GSK-3 (Glycogen Synthase Kinase - 3)

Definition
Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. This enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation1.

Related peptides
Two isoforms of GSK-3 are reported in mammals: a 51 kDa GSK-3 alpha and a 47 kDa GSK-3beta. These two isoforms exhibit about 98% homology in their kinase domains, but share only about 36% identity in the last 76 C-terminal amino acid residues.

Discovery
Glycogen synthase kinase- 3 was identified and purified to homogeneity, from rabbit skeletal muscle by Embi N et al in 19802.

Structural characteristics
GSK-3 is about 47,000 Daltons. GSK-3 comprises an N-terminal lobe composed of beta sheets and a C- terminal lobe that is mainly alpha helical. (4) Arg-96, Arg-180 and Lys-205 are found to be conserved in all identified GSK-3 homologues, suggesting conservation of the priming phosphate binding site and hence the substrate specificity of GSK-3 in all organisms3.

Mechanism of action
GSK-3 shows a preference for target proteins that are pre-phosphorylated at a “priming” residue located C-terminal to the site of GSK-3 phosphorylation. Priming phosphorylation, although not absolutely required, enhances the efficiency of phosphorylation of most GSK-3 substrates. The T-loop of GSK-3alpha is phosphorylated at Tyr279 and GSK-3beta at Tyr216, which play a role in forcing open the substrate-binding site of the enzyme. Uniquely, the T-loop of GSK-3 does not undergo any Thr phosphorylation. The function of missing pThr in the T-loop of GSK-3 is carried out by the phosphorylated residue of a primed substrate that binds to a positively charged pocket consisting of Arg96, Arg180, and Lys205 (for GSK-3beta). This arrangement optimizes the orientation of the kinase domain and places the substrate at the proper position within the catalytic groove for phosphorylation to take place4.

Function
Identified originally as a regulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now a well-established component of the Wnt signaling pathway, which is essential for setting up the entire body pattern during embryonic development. It may also play important roles in protein synthesis, cell proliferation, cell differentiation, microtubule dynamics and cell motility by phosphorylating initiation factors, components of the cell-division cycle, transcription factors and proteins involved in microtubule function and cell adhesion3.

References
1.Doble BW, Woodgett JR (2003). GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci, 116:175-1186.
2.Embi N, Rylatt DB, Cohen P (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J.Bioche,107:519-527.
3.Frame S, Cohen P (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem J, 359:1–16.