AMPK beta subunit targets metabolic stress sensing to glycogen

Curr Biol. 2003 May 13;13(10):867-71. doi: 10.1016/s0960-9822(03)00292-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases
  • Amino Acid Sequence
  • Animals
  • Gene Expression
  • Glycogen / metabolism*
  • Glycogen / pharmacology
  • Glycogen Phosphorylase / chemistry
  • Glycogen Phosphorylase / genetics
  • Glycogen Phosphorylase / metabolism
  • Glycogen Synthase / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Multienzyme Complexes / ultrastructure
  • Phylogeny
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / ultrastructure
  • Rats
  • Sequence Homology, Amino Acid
  • Stress, Physiological / metabolism*

Substances

  • Multienzyme Complexes
  • Protein Subunits
  • Glycogen
  • Glycogen Phosphorylase
  • Glycogen Synthase
  • PRKAA1 protein, human
  • PRKAA2 protein, human
  • PRKAB1 protein, human
  • PRKAB2 protein, human
  • PRKAG1 protein, human
  • PRKAG3 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases