CAMP-dependent protein kinase

In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (EC 2.7.11.11). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.

It should not be confused with AMP-activated protein kinase – which, although being of similar nature, may have opposite effects – nor be confused with cyclin-dependent kinases (Cdks), nor be confused with the acid dissociation constant pKa.

Protein kinase A or also known as cAMP-dependent protein kinase was discovered by chemists H. Fischer and Edwin G. Krebs in 1968. They won the Nobel Prize in Physiology or Medicine in 1992 for their work on phosphorylation and dephosphorylation and how it is relates to protein kinase A activity.

PKA is one of the most widely researched protein Kinase because of its uniqueness; out 540 different protein kinase genes that make up for human kinome, only one other protein kinase; CK2 exists in a tetramer complex.

The diversity of mammalian PKA subunits were realized after Dr. Stan Knight and others identified possible four subunit C genes and presence of four R subunit genes. In 1991; Susan Taylor and et al. crystallized PKA Cα subunit which revealed bi-lobe structure of kinase core for the very first time.

PKA is a tetramer. The PKA holoenzyme structure consists of a regulatory subunit and catalytic subunit. Catalytic subunit contains the active site, a domain to bind ATP and a domain to bind the regulatory subunit. The regulatory subunit has domains to bind to cyclic AMP, a domain that interacts with catalytic subunit and an auto inhibitory domain. There are two major forms of regulatory subunit; RI and RII.

The PKA enzyme is also known as cAMP-dependent enzyme because it is activated only when cAMP is present. Hormones such as glucagon and epinephrine begin the activation cascade (that triggers protein kinase A) by binding to a G protein–coupled receptor (GPCR) on the target cell. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor 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 released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP) – increasing cAMP levels. Four cAMP molecules are required to activate a single PKA enzyme. This is done by two cAMP molecules binding to each of the two cAMP binding sites (CNB-B and CNB-A) which produces a conformational change in the regulatory subunits on a PKA enzyme causing the subunits to detach exposing the two (now activated) catalytic subunits.

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