A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation

• Published in: Acta crystallographica. Section F, Structural biology and crystallization communications Structural biology and crystallization communications, 2010-02, Vol.66 (2), p.143-151
• Main Authors: Littler, Dene R., Walker, John R., Davis, Tara, Wybenga-Groot, Leanne E., Finerty Jr, Patrick J., Newman, Elena, Mackenzie, Farell, Dhe-Paganon, Sirano
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Amino Acid Sequence; AMP-activated kinases; AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - metabolism; Animals; Binding Sites; Biocatalysis; Crystallography, X-Ray; DFG-out conformation; Humans; kinases; Models, Molecular; Molecular Sequence Data; Protein Folding; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein Subunits - chemistry; Protein Subunits - metabolism; Sequence Alignment; Structural Communications
• ISSN: 1744-3091; 1744-3091; 2053-230X
• DOI: 10.1107/S1744309109052543

The AMP‐activated protein kinase (AMPK) is a highly conserved trimeric protein complex that is responsible for energy homeostasis in eukaryotic cells. Here, a 1.9 Å resolution crystal structure of the isolated kinase domain from the α2 subunit of human AMPK, the first from a multicellular organism, is presented. This human form adopts a catalytically inactive state with distorted ATP‐binding and substrate‐binding sites. The ATP site is affected by changes in the base of the activation loop, which has moved into an inhibited DFG‐out conformation. The substrate‐binding site is disturbed by changes within the AMPKα2 catalytic loop that further distort the enzyme from a catalytically active form. Similar structural rearrangements have been observed in a yeast AMPK homologue in response to the binding of its auto‐inhibitory domain; restructuring of the kinase catalytic loop is therefore a conserved feature of the AMPK protein family and is likely to represent an inhibitory mechanism that is utilized during function.