Structure and Physiological Regulation of AMPK

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.

Molecular Mechanisms of Adipogenesis: The Anti-Obesogenic Role of AMP-Activated Protein Kinase and Recently Reported Plant Products

“…Once activated, AMPK directly or indirectly promotes the phosphorylation of downstream targets including transcription and translational factors, metabolic enzymes, epigenetic factors, growth and proliferation pathways. The overall effect of this regulation is to reduce the synthesis of cholesterol, fatty acids, ribosomal RNAs (rRNAs) and proteins [98], making AMPK a potential target of high value for the development of pharmacological and natural anti-obesogenic compounds [99].…”

The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders

“…AMPK consists of a heterotrimeric complex composed of one catalytic subunit (α1/α2) and two regulatory subunits (β1/β2 and γ1/γ2/γ3) [19]. The alpha subunit contains a Ser/Thr kinase domain, which comprises Thr172 within the activation loop, followed by an autoinhibitory domain and a C-terminal domain (α-CTD), which interacts with the beta subunit [20]. The beta subunit contains a carbohydrate-binding module (CBM) in its N-terminus and a C-terminal domain, which contains the αγ subunit binding sequence (αγ-SBS) domain, which is involved in binding to alpha and gamma subunits [21].…”

“…The beta subunit contains a carbohydrate-binding module (CBM) in its N-terminus and a C-terminal domain, which contains the αγ subunit binding sequence (αγ-SBS) domain, which is involved in binding to alpha and gamma subunits [21]. Finally, the gamma subunit contains four tandem repeats of a structural module called cystathione-β-synthase (CBS) motifs, three of which constitute adenine nucleotide binding sites [20].…”

CD73‐dependent adenosine dampens interleukin‐1β–induced CXCL8 production in gingival fibroblasts: Association with heme oxygenase‐1 and adenosine monophosphate‒activated protein kinase

“…Adenosine monophosphate (AMP)‐activated protein kinase (AMPK) is a key regulator of cell metabolism with anti‐inflammatory effects . AMPK has been shown to have pleiotropic functions in inflammatory responses and tissue fibrosis in various models such as renal fibrosis, cancer, and osteoarthritis .…”

“…6 Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key regulator of cell metabolism with anti-inflammatory effects. 7 AMPK has been shown to have pleiotropic functions in inflammatory responses and tissue fibrosis in various models such as renal fibrosis, 8 cancer, 9 and osteoarthritis. 10 Activation of AMPK has been linked to reduced systemic oxidative stress through antioxidant defense pathways, preventing alveolar bone loss in the ligature-induced model of periodontitis.…”