AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy

Key Points

  • Mammalian AMP-activated protein kinase (AMPK) was discovered as a protein kinase that switches off lipid synthesis. The yeast orthologue, the SNF1 complex, was discovered in screens for mutations that caused failure to grow on carbon sources other than glucose.

  • The AMPK/SNF1 kinases exist as heterotrimeric complexes that are composed of catalytic α-subunits, β-subunits that bind to glycogen particles, and γ-subunits with tandem domains that bind AMP or ATP. Recent crystal structures are providing insights into the interactions between these domains and subunits.

  • Binding of AMP activates the mammalian AMPK complex by causing allosteric activation and by inhibiting dephosphorylation of the critical activating site that is phosphorylated by upstream kinases. Upstream kinases that have recently been identified include the tumour suppressor LKB1 and calmodulin-dependent kinase kinase-β.

  • Mutations in the γ2 isoforms that cause human heart disease interfere with the binding of the regulatory nucleotides AMP and ATP. AMP binding to wild-type AMPK appears to prevent the interaction of an inhibitory pseudosubstrate sequence (which is located in the N-terminal AMP-binding domain) with the substrate-binding groove.

  • AMPK phosphorylates metabolic enzymes, transcription factors and co-activators that promote ATP-producing catabolic pathways and inhibit ATP-consuming biosynthetic pathways. It also inhibits cell growth and proliferation by triggering phosphorylation events that inhibit the TOR (target of rapamycin) pathway and cause stabilization of cell-cycle inhibitors such as p53 and p27.

  • The extension of lifespan in response to sublethal stresses, such as caloric restriction, requires a specific isoform of AMPK in Caenorhabditis elegans. Recent unexpected findings also suggest that AMPK is involved in the establishment of cell polarity in insects as well as mammals.

Abstract

The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.

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Figure 1: Regulation of energy homeostasis by the AMPK system.
Figure 2: Activation of AMPK by cytokines, drugs and polyphenols, and key downstream events.
Figure 3: Domain structure of AMPK subunits.
Figure 4: Structure of the core of the Schizosaccharomyces pombe αβγ complex.
Figure 5: Models for regulation by AMPK/SNF1 of glucose uptake in muscle and gene expression in yeast.
Figure 6: The opposing effects of insulin and AMPK activation on the target-of-rapamycin (TOR) pathway.

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Acknowledgements

Recent studies in the author's laboratory have been supported by Programme Grants from the Wellcome Trust and by the EXGENESIS Integrated Project of the European Commission.

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DATABASES

OMIM

Peutz–Jeghers syndrome

type 2 diabetes

Wolff–Parkinson–White syndrome

Protein Data Bank

2FH9

2H6D

2OOX

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Glossary

Non-fermentable carbon source

A carbon source (for example, glycerol) that cannot be metabolized by anaerobic fermentation in yeast, and is only metabolized by oxidative, aerobic metabolism.

Adenylate kinase

An enzyme that catalyses the reversible interconversion of ATP, ADP and AMP via the reaction 2ADP ↔ ATP + AMP.

Ser/Thr kinase domain

A kinase domain is a region of 300 amino acids that folds into a structure that catalyses the phosphorylation of proteins. Ser/Thr kinases are specific for phosphorylation of Ser and Thr side chains.

Activation loop

A feature that is conserved in many protein kinases. In many cases, phosphorylation of the activation loop is required for the kinase to be active.

Ubiquitin-associated domain

A type of protein domain. The role of some, but not all, of these domains is to cause association with ubiquitylated or polyubiquitylated proteins.

α1–6-linked branch point

A branch point in α1–4-linked glucans (such as starch or glycogen) that is formed by a linkage between carbon-1 (in the α-anomeric configuration) of the glucose at one end of the side chain, and carbon-6 of a glucose unit on the main chain to which the side chain is attached.

α1–4-linked glucan

A polymer of glucose (for example, amylose) that is formed by linkages between carbon-1 of one glucose unit and carbon-4 of the next, with all glucose units in the α-anomeric configuration.

Ventricular pre-excitation

A clinical condition in which the delay between the excitation of the atria (small chambers) and ventricles (large chambers) of the heart is reduced.

Calmodulin

A small protein that binds Ca2+, causing a conformational change that causes the complex to bind to and activate many downstream target proteins.

MAP kinase kinase kinase

A Ser/Thr protein kinase at the head of a cascade of three protein kinases, the final one being a mitogen-activated protein kinase such as ERK1 or ERK2.

GLUT4

A member of the plasma-membrane glucose transporter (GLUT) family expressed in insulin-sensitive tissues such as muscle and adipose tissue. GLUT4 translocates to the membrane in response to insulin.

GTPase-activating protein

A protein that activates the intrinsic GTP-hydrolysing activity of small GTP-binding proteins of the Ras/Rab family.

Rab protein

A member of the family of small GTP-binding proteins related to Ras, most of which are thought to be involved in the regulation of membrane traffic.

Cyclin

A protein that controls progress through the cell division cycle by binding to and activating a cyclin-dependent protein kinase.

G1–S boundary

An event in the cell division cycle: the boundary between the first phase (Gap 1) and the second (S phase, when DNA replication occurs). Quiescent (non-dividing) cells are usually arrested just before the G1–S boundary.

AU-rich element

A region in mRNA that is rich in the bases adenine and uracil. It is often a binding site for proteins that control mRNA degradation.

Autophagy

A process that occurs inside cells in which cytoplasmic components are engulfed by membrane vesicles and degraded. It is thought to be used to recycle amino acids and other components.

Anterior–posterior axis

The line between the head and tail of an organism.

Apical–basal polarity

In epithelial cells, which separate the interior of an organism from the exterior or the gut, the term apical–basal polarity refers to the unequal distribution of proteins and other materials between the apical side (facing the exterior or the gut) and the basal side (facing the interior).

Dauer larval form

An alternative developmental stage in worms, which is activated under stressful conditions. Dauer larvae are sterile and are adapted for long-term survival.

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Hardie, D. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774–785 (2007). https://doi.org/10.1038/nrm2249

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