Figure 1.

Regulation of glycogen metabolism by glycogen synthase kinase 3 (GSK3). (a) Casein kinase 2 (CK2) phosphorylates a priming Ser residue in the C terminus of glycogen synthase (Ser657 in the muscle isoform of Homo sapiens) to initiate a relay of GSK3-catalysed phosphorylations, as described in the text. (b) Glycogen synthase activity is regulated by a phosphorylation–dephosphorylation cycle. In the preprandial state, plasma insulin concentrations are low and GSK3 is active. GSK3 phosphorylates glycogen synthase and converts it to the less-active (glucose-6-phosphate (G6P) dependent) form, thus inhibiting glycogen synthesis. When plasma insulin concentrations rise after feeding, insulin promotes phosphorylation of GSK3 and inhibits GSK3 activity. Dephosphorylation of glycogen synthase by protein phosphatases (GS phosphatase) subsequently increases the activity of glycogen synthase and promotes glycogen synthesis. (c) GSK3α and GSK3β exhibit a high degree of homology in their kinase domains, diverging at their N- and C-terminal regions. GSK3α contains an N-terminal Gly-rich domain of unknown function. However, Gly-rich domains are classically associated with binding of nucleotides (Bossemeyer, 1994), though this domain is distinct from the ATP-binding site in the kinase domain. Both isoforms are constitutively phosphorylated on a Tyr residue in the kinase domain and this phosphorylation is required for activity. Phosphorylation of a conserved N-terminal Ser residue inhibits the activity of GSK3.