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AMPK goes interactive

Nature Reviews Molecular Cell Biology volume 8, page 852 (2007)Cite this article

AMP-activated protein kinase (AMPK) regulates metabolism by sensing changes in the AMP:ATP ratio in eukaryotic cells. The binding of AMP to AMPK and activation of its Ser/Thr protein-kinase domain have been well-characterized by previous biochemical and genetic analyses. Two studies now shed light on the structural basis for these mechanisms in mammalian AMPK and the AMPK homologue SNF1 from Saccharomyces cerevisiae.

Gamblin and colleagues determined the crystal structure of the mammalian AMPK regulatory fragment comprising the C-terminal domains of the α- (catalytic) and β- (regulatory) subunits and the full-length regulatory γ-subunit that contains three AMP-binding sites: two that bind either AMP or Mg.ATP and one containing a tightly bound, non-exchangeable AMP (which is not involved in AMP–ATP sensing). No significant conformational changes were observed between the AMP-bound (active) and ATP-bound (inactive) AMPK forms, so how do increased concentrations of AMP regulate AMPK activity? The authors propose that AMP binding to the two exchangeable sites allows the formation of inter-subunit interactions that cannot form when ATP is bound. This allosteric effect leads to quaternary structure changes that enhance the activity of the kinase domain and reduce its dephosphorylation rate when AMP is bound. The two exchangeable AMP–ATP sites are found on opposite faces of the disc-shaped γ-subunit in the AMPK structure, which suggests that distinct inter-subunit interactions occur that might enable separate mechanisms for allosteric activation and dephosphorylation protection by AMP binding.

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References

ORIGINAL RESEARCH PAPERS

  1. Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007)

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  2. Amodeo, G. A. et al. Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449, 492–495 (2007)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007)

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AMPK goes interactive. Nat Rev Mol Cell Biol 8, 852 (2007). https://doi.org/10.1038/nrm2286

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  • DOI: https://doi.org/10.1038/nrm2286

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