Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells
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AMP-activated protein kinase (AMPK) plays a major role in regulating metabolism and has attracted significant attention as a therapeutic target for treating metabolic disorders. AMPK activity is stimulated more than 100-fold by phosphorylation of threonine 172 (Thr172). Binding of AMP to the γ subunit allosterically activates the kinase. Additionally, many small molecules, e.g. 991, have been identified that bind between the kinase domain and the carbohydrate-binding module of the β subunit, stabilising their interaction and leading to activation. It was reported recently that non-phosphorylated Thr172 AMPK is activated by AMP and A769662. We present here the crystal structure of non-phosphorylated Thr172 AMPK in complex with AMP and 991. This structure reveals that the activation loop, as well as the complex overall, is similar to the Thr172 phosphorylated complex. We find that in the presence of AMP and 991 non-phosphorylated Thr172, AMPK is much less active than the Thr172 phosphorylated enzyme. In human cells, the basal level of Thr172 phosphorylation is very low (∼1%), but is increased 10-fold by treatment with 2-deoxyglucose. In cells lacking the major Thr172 kinases, LKB1 and CaMKKβ, Thr172 phosphorylation is almost completely abolished, and AMPK activity is virtually undetectable. Our data show that AMP and 991 binding to non-phosphorylated Thr172 AMPK can induce an ordered, active-like, conformation of the activation loop explaining how AMPK activity can be measured in vitro without Thr172 phosphorylation. However, in a cellular context, phosphorylation of Thr172 is critical for significant activation of AMPK.
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Allosteric AMPK activation can occur in non-phosphorylated AMPK, with even higher fold activation than phosphorylated AMPK.
“Lastly, allosteric AMPK activation can also occur in non-phosphorylated AMPK, with even higher fold activation than phosphorylated AMPK [40].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [40]
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AMPK: An energy sensor for non-small cell lung cancer progression and treatment
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Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739
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- Authors
- Willows, R., Sanders, M. J., Xiao, B., Patel, B. R., Martin, S. R., Read, J., Wilson, J. R., Hubbard, J., Gamblin, S. J., & Carling, D.
- Affiliations
- Hammersmith Hospital (GB)
- The Francis Crick Institute (GB)
- AstraZeneca (United Kingdom) (GB)
- Francis Crick Insitute, 1 Midland Road, London NW1 1AT, U.K.
- Corresponding author
- Carling, David
- ORCID
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2017-08-22
- Volume
- 474
- Issue
- 17
- Pages
- 3059-3073
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC5565919
- OpenAlex
- W2735497230
- Semantic Scholar
- 8b25222084ce8f550eb7c75cbedd795169092b90
- Cited by
- 190
- References
- 52
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 21 · 2023: 18 · 2022: 23 · 2021: 36 · 2020: 18 · 2019: 18 · 2018: 9 · 2017: 3
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- AstraZeneca
- University of Dundee
- Wellcome Trust (FC001078)
- Francis Crick Institute (10015, 10078, FC001078)
- Cancer Research UK (FC001078)
- Medical Research Council (FC001078)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AMPK, Thr172 phosphorylation, upstream kinases, LKB1, CaMKKβ, AMPK activation, AMP binding, crystal structure, 2-deoxyglucose, metabolic regulation
- MeSH terms
- A549 Cells, AMP-Activated Protein Kinase Kinases, Biphenyl Compounds, Enzyme Activation, Humans, Phosphorylation, Pyrones, Thiophenes, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases, HEK293 Cells
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