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Structural basis of AMPK regulation by adenine nucleotides and glycogen

Xiaodan Li1, Lili Wang1, X Edward Zhou2

  • 11] Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China [2] School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China [3] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.

Cell Research
|November 22, 2014
PubMed

Insights

AMP-activated protein kinase (AMPK), a key energy regulator and drug target, is modulated by AMP and glycogen. Structural and biochemical studies reveal how these molecules alter AMPK

Area of Science:

  • Biochemistry and Structural Biology
  • Molecular Medicine
  • Metabolic Regulation

Background:

  • AMP-activated protein kinase (AMPK) is a critical cellular energy sensor.
  • AMPK plays a vital role in maintaining energy homeostasis.
  • AMPK is a significant therapeutic target for metabolic diseases like diabetes and obesity, as well as cancer.

Purpose of the Study:

  • To elucidate the structural basis of allosteric modulation of human AMPK by AMP and glycogen.
  • To understand the mechanism by which AMP and glycogen binding affects AMPK activity.
  • To provide insights into AMPK regulation for potential therapeutic interventions.

Main Methods:

  • Low-resolution crystal structures of the human α1β2γ1 holo-AMPK complex were determined (4.05 Å and 4.60 Å).
  • A high-resolution (2.95 Å) crystal structure of the human kinase domain (KD) with the autoinhibitory domain (AID) was solved.
  • Extensive biochemical and mutational studies were conducted to validate structural findings.

Main Results:

  • Crystal structures reveal the holo-AMPK complex bound to allosteric modulators AMP and cyclodextrin (glycogen mimic).
  • Structures were obtained for both phosphorylated and non-phosphorylated states of AMPK.
  • The study illustrates how AMP and glycogen binding shifts the equilibrium between different interactions involving the AID and carbohydrate-binding module.

Conclusions:

  • AMP and glycogen act as allosteric modulators of AMPK through distinct binding interactions.
  • These interactions influence the conformational state and activity of AMPK.
  • The findings provide a mechanistic understanding of AMPK regulation by key metabolic signals.

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