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

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Abstract
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.