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Originally published In Press as doi:10.1074/jbc.M005541200 on August 9, 2000

J. Biol. Chem., Vol. 275, Issue 45, 35034-35039, November 10, 2000
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Identification of Binding Sites on Protein Targeting to Glycogen for Enzymes of Glycogen Metabolism*

Noel M. FongDagger §, Timothy C. JensenDagger , Ami S. Shah§, Nita N. Parekh§, Alan R. SaltielDagger §, and Matthew J. BradyDagger ||

From the Dagger  Department of Cell Biology, Pfizer Global Research and Development, Ann Arbor, Michigan 48105 and the § Department of Physiology, the University of Michigan School of Medicine, Ann Arbor, Michigan 48109

The activation of protein phosphastase-1 (PP1) by insulin plays a critical role in the regulation of glycogen metabolism. PTG is a PP1 glycogen-targeting protein, which also binds the PP1 substrates glycogen synthase, glycogen phosphorylase, and phosphorylase kinase (Printen, J. A., Brady, M. J., and Saltiel, A. R. (1997) Science 275, 1475-1478). Through a combination of deletion analysis and site-directed mutagenesis, the regions on PTG responsible for binding PP1 and its substrates have been delineated. Mutagenesis of Val-62 and Phe-64 in the highly conserved (K/R)VXF PP1-binding motif to alanine was sufficient to ablate PP1 binding to PTG. Phosphorylase kinase, glycogen synthase, and phosphorylase binding all mapped to the same C-terminal region of PTG. Mutagenesis of Asp-225 and Glu-228 to alanine completely blocked the interaction between PTG and these three enzymes, without affecting PP1 binding. Disruption of either PP1 or substrate binding to PTG blocked the stimulation of PP1 activity in vitro against phosphorylase, indicating that both binding sites may be important in PTG action. Transient overexpression of wild-type PTG in Chinese hamster ovary cells overexpressing the insulin receptor caused a 50-fold increase in glycogen levels. Expression of PTG mutants that do not bind PP1 had no effect on glycogen accumulation, indicating that PP1 targeting is essential for PTG function. Likewise, expression of the PTG mutants that do not bind PP1 substrates did not increase glycogen levels, indicating that PP1 targeting glycogen is not sufficient for the metabolic effects of PTG. These results cumulatively demonstrate that PTG serves as a molecular scaffold, allowing PP1 to recognize its substrates at the glycogen particle.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

|| To whom correspondence and reprint requests should be addressed: Dept. of Cell Biology, 2800 Plymouth Rd., Ann Arbor, MI 48105. Tel: 734-622-5926; Fax: 734-622-5668.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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