Allosteric Regulation of PKA by cAMP

In this lecture the fundamental allosteric mechanism for regulation of PKA by cAMP will be described. Cyclic AMP serves as a universal intracellular second messenger that translates an extracellular signal into a biological response. The cAMP binding domain also has been conserved throughout biology, and this highly dynamic module serves as the docking site for cAMP. The subdomains of this module define the two allosteric states that mediate the cAMP signal. Two cAMP binding domains are contained within the PKA regulatory subunits, and these serve as the major receptors for cAMP in every eukaryotc cell. In the absence of cAMP the dimeric regulatory subunit is bound to two catalytic subunits, and this generates an inactive tetrameric holoenzyme complex. Binding of cAMP to the regulatory subunit causes a major conformational change that leads to dissociation of the regulatory subunit and activation of the catalytic activity. The transition between these two states defines the allosteric basis for PKA signaling.