Regulation of the AMPK Complex

AMPK/Snf1 complexes are inactive unless phosphory-lated on a threonine residue within the activation loop of the a subunit [13,14] by upstream kinases that remain unidentified. AMPK complexes are allosterically activated by AMP, with the extent of activation (up to sevenfold) depending on the identity of the a and y subunits [6]. AMP also promotes phosphorylation and activation of the kinase, via a three-fold mechanism of binding to AMPK and (1) making it a better substrate for the upstream kinase, (2) making it a worse substrate for the protein phosphatase, and (3) binding to and activating the upstream kinase. This multistep mechanism generates great sensitivity, such that over a critical range of concentrations a small change in AMP produces a large change in kinase activity [15]. Effects of AMP that are due

Figure 1 Model for the changes in interdomain interactions in the AMPK complex. In both the inactive and active conformations, the P subunit acts as a scaffold that binds a and y via the conserved KIS and ASC domains. In the inactive conformation (top), the kinase domain of a is inhibited by interactions with the autoinhibitory region on the same subunit. In the active conformation (bottom), this interaction is prevented because the autoinhibitory region on a now interacts with the CBS domains on y, instead of with the kinase domain. AMP promotes this conformation by stabilizing the a^y interaction, while ATP binding at the allosteric site disrupts it. In the active conformation, the kinase domain is free to be phos-phorylated and activated by the upstream kinase and to phosphorylate downstream targets. (From Hardie, D. G. and Hawley, S. A., BioEssays 23, 1112-1119, 2001. With permission.)

Figure 1 Model for the changes in interdomain interactions in the AMPK complex. In both the inactive and active conformations, the P subunit acts as a scaffold that binds a and y via the conserved KIS and ASC domains. In the inactive conformation (top), the kinase domain of a is inhibited by interactions with the autoinhibitory region on the same subunit. In the active conformation (bottom), this interaction is prevented because the autoinhibitory region on a now interacts with the CBS domains on y, instead of with the kinase domain. AMP promotes this conformation by stabilizing the a^y interaction, while ATP binding at the allosteric site disrupts it. In the active conformation, the kinase domain is free to be phos-phorylated and activated by the upstream kinase and to phosphorylate downstream targets. (From Hardie, D. G. and Hawley, S. A., BioEssays 23, 1112-1119, 2001. With permission.)

to binding to AMPK itself are antagonized by high concentrations of ATP. The system therefore responds to rises in cellular AMP: ATP, leading to the concept that it is a sensor of cellular energy charge, or fuel gauge [16]. This view was reinforced by findings that the kinase is inhibited by phosphocreatine [17].

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