PPP1R3A: Muscle Glycogen Protein Phosphatase Regulatory Subunit

Protein Phosphatase 1 (PP1) is a widely expressed protein which removes phosphate groups bound to serine/threonine residues of proteins, thereby reversing the actions of protein kinases. The specificity of PP1 is controlled by several regulatory subunits, which direct PP1 to specific locations and substrates. Examination of several PP1 targeting proteins identified a small common peptide motif R/K-V/I-X-F/W , which is present in most targetting subunits (Johnson et al. 1996).

One of these targetting subunits is GM (primarily identified and characterized by the lab of Sir Philip Cohen is PPP1R3A see OMIM , which targets PP1 to glycogen in muscle. PP1-GM is responsible for the dephosphorylation of several key glycogen enzymes including phophorylase and glycogen synthase. The dephophorylated state of these enzymes favors increased glycogen synthesis (by activating glycogen synthase and deactivating glycogen phosphorylase). The PP1-GM complex is activated by insulin (through phosphorylation of GM on serine 46; Liu and Brautigan 2000) and deactivated by adrenergic stimulation (through phosphorylation on serine 23; Walker et al. 2000).

There are several naturally occuring GM mutants which lead to insulin resistence/diabetes, including a D905Y polymorphism, a deletion in the 3' untranslated region and a frameshift mutation at codon 662. Each of these leads to decreased expression or activity of the protein. Mouse knockout models of GM also have a diabetic phenotype. GM was the founding member of a larger class PP1 glycogen targetting molecules, incuding GL, PTG, R5 and R6. GM was also a seminal example of the importance of protein phosphatase regulation in biological systems.

References

Johnson, D.F., G. Moorhead, F.B. Caudwell, P. Cohen, Y.H. Chen, M.X. Chen, and P.T. Cohen, Identification of protein-phosphatase-1-binding domains on the glycogen and myofibrillar targetting subunits. Eur J Biochem, 1996. 239(2):317-25. Pubmed.

Liu, J. and D. L. Brautigan. 2000. Insulin-stimulated phosphorylation of the protein phosphatase-1 striated muscle glycogen-targeting subunit and activation of glycogen synthase. J Biol Chem. 275(21):15940-7. PubMed.

Walker, K. S., P.W. Watt and P. Cohen. 2000. Phosphorylation of the skeletal muscle glycogen-targetting subunit of protein phosphatase 1 in response to adrenaline in vivo. FEBS Lett 466(1):121-4. PubMed.