Structure of Mammalian AMPK and its regulation by ADP

By B. Xiao, M. Sanders, E. Underwood, R. Heath, Faith V. Mayer, D. Carmena, C. Jing, P. Walker, J. Eccleston, L. Haire and 6 more. Nature, 2011

941 citations recorded by the source corpus.

The heterotrimeric AMP-activated protein kinase (AMPK) has a key role in regulating cellular energy metabolism; in response to a fall in intracellular ATP levels it activates energy-producing pathways and inhibits energy-consuming processes. AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and, most recently, cancer. AMPK is converted from an inactive form to a catalytically competent form by phosphorylation of the activation loop within the kinase domain: AMP binding to the γ-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation. Here we show that ADP binding to just one of the two exchangeable AXP (AMP/ADP/ATP) binding sites on the regulatory domain protects the enzyme from dephosphorylation, although it does not lead to allosteric activation. Our studies show that active mammalian AMPK displays significantly tighter binding to ADP than to Mg-ATP, explaining how the enzyme is regulated under physiological conditions where the concentration of Mg-ATP is higher than that of ADP and much higher than that of AMP. We have determined the crystal structure of an active AMPK complex. The structure shows how the activation loop of the kinase domain is stabilized by the regulatory domain and how the kinase linker region interacts with the regulatory nucleotide-binding site that mediates protection against dephosphorylation. From our biochemical and structural data we develop a model for how the energy status of a cell regulates AMPK activity.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/087e0158670c3c064edb9c13cc23f33fcdc95268

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Citations in the corpus

The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis (2016, neutral): “For example, AMP-activated protein kinase (AMPK) integrates the relative ATP concentration against AMP and/or ADP concentrations for signaling (Oakhill et al., 2011; Xiao et al., 2011).”
New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis (2018, background): “AMPK is activated physiologically by an increase of the cellular AMP/ATP ratio and pharmacologically by metformin, thiazolidinediones (TZDs) and statins [152].”
The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, positive): “Recent studies showing that ADP can bind to the nucleotide-binding pockets in the γ subunit suggest it may be the physiological nucleotide for AMPK activation under a variety of cellular stresse”
Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “While AMP binding to the -subunit allosterically enhances AMPK kinase activity and prevents the dephosphorylation of T172, ATP is known to counteract the activating properties of AMP (30).”
AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, positive): “Although allosteric activation is only caused by AMP, it has recently been found that the effects on phosphorylation and dephosphorylation can also be produced by AD”
Hallmarks of Cellular Senescence. (2018, positive): “acts as a sensor of the reduced energetic state, further activating catabolic pathways while inhibiting biosynthetic ones, and regulating p53 and other targets [91].”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “As such, AMPK functions as a sensor of the cellular adenylate energy charge (84, 85).”