Metabolic regulation through second-site phosphorylation.
Protein phosphorylation is the most prevalent covalent reversible modification used for the regulation of many biological functions. The dynamic phosphorylation state of cellular proteins results from the balance between the activities of protein kinases and phosphatases. Even autophosphorylation, shared by practically all protein kinases, is also considered as a mode of enzyme regulation. Phosphodephosphorylation reactions seem also to be regulated at the substrate level, and the structure of a target protein can be strongly altered through phosphorylation in a way which may either promote or depress the further action of a protein kinase or phosphatase. Second-site phosphorylation may have various consequences on the kinetic properties of the enzyme-substrate. Glycogen synthase is possibly one of the most complex examples of enzyme regulation through interactions between phosphorylation sites. An interesting example of regulation at the substrate level in a network protein phosphorylations, is provided by the effects of casein kinase-1 (CK-1), casein kinase-2 (CK-2) and protein kinase FA (PKFA) on the modulator protein of the ATP, Mg-dependent phosphatase. The crucial step in the activation of the enzyme is the transient phosphorylation of the modulator at the Thr-72 residue catalyzed by PKFA. The CK-2 mediated phosphorylation occurs at three Ser residues: Ser-86, Ser-120 and Ser-121. Although by itself CK-2 does not elicit any phosphatase activity, it potentiates the subsequent activation brought about by PKFA. The phosphorylation mediated by CK-1, probably directed toward Ser-86, blocks the activation of the ATP,Mg-dependent phosphatase mediated by PKFA.
Agostinis
P
P
Pinna
L A
LA
Merlevede
W
W
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047388:Casein Kinases; D004789:Enzyme Activation; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D010085:Oxidative Phosphorylation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010764:Phosphorylase Kinase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*
D011506:Proteins; D006006:Glycogen Synthase; D011494:Protein Kinases; D010764:Phosphorylase Kinase; D047388:Casein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases