Abstract
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric αβγ complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK’s kinase activity, allowing it to upregulate ATP-generating catabolic pathways and to reduce energy-consuming catabolic pathways and cellular programs. AMPK senses the cellular energy state by competitive binding of the three adenine nucleotides AMP, ADP, and ATP to three sites in its γ subunit, each, which in turn modulates the activity of AMPK’s kinase domain in its α subunit. Our current understanding of adenine nucleotide binding and the mechanisms by which differential adenine nucleotide occupancies activate or inhibit AMPK activity has been largely informed by crystal structures of AMPK in different activity states. Here we provide an overview of AMPK structures, and how these structures, in combination with biochemical, biophysical, and mutational analyses provide insights into the mechanisms of adenine nucleotide binding and AMPK activity modulation.
Highlights
adenosine monophosphate protein kinase (AMPK) is the primary energy sensor and regulator of energy homeostasis in eukaryotes. It is activated by energy stress in response to increased adenosine triphosphate (ATP) consumption or decreased ATP production, which are sensed as low ratios of ATP to Adenosine monophosphate (AMP) and ADP
The structure of the yeast and mammalian AMPK core scaffolds revealed a disk-shaped γ subunit composed of four CBS sites
AMPK is a molecular machine consisting of the adenine nucleotide-binding core (γ subunit plus αand β-CTDs), the catalytic kinase domain (KD), and at least four dynamic domains (AID, carbohydrate-binding module (CBM), and the α- and β-linkers)
Summary
AMPK is a heterotrimeric αβγ protein kinase. The α subunits contain a canonical Ser/Thr kinase domain (KD), an autoinhibitory domain (AID), an adenine nucleotide sensor segment termed an α-linker, and a β subunit-interacting C-terminal domain (α-CTD), the latter of which contains. 2018, 19, 3534 kinase domain (KD), an autoinhibitory domain (AID), an adenine nucleotide sensor segment termed an α-linker, and a β subunit-interacting C-terminal domain (α-CTD), the latter of which contains the the ST loop, which harbors proposed phosphorylation sites for AKT [15], PKA [16], and GSK [17]. AMP-bound AMPK α2 β1 γ1 /991 ((B); PDB: 4CFE) and α1 β2 γ1 /cyclodextrin (CD) ((C); PDB: 4RER). Sci. 2018, 19, 3534 of phosphorylated, AMP-bound AMPK α2β1γ1/991 ((B); PDB: 4CFE) and of 15.
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