MRC National Institute for Medical Research, London
Science for Health
ADP is a universal signal of low energy in cells
11 November 2011
Researchers at NIMR have discovered the metabolic signal that allows the adaptation of budding yeast for growth on low glucose or non-glucose sources. The research is published in Cell Metabolism.
The AMP-activated protein kinase (AMPK) and sucrose non-fermenting-1 (SNF1) protein kinase complexes are evolutionarily-conserved metabolic sensors found in all eukaryotes. Their primary function is to maintain energy homeostasis and cell survival. They do this by detecting changes in nutrient availability and ATP levels within cells.
When the concentration of glucose in yeast cells falls, this leads to activation of SNF1 and derepression of glucose-repressed genes. This allows yeast cells to maintain their energy homeostasis and cell survival by utilising alternative carbon sources, e.g. sucrose. Despite numerous studies, the identity of the metabolic signal that regulates SNF1 activity in response to glucose availability has remained elusive.
Using biochemical and biophysical approaches Steve Gamblin (pictured) and his group in NIMR's Division of Molecular Structure, working with David Carling's group at the MRC Clinical Sciences Centre, have identified ADP as the metabolic signal that activates SNF1 during periods of low glucose. Their work shows that ADP prevents inactivation of SNF1, by inhibiting dephosphorylation of a critical phosphorylated threonine residue in the activation T-loop. There are two ADP binding sites in SNF1, and it is the binding at the weaker of the two sites that mediates this protection.
A crystal structure of a truncated form of SNF1 was determined and shows the location of the tight nucleotide binding site, complexed with AMP, ADP or NADH. This shows for the first time the Saccharomyces cerevisiae SNF1 complex bound to nucleotides.
Our group recently demonstrated that ADP regulates the mammalian AMPK. This raises the possibility that ADP might represent a ‘unifying trigger’ for activation of AMPK orthologs in all species.
Steve Gamblin
Click image to view at full-size
Ribbon representation of the structure of the regulatory fragment determined in this study. The Snf1 (α) subunit is coloured blue, the Sip2 (β) subunit coloured in green and Snf4 (γ) subunit in red. The positions of ADP are shown in ball-and-stick representation and a closer view of ADP (white) and NADH (yellow) binding to site 4 is shown to the right.
Original article
ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase
Faith V. Mayer, Richard Heath, Elizabeth Underwood, Matthew J. Sanders, David Carmena, Rhonda R. McCartney, Fiona C. Leiper, Bing Xiao, Chun Jing, Philip A. Walker, Lesley F. Haire, Roksana Ogrodowicz, Stephen R. Martin, Martin C. Schmidt, Steven J. Gamblin, David Carling (2011).
Cell Metabolism, 14(5):707-714. Publisher abstract
© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA
Top of page