The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor.
AMPK beta subunits contain a conserved domain that causes association with glycogen. Although glycogen availability is known to affect AMPK regulation in vivo, the molecular mechanism for this has not been clear. We now show that AMPK is inhibited by glycogen, particularly preparations with high branching content. We synthesized a series of branched oligosaccharides and show that those with a single alpha1-->6 branch are allosteric inhibitors that also inhibit phosphorylation by upstream kinases. Removal of the outer chains of glycogen using phosphorylase, thus exposing the outer branches, renders inhibition of AMPK more potent. Inhibition by all carbohydrates tested was dependent on the glycogen-binding domain being abolished by mutation of residues required for carbohydrate binding. Our results suggest the hypothesis that AMPK, as well as monitoring immediate energy availability by sensing AMP/ATP, may also be able to sense the status of cellular energy reserves in the form of glycogen.
McBride
Andrew
A
Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Ghilagaber
Stephanos
S
Nikolaev
Andrei
A
Hardie
D Grahame
DG
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002417:Cattle; D004734:Energy Metabolism; D006003:Glycogen / Q000494:pharmacology*; D006006:Glycogen Synthase / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009844:Oligosaccharides / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats
D009844:Oligosaccharides; D006003:Glycogen; D006006:Glycogen Synthase; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases