemistry 2002 Oct 4; 277(40):36955-61.<
  6. Chaturvedi D, Poppleton HM, Stringfield T, Barbier A, Patel TB. Subcellular Localization and Biological Actions of Activated RSK1 Are Determined by Its Interactions with Subunits of Cyclic AMP-Dependent Protein Kinase. Molecular and cellular biology 2006 Jun; 26(12):4586-600.
  7. Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 1997 May 2; 89(3):413-24.
  8. Zhang L, Duan CJ, Binkley C, Li G, Uhler MD, Logsdon CD, Simeone DM. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Molecular and cellular biology 2004 Mar; 24(5):2169-80.
  9. Yang H, Lee CJ, Zhang L, Sans MD, Simeone DM. Regulation of transforming growth factor beta-induced responses by protein kinase A in pancreatic acinar cells. American journal of physiology. Gastrointestinal and liver physiology 2008 Jul; 295(1):G170-G178.

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