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-subunit regulates AMP-activated protein kinase activity
1 Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
3 Endocrinology and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan
4 Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: hsakoda-tky{at}umin.ac.jp.
AMP-activated protein kinase (AMPK) regulates both glycogen and lipid metabolism functioning as an intracellular energy sensor. In this study, we identified a 160 KDa protein in mouse skeletal muscle lysate using a GST-AMPK fusion protein pull-down assay. Mass spectrometry and a Mascot search revealed this protein to be a glycogen debranching enzyme (GDE). The association between AMPK and GDE was observed not only in the overexpression system but also endogenously.
Next, we showed the 
1 subunit of AMPK to be responsible for the association with GDE. Furthermore, experiments using deletion mutants of the 1 subunit of AMPK revealed amino acids 68-123 of the 1 subunit to be sufficient for GDE binding. W100G and K128Q, 1 subunit mutants, are reportedly incapable of binding to glycogen, but both bound GDE, indicating that the association between AMPK and GDE does not involve glycogen. Rather, the AMPK-GDE association is likely to be direct.
Overexpression of amino acids 68-123 of the 1 subunit inhibited the association between endogenous AMPK and GDE. While GDE activity was unaffected, basal phosphorylation and kinase activity of AMPK, as well as phosphorylation of Acetyl-CoA carboxylase, were significantly increased. Thus, it is likely that the AMPK-GDE association is a novel mechanism regulating AMPK activity and the resultant fatty acid oxidation and glucose uptake.
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