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A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation
Open accessAbstract
The growth factor-activated AGC protein kinases RSK, S6K, PKB, MSK and SGK are activated by serine/threonine phosphorylation in the activation loop and in the hydrophobic motif, C-terminal to the kinase domain. In some of these kinases, phosphorylation of the hydrophobic motif creates a specific docking site that recruits and activates PDK1, which then phosphorylates the activation loop. Here, we discover a pocket in the kinase domain of PDK1 that recognizes the phosphoserine/phosphothreonine in the hydrophobic motif by identifying two oppositely positioned arginine and lysine residues that bind the phosphate. Moreover, we demonstrate that RSK2, S6K1, PKBalpha, MSK1 and SGK1 contain a similar phosphate-binding pocket, which they use for intramolecular interaction with their own phosphorylated hydrophobic motif. Molecular modelling and experimental data provide evidence for a common activation mechanism in which the phosphorylated hydrophobic motif and activation loop act on the alphaC-helix of the kinase structure to induce synergistic stimulation of catalytic activity. Sequence conservation suggests that this mechanism is a key feature in activation of >40 human AGC kinases.
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“Similar to other AGC protein kinases, SGK1 possesses a kinase domain featuring a pocket that recognizes hydrophobic motifs containing phosphoserine/phosphothreonine. This pocket achieves recognition through phosphorylation of two oppositely positioned arginine and lysine residues. This structural characteristic enables SGK1’s distinct substrate affinity in biological processes”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Frodin et al., 2002
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Metadata
- Authors
- Frödin, M., Antal, T. L., Dümmler, B. A., Jensen, C. J., Deak, M., Gammeltoft, S., & Biondi, R. M.
- Affiliations
- Glostrup Hospital (DK)
- University of Dundee (GB)
- Corresponding author
- Frödin, Morten
- Venue
- The EMBO Journal
- Published
- 2002-10-15
- Volume
- 21
- Issue
- 20
- Pages
- 5396-5407
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC129083
- OpenAlex
- W2018380860
- Cited by
- 275
- References
- 33
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 7 · 2013: 11 · 2012: 20
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Kræftens Bekæmpelse
- Novo Nordisk
- Novo Nordisk Fonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- AGC protein kinases, PDK1, kinase activation mechanism, RSK2, S6K1, MSK1, SGK1, activation loop, αC-helix, intramolecular interactions, growth factor signaling
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Amino Acid Sequence, Animals, Binding Sites, Enzyme Activation, Growth Substances, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Phosphoserine, Phosphothreonine, Protein Kinases, Proto-Oncogene Proteins, Recombinant Proteins, Signal Transduction, Conserved Sequence, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Immediate-Early Proteins, Amino Acid Motifs, Ribosomal Protein S6 Kinases, 90-kDa, Proto-Oncogene Proteins c-akt, Mice, Hydrophobic and Hydrophilic Interactions, 3-Phosphoinositide-Dependent Protein Kinases, In Vitro Techniques
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