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Kinase Domain of Human AMP-activated Protein Kinase alpha2 (AMPKα2)

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PDB Code 2H6D Target Class Protein Kinase Target AMPKA2 Alias AMPK, AMPK2, PRKAA Disease Area/Function metabolism Date Deposited May 31 2006 Authors D.R.LITTLER, J.R.WALKER, L.WYBENGA-GROOT, E.M.NEWMAN, C.BUTLER-COLE, F.MACKENZIE, P.J.FINERTY, J.WEIGELT, M.SUNDSTROM, C.H.ARROWSMITH, A.M.EDWARDS, A.BOCHKAREV, S.DHE-PAGANON, STRUCTURAL GENOMICS CONSORTIUM (SGC)

About this structure

AMPK is a master regulator of metabolism and thus controls the energy status at a cellular level. It is increasingly becoming evident that AMPK is also involved in energy regulation at the level of the whole organism through its response to hormonal cues and nutrient availability[1,2]. Interest in this area has been sparked by the discovery that some AMPK isoforms are indirectly activated by leptin, a hormone that regulates food-intake, and by metformin and thiazolidinediones, both currently popular treatments for Type 2 diabetes[2].

The energy status of a cell is intimately associated with the ratio in the concentration of ATP and ADP (or AMP). AMPK senses changes in the AMP:ATP ratio, being activated simultaneously by falling concentrations of ATP and rising concentrations of AMP. In response, it acts to shut down ATP consuming pathways and activate ATP producing pathways. AMPK phosphorylates the bottleneck enzymes in these pathways. Phosphorylation down-regulates those involved in anabolism and up-regulates those involved in catabolism, restoring the ATP:ADP balance.

In the basal state, AMPK activity is very low. Activation of AMPK includes phosphorylation of its activation loop threonine by an upstream kinase as well as γ-subunit-mediated release of the α-subunit autoinhibitory region. There are multiple isoforms of each subunit in the human genome including two isoforms of the α and β subunits (α1, α2, β1 and β2) and three of the γ (γ1, γ2 and γ3)[3]. We have solved the minimal-kinase domain of the α2 subunit at 1.9Å resolution. The structure reveals the canonical kinase fold with an interesting conformation by its activation loop. Notably, the conserved and catalytically important DFG motif, which is located immediately N-terminal to the activation loop, is flipped out and inserted into the ATP binding pocket. In addition, the amino-terminal lobe clamps down tightly against the DFG motif, mimicking the closed lobe orientation seen in certain other kinases. This may represent a mechanism of auto-inhibition used by AMPK.

References

  1. Management of Cellular energy by the AMP-activated protein kinase system Hardie D. G., Scott J. W., Pan D. A. and Hudson E. R. FEBS Letters 546 pp 113-120 (2003)
  2. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Kahn B. B., Alquier T., Carling D. and Hardie G. D. Cell Metabolism Jan. Vol 1. (2005)
  3. Functional Domains of the α1 Catalytic Subunit of the AMP-activated Protein Kinase Crute B. E., Seefeld K., Gamble J., Kemp B. E. and Witters L. A. J. Biol. Chem. 273 (52) pp. 35347-35354 (1998)