Glycogen-bound protein phosphatase

Fig. 7.20. Regulation of glycogen-bound protein phosphatase I. Regulation of the activity of protein phosphatase I (PPI) takes place by phosphorylation of the G subunit. The G subunit is phos-phorylated at positions PI and P2, in the process of a signal chain mediated activation of protein kinase A. As a consequence of the phosphorylation, the catalytic subunit dissociates. The phosphatase activity of the free catalytic subunit is inhibited by association with a cytosohc protein phosphatase inhibitor (I), the binding of which is also controlled via a protein kinase A mediated phosphorylation. The phosphorylated G subunit can be dephosphorylated again by protein phosphatase 2A and may bind a catalytic PPI subunit once more.

Fig. 7.21. Activation of glycogen-bound protein phosphatase I by insulin. Insulin has a stimulating effect on glycogen synthesis by initiating the dephosphorylation and activation of glycogen synthase and the dephosphorylation and inhibition of glycogen phosphorylase. Both enzymes (substrate S in the figure) are dephosphorylated by protein phosphatase PPIG. Insulin mediates the activation of a protein kinase (insulin-sensitive protein kinase) within an insulin-stimulated signal pathway, which phosphorylates and thus activates protein phosphatase PPIG at the PI site.

The catalytic subimit of protein phosphatase I is associated with a glycogen binding protein, also known as the G submit of protein phosphatase I (Fig. 7.20). The G subunit is tightly bound to glycogen. Association of the catalytic subimit with the G subunit creates a form of protein phosphatase I known as protein phosphatase I-G... 

Hormonal stimulation of the cell and the associated activation of protein kinase A lead to phosphorylation at the PI and P2 sites of protein phosphatase I. Consequently, the enzyme dissociates from the G subunit and can no longer dephosphorylate the glycogen-bound substrate. PPI is released into the cytosol but still retains activity in this form towards substrates not associated with glycogen. 

Protein phosphatase 1 An enzyme that will hydrolyze phosphate groups from target proteins snch as glycogen synthase, phosphorylase, phos-phorylase kinase, and the phosphorylated form of inhibitor 1. The phos-phorylated inhibitor 1 is a substrate that binds well but is hydrolyzed slowly. While bound to protein phosphatase 1, the phosphorylated inhibitor 1 serves as an inhibitor of the enzyme. 

All known actions of glucagon are mediated by protein kinases that are activated by cyclic AMP. The activation of the cyclic AMP cascade results in a higher level of phosphorylase a activity and a lower level of glycogen synthase a activity. Glucagon s effect on this cascade is reinforced by the diminished binding of glucose to phosphorylase a, which makes the enzyme less susceptible to the hydrolytic action of the phosphatase. Instead, the phosphatase remains bound to phosphorylase a, and so the synthase stays in the inactive phosphorylated form. Consequently, there is a rapid mobilization of glycogen. 

Glycogen phosphorylase (14.48) mw = 370,000, exists in active (A) and relatively inactive (B) forms which differ in quaternary structure and phosphate content. The active phosphorylase (A) contains two phosphate groups bound to two serine units, out of a total of 30 serine units in each protein molecule. This enzyme is hydrolysed by phosphorylase phosphatase to produce the inactive (B) form which is devoid of phosphate groups. Re-phosphorylation to produce the active (A) form can be achieved with ATP and phosphorylase kinase. 

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