AMPK beta subunit targets metabolic stress sensing to glycogen.
AMP-activated protein kinase (AMPK) is a multisubstrate enzyme activated by increases in AMP during metabolic stress caused by exercise, hypoxia, lack of cell nutrients, as well as hormones, including adiponectin and leptin. Furthermore, metformin and rosiglitazone, frontline drugs used for the treatment of type II diabetes, activate AMPK. Mammalian AMPK is an alphabetagamma heterotrimer with multiple isoforms of each subunit comprising alpha1, alpha2, beta1, beta2, gamma1, gamma2, and gamma3, which have varying tissue and subcellular expression. Mutations in the AMPK gamma subunit cause glycogen storage disease in humans, but the molecular relationship between glycogen and the AMPK/Snf1p kinase subfamily has not been apparent. We show that the AMPK beta subunit contains a functional glycogen binding domain (beta-GBD) that is most closely related to isoamylase domains found in glycogen and starch branching enzymes. Mutation of key glycogen binding residues, predicted by molecular modeling, completely abolished beta-GBD binding to glycogen. AMPK binds to glycogen but retains full activity. Overexpressed AMPK beta1 localized to specific mammalian subcellular structures that corresponded with the expression pattern of glycogen phosphorylase. Glycogen binding provides an architectural link between AMPK and a major cellular energy store and juxtaposes AMPK to glycogen bound phosphatases.
St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Australia.
Galina
G
Polekhina
Abhilasha
A
Gupta
Belinda J
BJ
Michell
Bryce
B
van Denderen
Sid
S
Murthy
Susanne C
SC
Feil
Ian G
IG
Jennings
Duncan J
DJ
Campbell
Lee A
LA
Witters
Michael W
MW
Parker
Bruce E
BE
Kemp
David
D
Stapleton
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D015870:Gene Expression; D006003:Glycogen / Q000378:metabolism* / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D010802:Phylogeny; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013312:Stress, Physiological / Q000378:metabolism*
D009097:Multienzyme Complexes; D021122:Protein Subunits; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; C526181:PRKAA2 protein, human; C526182:PRKAB1 protein, human; C526183:PRKAB2 protein, human; C526222:PRKAG1 protein, human; C526225:PRKAG3 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human