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. Author manuscript; available in PMC: 2017 Dec 12.
Published in final edited form as: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251–262. doi: 10.1038/nrm3311

Figure 1.

Figure 1

Model for the mechanism by which AMPK is activated by increases in AMP and ADP (top), as the cellular concentrations of ATP, ADP and AMP change (bottom). The model at the top represents different states of the three subunits of AMPK (see Fig. 2 for details of domains). The graph at the bottom shows changes in the predicted concentrations of ATP, ADP and AMP on going from an unstressed, fully charged cell (left) to a cell undergoing a severe energy stress (right), corresponding to a 10-fold increase in ADP:ATP ratio. The graph was generated by assuming that the adenylate kinase reaction was at equilibrium. Note that in a fully charged cell (left), AMP concentration is very low, but that its % change in concentration as ADP/ATP increases is always much greater than those of ATP or ADP. In the model at the top, the basal state (top left) has sites 1 and 3 in the γ subunit occupied by ATP (site 4 is always occupied by AMP). Replacement of ATP by ADP (or AMP) at site 3 during moderate stress (top centre) promotes phosphorylation of Thr172 (bottom centre), causing a 100-fold increase in activity (indicated by two stars). Replacement of ATP by AMP at site 1 during more severe stress causes a further 10-fold allosteric activation (indicated by a third star, bottom right). As cellular energy status returns to normal, AMP at site 1 and ADP or AMP at site 3 are progressively replaced by ATP (moving from right to left on the bottom row). This promotes the dephosphorylation of Thr-172 and a return to the basal state.